bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18753: Mechanisms of Left Ventricular Reverse Remodeling: Insights From a Novel Murine Model of Hypertensive Ischemic Cardiomyopathy
Authors: Weinheimer Carla J , Evans Sara , Liang Yun , Barger Philip M , Mann Douglas L , Kovacs Attila
Published: April 2024

Background:
All approved therapies for heart failure (HF) lead to reverse LV remodeling (LVRR). The lack of genetically tractable animal models of LVRR has prevented further understanding of the biology of LVRR. Here we present a murine model of HF that mimics hypertensive ischemic cardiomyopathy, which undergoes LVRR with hemodynamic unloading.

Methods:
Wild type mice were subjected to Sham (n=6), or transverse aortic constriction (TAC) with LAD ligation (MI), leading to progressive LV remodeling (n=12). Hemodynamic unloading was accomplished by debanding (DB) the aorta 2 wks post MI/TAC (n=6), whereas the band remained intact in the HF group (n=6). Both DB and HF groups were followed for 4 more weeks. 2D echo speckle tracking was performed at 1 & 14 days post-MI/TAC, and at 4 wks post-DB. Hearts were analyzed by LV morphometry, histology and transcriptional profiling.

Results:
2-D echo at 1 and 14 days post-MI/TAC showed progressive LV dilatation (1d=34ul, 14d=62ul; p<0.01). LVRR occurred 4 wks post-DB, with near normalization of LV volumes (p=NS vs sham). In contrast, LV volumes increased ~ 3-fold (p<0.01 vs sham) in the HF group. LV ejection fraction (LVEF) continued to decrease over 4 weeks in HF hearts (36% vs 31%, p<0.05), whereas LVEF increased in post-DB hearts (33% vs 42%, p<0.01). LV weights were significantly (p < 0.05) smaller in the DB group (85±13g) compared to the HF group (133±16g) at 4 weeks. Myocyte size decreased significantly (p<0.05) in DB hearts (409±41μ
2
) compared to HF hearts (446±41μ
2
), whereas interstitial fibrosis was not different (p > 0.05). Transcriptional profiling showed that, relative to HF hearts, LVRR in post DB hearts was accompanied by significant (p < 0.05) decreases in extracellular matrix gene expression, and significant increases in α-myosin heavy chain, calcium channels and adenylate cyclase gene expression.

Conclusion:
We developed a genetically tractable mouse model of hypertensive ischemic cardiomyopathy that undergoes LVRR following unloading. LVRR is accompanied by favorable changes in LV structure and function, myocyte size, as well as changes in contractile protein and calcium handling genes. Genetic manipulation of this model will permit a clearer understanding of the molecular mechanisms responsible for LVRR.
Abstract 18759: Poor Quality of Life Predicts Adherence to a Weight-Loss Intervention in Overweight and Obese Patients With Heart Failure
Authors: Motie Marjan , Lennie Terry A , Evangelista Lorraine S
Published: April 2024

Background:
Poor quality of life (QOL) has a known association with cardiometabolic risk that is also correlated with weight, diet, physical activity, and smoking. However, the effect of QOL on adherence (i.e. completing the study protocol) to a dietary intervention in heart failure (HF) patients has not been studied. We investigated the relationship between QOL and adherence with completing a 3 month intensive weight loss intervention in a cohort of obese HF patients with metabolic complications and tested a model that included age, gender, race, baseline weight, functional status, and QOL on adherence.

Methods:
Data on QOL of overweight and obese patients with HF who participated in a larger clinical trial comparing a high protein and standard protein diet were collected at baseline and 3 months using the Minnesota Living with Heart Failure (MLHF) Questionnaire. Comparisons were made between participants who completed the 3 month dietary intervention (i.e. completers) and participants who did not (i.e. non-completers).

Results:
Forty-nine patients - mean age 59.1 ± 9.8; weight 248.8 ± 29.7 pounds; EF 37.3 ± 12.5%; peak VO2 12.5 ± 3.7 mg/kg/ml; 55% White; 20% Hispanics; 16% Blacks; 8% Asians - participated in the study; 34 (70%) completed the intensive phase of the dietary intervention. There were statistically significant differences in QOL scores between completers and non-completers (Table 1). There were no age or gender differences between completers and non-completers; Whites were less likely to complete the intervention compared to their counterparts (p = 0.046). In a model controlling for age, gender, race, baseline weight, and functional status, QOL explained an additional 19% of the variance in adherence.

Conclusion:
Our findings elucidate the need to integrate QOL assessments and strategies in clinical trials involving dietary interventions as potential key to enhancing adherence.
Abstract 18760: Homeostatic Intracellular Repair Response (HIR
2
) is Affected by Glycemic Control in Diabetics Undergoing Cardiac Surgery
Authors: Sengstock David , Jahania Salik , Andres Allen , Ito Bruce R , Gottlieb Roberta A , Mentzer Robert M
Published: April 2024

Background:
We previously reported that HIR
2
is activated in the human heart during cardiac surgery. The mechanism underlying HIR
2
is adaptive autophagy, a beneficial stress response to ischemia, hypoxia, and nutritional depletion. It is a process that eliminates damaged mitochondria and protein aggregates. Preclinical studies in animal models have shown that HIR
2
is impaired in the setting metabolic syndrome. To confirm our previous clinical findings and test the hypothesis that HIR
2
is altered in patients with Type II diabetes (T2DM), autophagy was examined in heart tissue obtained from a cohort of patients with and without the disease.

Methods:
Biopsies of the right atrium were obtained before initiation and after weaning from cardiopulmonary bypass in 19 patients undergoing conventional cardiac surgery. The Society of Thoracic Surgeons’ database was used to identify individuals with T2DM (n=8). HbA1c was used as a measure of diabetic control. Autophagy was measured by immunoblotting for Beclin-1, LC3, Atg5-12, and p62, and normalized to actin levels. The pre-post difference in p62 (Δp62) was used to assess autophagic flux.

Results:
Consistent with previously observed, heart surgery was associated with a significant reduction (all p < 0.01) in Beclin-1 (1.18 ± 0.18 vs. 1.73 ± 0.24), Atg5-12 (0.74 ± 0.10 ± vs.1.11 ± 0.14), and p62 (0.89 ± 0.11 vs. 1.51 ± 0.20), but not LC3. As shown below, depletion of p62 during surgery significantly correlated with Atg5-12 and Beclin-1 across all patients. Notably, in diabetics there was a decrease in the magnitude of the cardiac HIR
2
response (Δp62) as a function of glycemic control (HbA1c).

Conclusion:
These results confirm our previous findings indicating a robust activation of HIR
2
in patients undergoing cardiac surgery. Importantly, in patients with T2DM this adaptive response appears to be substantially blunted, and may explain, in part, the increased morbidity and mortality associated with this at-risk patient population.
Abstract 18766: Myocardial Blood Flow and Viability in Children Post Palliation of Hypoplastic Left Heart Syndrome Assessed With MRI
Authors: Rickers Carsten , Jerosch-Herold Michael , Wegner Philip , Hart Christopher , Pardun Eileen , Voges Inga , Kramer Hans Heiner
Published: April 2024

Introduction:
Myocardial blood flow in the systemic right ventricle in Hypoplastic Left Heart Syndrome (HLHS) is largely unknown.The aim of this study was to examine with MRI regional and global myocardial perfusion reserve, viability and function in HLHS after completion of Fontan circulation.

Methods:
In 42 HLHS patients (6.0 ±2.3 yrs) and 14 heart healthy controls (6.8 ±3.9 yrs), MRI first-pass perfusion (0.03 mmol/kg Gd-DTPA; TR/TE/α=2.6/1.1/20°) and late gadolinium enhancement (LGE) imaging was performed using a 3 Tesla scanner (Philips Achieva). Quantitative myocardial blood flow at rest and stress (Adenosin 140 mcg/kg/min) was calculated in 4 anatomical RV segments per slice using a model independent deconvolution. A total of 672 segments were analysed. CMR results were compared to conventional x-ray guided coronary angiography in all HLHS pts.

Results:
HLHS patients showed impaired myocardial perfusion reserve (MPR, hyperemic/resting flow) as compared to the right or left ventricle of healthy children (2,4 ±0,6 vs. 3,1±0,9 (RV); p<0,05 or 2,58±0,70 vs. 3,4±1,13 (LV); p<0,01). HLHS subgroups with a large rudimentary LV (n=25) showed lower septal perfusion, areas of non-viable myocardium (20.8 vs 3%) and a lower cardiac index (2.3±0.7 vs. 3.3±0.8 l/m
2
/min; p<0,05). The diameter of the pre-coronary segment of the hypoplastic aorta did not correlate with myocardial blood flow. All HLHS patients had patent epicardial coronary arteries.

Conclusion:
The global impairment of coronary flow reserve in HLHS patients after Fontan may indicate altered vasoreactivity due to extensive aortic surgery. Furthermore, in HLHS subgroups with a large rudimentary LV, scar tissue and a reduced cardiac index can be observed. These findings may be of prognostic significance for the long-term outcome in HLHS.
Abstract 18794: More Than a Biomarker_ANP Modulates Heart Failure, Cardiac Function and Survival in Dilated Cardiomyopathy
Authors: Wang Dong , Gladysheva Inna P , Fan T. Michael , David Sullivan Ryan , Reed Guy L.
Published: April 2024

Although atrial natriuretic peptide (ANP) is an established biomarker for heart failure, there is significant controversy whether ANP modifies or affects the progression of heart failure in patients with reduced contractile function and dilated cardiomyopathy (DCM). Therefore we examined the effects of ANP on survival, heart failure progression, fibrosis and cardiac function in a well-established model of DCM caused by the cardiac-targeted expression of a dominant negative CREB transgene. By comparison to DCM mice with normal ANP levels (DCM, ANP+/+) mice with partial ANP deficiency (DCM, ANP+/-) had reduced survival (p<0.001) and, mice with full ANP deficiency (DCM, ANP-/-), had even greater reductions in survival than those with normal ANP or partial ANP deficiency (p<0.001). Radiography showed that ANP-deficient DCM mice developed more severe heart failure with pleural effusions and pronounced cardiomegaly. These mice showed increased alveolar congestion (22.9±1.5% vs. 57.3±3.2%, p<0.001) and increased heart weights (heart:body weight 0.54±0.04% vs. 0.95±0.05%). ANP-deficient DCM mice showed a more marked reduction in cardiac function as evidenced by decreased EF% (30.7±3.2 % vs. 16.0 ±1.5 %, p<0.001) and enhanced cardiac dilation (LVIDd 4.51±0.11 mm vs. 5.85±0.10 mm, p<0.001; LVIDs 3.9±0.1 mm vs. 5.0 mm±0.2, p<0.001). ANP-deficient DCM mice had more severe cardiac interstitial fibrosis (4.54±0.3 % vs. 12.58±0.62%, p<0.01) and perivascular fibrosis (ratio to lumen area 0.58±0.07 vs. 2.53±0.26, p<0.01) as well as eccentric cardiomyocyte hypertrophy (cross sectional area 662±12 μm2 vs. 905±23 μm2, p<0.001). Levels of cGMP were significantly reduced in ANP-deficient DCM mice (p<0.001). We conclude that ANP profoundly modulates the progression of DCM in mice by reducing the severity of heart failure, improving contractility, reducing ventricular dilation, preventing cardiac fibrosis and extending survival. Thus ANP is not only a key biomarker, but it also modulates the progression of heart failure, cardiac function and remodeling in DCM.
Abstract 18813: Prevalence and Distribution of Behavioral Cardiovascular Disease Risk Factors in Sub-Saharan Africa: The World Health Organization’s World Health Survey
Authors: Kamau Mercy W , Stuart-Shor Eileen , Shi Ling , Hayman Laura
Published: April 2024

Introduction:
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally accounting for 30% of total deaths worldwide with 82% of these deaths occurring in low/middle income countries (LMIC). WHO targeted 4 behavioral risk factors (physical inactivity, unhealthy diet, tobacco use, harmful use of alcohol) as the foundation of the WHO framework on prevention and control of CVD in LMIC. The purpose of this study was to examine the prevalence, distribution and association of these 4 risk factors in selected countries of Sub-Saharan Africa (SSA).

Methods:
Secondary analysis was conducted on data from the population-based WHO World Health Survey using data from 4 countries in SSA to reflect low (Senegal), middle (Ghana, Kenya), and high (South Africa) GDP. The data was weighted to account for country-specific sample sizes and pooled to provide regional prevalence estimates. The analysis controlled for age, gender, living location (rural/urban) and education. Analysis included Chi-square and logistic regression.

Results:
The pooled data among 13,850 subjects revealed high prevalence of unhealthy diet (67%), with lower prevalence of physical inactivity, tobacco use and harmful alcohol (12%, 14%, 6%, respectively). Country-specific analysis revealed that prevalence of behavioral CVD risk factors varied by socio-demographic variables within the countries of interest. Physical inactivity and unhealthy diet was higher among older individuals (p<.05) and female (p<.05). Tobacco use and harmful use of alcohol was higher in middle age men (p<.001) with a trend for higher use in rural locations. Among the selected countries significant differences include: Kenya had the highest prevalence of unhealthy diet (OR=12.5, 95%CI=11.1-14.3). South Africa had the highest prevalence of physical inactivity (OR=7.8, 95%CI=6.8-9.1) and tobacco use (OR=2.8, 95%CI=2.4-3.3). Ghana had the highest prevalence of harmful use of alcohol (OR=3.8, 95%CI=3.1-4.6).

Conclusions:
This study demonstrates within and between-country differences in the prevalence and distribution of the 4 CVD behavioral risk factors. These results highlight the necessity of local and region-specific data to tailor policy, resource allocation and prevention measures.
Abstract 18815: Genetic Deletion of Telomerase Promotes Premature Cardiac Aging
Authors: Kim Junghyun , Sanada Fumihiro , Candiracci Manila , Valeriani Fiorenza , Czarna Anna , Cannata Antonio , Goihberg Polina , Hosoda Toru , Kajstura Jan , Rota Marcello , Anversa Piero , Leri Annarosa
Published: April 2024

Telomere length shortens with age and predicts the onset of cellular senescence and organ aging with progressive deterioration of function. It remains, however, to be documented whether loss of telomeric DNA in cardiac stem cells (CSCs) and myocytes is causally involved in the manifestations of the aging cardiomyopathy. To test this possibility, the third generation of mice carrying a deletion of the RNA component of telomerase (Terc
-/-
mice) was studied early in life at 3-12 months of age. Wild type (WT) senescent mice at 30 months of age were included in the analysis to establish whether accelerated aging in Terc
-/-
mice recapitulates physiological aging. Initial studies indicated that Terc
-/-
mice, at 4 months of age, displayed attenuated left ventricular (LV) function with respect to age-matched WT by echocardiography and hemodynamics. In contrast, severe alterations in cardiac performance were apparent at 12 months. Telomere length in Terc
-/-
mouse CSCs and myocytes was ~50-70% shorter than in age-matched WT cells at 4-6 months of age but was comparable to that found in 30 month-old WT cells. CSC number was 60% lower in Terc
-/-
than age-matched WT mice, and the fraction of BrdU-positive CSCs decreased 1.4-fold. The absence of Terc led to a 50% reduction in myocyte turnover, which was coupled with myocyte loss. BrdU and Ki67 labeling were decreased, respectively, 65% and 60% in Terc
-/-
myocytes. Old CSCs formed a senescent progeny composed of myocytes, which carried markedly shortened telomeres, were more prone to apoptosis, and showed a severe depression in cell shortening and re-lengthening. By mRNA screening performed in Terc
-/-
myocytes at 12 months, multiple apoptosis-related genes, including protein kinase A (PKA), PI3KR1, Caspase 1, and BAG3 were found to be modified. Moreover, the renewal of endothelial cells was 75% lower in Terc
-/-
mice mimicking the rarefaction in capillary typically seen in the old myocardium. Our findings document that loss of telomerase is a critical determinant of cardiac aging with reduced cardiomyogenesis and vasculogenesis. Understanding basic mechanisms of telomere biology in CSCs and cardiomyocytes holds the potential to advance the clinical paradigm of the senescent myopathy.
Abstract 18846: The Dual Effects of Shear Stress on Vascular Endothelial Autophagy and Mitochondrial DNA Damage
Authors: Jen Nelson , Li Rongsong , Fang Karen , Quigley Katherine , Beebe Tyler , Lee Juhyun , Cao Hung , Ann David , Hsiai Tzung
Published: April 2024

Vascular oxidative stress preferentially develops at arterial curvatures and branching points where oscillatory shear stress (OSS) occurs. Autophagy, a tightly regulated intracellular bulk degradation/recycling system, is implicated in endothelial homeostasis. In this study, we assessed the effects of OSS on autophagy and mitochondrial DNA (mtDNA) damage. Human aortic endothelial cells (HAEC) exposed to OSS (τ
av
g
= 0±3 dyne/cm
2
for 4 hours) increased relative LC3-II/LC3-I ratios (control: 1.0±0.02, OSS: 2.4±0.51,
p
<0.01, n=4), as supported by an increase in autophagosome punctures by LC3-green fluorescence protein (LC3-GFP). OSS-induced increase in LC3-II/LC3-I ratios were significantly attenuated in response to N-acetyl cysteine (NAC), MnSOD over-expression, and JNK siRNA (siJNK) knockdown (
p
<0.05, n=4). Inhibition of autophagy by ATG5 siRNA increased OSS-induced MitoSox intensity for mitochondrial superoxide (mtO
2
•-
) by 2.03±0.25-fold (
p
< 0.05, n=4), whereas Rapamycin-induced autophagy reduced OSS induced MitoSox intensity by 78.4% (
p
<0.05, n=4). OSS-induced reduction of mitochondrial complex II activity was also attenuated in response to Rapamycin (OSS: 62.1±11.2%; Rapamycin+OSS: 130.1±40.4% (relative to static control),
p
<0.05, n=4). In comparison with static and pulsatile flow (PSS=23 dyne/cm
2
) conditions, OSS also significantly increased mtDNA damage by 4.5±1.3-fold (
p
<0.01, n=4), which was significantly reversed in response to NAC, MnSOD over-expression, and siJNK knockdown (
p
<0.05, n=4). In the fat-fed New Zealand White rabbits, quantification for immuno-staining revealed prominent endothelial JNK phosphorylation and DNA damage in the OSS-exposed aortic arch in contrast with nearly absent staining in the PSS-exposed descending aorta (
p
< 0.05, n=4). Furthermore, analysis of caspase-3 activity was negative for OSS-exposed HAEC and OSS-exposed aorta area from normal diet-fed animals. Despite atherogenic nature of OSS, our findings suggest that OSS imparts dual effects in endothelial autophagy and mtDNA damage with an implication in maintaining homeostasis.
Abstract 18849: Arterial Calcification Can Be Inhibited via Maintained Mitochondrial Homeostasis in Chronic Kidney Disease
Authors: Chung Chih-Ping , Lim Kenneth , Lu Tzongshi
Published: April 2024

Background:
Vascular calcification (VC) is a significant contributor to cardiovascular mortality in patients with chronic kidney disease and chronic inflammatory conditions. Previous work by our group has shown that HSP72 is an inducible protein that can preserve mitochondrial complexes II, IV, NADH cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome c oxidase (CCO) activities and prevent cardiomyocyte apoptosis. We recently reported that heat shock protein 72 (HSP72) could be induced in human arteries and prevent human aortic smooth muscle cell (HA-SMC) calcification. However, the molecular mechanisms involved in vasculo-protective effects of HSP72 have yet to be elucidated. In this study, we postulate that inducible HSP72 may exert vasculo-protective effects by stabilizing HA-SMCs phenotype through inhibition of mitochondrial dysfunction.

Methods:
In vitro
long-term
calcification model:
HA-SMCs treated with calcification medium (CM) containing 5mM CaCl
2
and 5mM β-glycerophosphate for 21 days.

Results:
Our results show that inducible HSP72 and mitochondrial HSP (HSPA5) are significantly expressed following heat shock treatment in HA-SMCs. Inducible HSP72 inhibited the development of VC in our long-term calcification model,
in vitro
. We next showed that JC-1 complex, an indicator of mitochondrial membrane potential stability and mitochondrial respiratory chain complexes II, IV was preserved in HA-SMCs treated with calcification medium following induction of HSP72. These cellular protective effects were however abolished following HSP72 knockdown by HSP72 siRNA. Furthermore, p53, Bax and Bak were up-regulated and Bcl-2 was down-regulated in HA-SMCs treated in calcification medium and these pro-apoptotic changes could be reversed following induction of HSP72.

Conclusion:
HSP72’s anti-calcific effects involve stabilization of mitochondrial function and inhibition of HA-SMC apoptosis. We suggest treatment strategies involving induction of HSP72 as a new approach to inhibit VC.
Abstract 18866: HDL Subclass Heterogeneity Relates to Differences in Risk of Incident Coronary Heart Disease
Authors: Akinkuolie Akintunde O , Paynter Nina , Padmanabhan Latha , Mora Samia
Published: April 2024

Background:
Raising the cholesterol fraction of HDL particles is targeted as a cardiovascular disease reduction strategy. However, HDL particles are highly heterogeneous in composition and structure, which may relate to differences in their anti-atherogenic potential. We prospectively evaluated the association of HDL subclasses, as defined by a recently proposed nomenclature aimed to harmonize cross-comparison across different HDL subfractionation techniques, with the risk of incident coronary heart disease (CHD) in initially healthy women.

Methods:
Baseline HDL subclass concentrations were measured and categorized into 5 groups (very large, large, medium, small, and very small) by nuclear magnetic resonance spectroscopy in 27 177 participants of the Women’s Health Study (median follow-up 17 years). First report of incident CHD (myocardial infarction, coronary revascularization, and CHD death) was ascertained (n=1 056 cases).

Results:
Multivariable Cox regression HRs (95%CIs) adjusted for age, ethnicity, blood pressure, smoking, postmenopausal status, hormone therapy, and treatment assignment showed inverse associations with incident CHD for quartile 4 vs 1 concentrations of very large 0.50 (0.42-0.61), large 0.53 (0.44-0.62), and medium 0.69 (0.58-0.82) HDL subclasses (all p-trend<0.0001, Table). Conversely, small and very small HDL subclasses were associated with an increased risk: HRs 1.24 (1.03-1.48, p-trend=0.04) and 1.74 (1.45-2.08, p-trend<0.0001), respectively. After additionally adjusting for potential mediating factors (BMI, diabetes, and lipid/lipoprotein concentrations), only the large HDL subclass remained statistically significantly associated with CHD (p-trend=0.0004, Table).

Conclusion:
In this prospective study of 27,177 initially healthy women followed for 17 years, associations with risk of incident CHD differed by HDL particle subclass, which may be relevant for the development of HDL-modulating therapies.
Abstract 18878: Development of a Unique Mode of Cardiac Remodeling in Muscular Dystrophy Patients
Authors: Martin Ryan C , Ayers Colby R , Patel Parag C , Markham David W , Thibodeau Jennifer T , Matulevicius Susan A , Drazner Mark H , Mammen Pradeep P
Published: April 2024

The muscular dystrophies (MD) represent an array of inherited myogenic disorders involving mutations and dysregulations of a variety of cytoskeleton or nuclear proteins. Many MD patients also develop a commitant cardiomyopathy. Despite the high incidence of end-stage cardiomyopathy in MD patients there is limited data regarding the mode of maladaptive cardiac remodeling that develops in these patients. In this retrospective study, we examined the hypothesis that MD patients with a cardiomyopathy develop a unique mode of cardiac remodeling as compared to patients with other forms of nonischemic cardiomyopathy. We examined the cardiac MRIs of 3 cohorts (N = 35 per cohort): patients with neuromuscular disorders with associated cardiomyopathy; patients with primary idiopathic nonischemic cardiomyopathy (NICM); and healthy patients from the Dallas Heart Study (DHS). The cardiac MRIs in each group were reviewed, assessing objective measurements of left ventricular ejection fraction (LVEF), mass (LVM), and end diastolic volume (LVEDV). LVM and LVEDV were indexed for body surface area. In addition, left ventricular concentricity
0.67
(LV Conc
0.67
= LVM / LVEDV
0.67
), a surrogate marker for wall thickness known to decrease in advanced nonischemic heart failure, was computed for each patient. Despite a preserved ejection fraction in the neuromuscular cohort compared to the NICM cohort (58% vs. 30 %, p<0.05), both displayed similar reduced LV Conc
0.67
(4.69 ± 1.05 and 5.16 ± 1.47) compared to the DHS cohort (7.27 ± 0.83). However, whereas the nonischemic cohort demonstrated hypertrophy with marked dilation (95.8 vs. 84.6 g/m
2
and 119.4 vs. 54.7 mL/m
2
, DHS comparison, p<0.05), the neuromuscular cohort demonstrated a reduced cardiac mass (65.6 vs. 84.6 g/m
2
, p<0.05) with only moderate dilation (74.5 vs. 54.7 mL/m
2
, p<0.05) compared to the DHS population. In conclusion, our data suggests that MD patients develop a unique mode of cardiac remodeling and highlights that novel signaling pathways are involved in the development of cardiomyopathy in these patients.
Abstract 18908: Trends in Endocarditis Hospitalizations: Impact of the 2007 American Heart Association Guidelines on Adults With Congenital Heart Disease
Authors: Alexander Craig H , Sexson-Tejtel S. Kristen , Morris Shaine A , Lopez Keila N
Published: April 2024

Introduction:
In 2007, the American Heart Association (AHA) modified the recommendations for infective endocarditis (IE) antibiotic prophylaxis for all but the individuals at the highest risk of acquiring IE. The impact of these guidelines remains unclear, particularly for adults with congenital heart disease (CHD). Our objective was to evaluate the trend in IE hospitalization and mortality before and after implementation of the revised AHA guidelines.

Hypothesis:
We hypothesized no change in the overall trend in IE hospitalization and mortality, including those adults with CHD, in the period after adoption of the 2007 AHA endocarditis guidelines.

Methods:
We utilized the Texas Hospital Inpatient Discharge Public Use Data File to identify all patients hospitalized between 2001and 2011 with IE in Texas. We evaluated the trend over time of IE admission and the percentage of those with CHD. We also assessed mortality and need for surgery during the hospital admission.

Results:
We identified 29, 537 IE cases. There was a steady increase in IE hospitalizations over the 10-year period from 1515 cases in 2001 to 3009 in 2011, comprising an increasing proportion of total IE admissions (0.13% in 2001 to 0.17% in 2011, p for trend <0.0001).

Of the patients admitted with IE, 3.3% had CHD. While both IE and percentage with CHD increased overtime, neither had a significant change after the 2007 AHA guidelines (Figure 1). Overall CHD mortality decreased from 14.2% in 2001 to 13.7% in 2011 (p=0.09). Overall mortality for the 10-year period was 14.2% without CHD and 9.1% with CHD (p<0.0001). Adults were three times more likely to undergo surgery if they had CHD (25.4% vs 8.1%; p<0.0001).

Conclusions:
We found no evidence that the 2007 AHA antibiotic prophylaxis guidelines was associated with a significant change in IE admissions across Texas hospitals, even when accounting for adults with CHD. Overall IE admissions, including those with CHD have continued to increase steadily.
Abstract 18918: Distinct Gene Expression Profiles of the Mitral Valve Leaflets in Barlow’s Disease and Fibroelastic Defficiency
Authors: Absi Tarek S , Galindo Cristi L , Petracek Michael , Lenihan Daniel , Leacche Marzia , Sawyer Dougals B , Byrne John , Su Yan Ru
Published: April 2024

OBJECTIVES:
The mitral valve (MV) leaflets in severe MR undergo structural remodeling associated with multiple degenerative and adaptive changes. We hypothesized that the gene expression profiles of the posterior MV leaflets from patients with bileaflet prolapse (Barlow’s valves) are distinct from those with only posterior leaflet degeneration (fibroelastic deficiency or MMR), reflecting different underlying pathophysiologic processes.

Methods:
MVs were obtained from 12 Barlow’s patients (9 m, 3 f; age= 59.8±12.2 y, LVEF=60.4±5.8%) and 17 MMR patients (10 m, 7 f, age= 54.2±6.6 y, LVEF=59.7±5.1%) undergoing surgery for severe MR. Normal MV were obtained from 6 unmatched donor hearts (4 m, 2 f, age= 41.5±10.7 y, LVEF=57.5±8.8%). RNA was extracted and cDNA microarray was carried on the Affymetrix Gene Chip 1.1. Normalization and two-way ANOVA analysis were performed. Only genes that resulted in >1.5 fold difference and p <0.05 were considered significantly altered.

RESULTS:
Of ~29,000 genes examined, 973 (3.3%) were differentially expressed between the two disease groups. Principal component analysis and Hierarchical clustering of the normalized fluorescence signal values for these genes
successfully differentiated
all the Barlow’s from the MMR samples (Figure 1). Based on functional analysis, selected statistically significant enriched biological processes are listed in (table1).

Conclusions:
MV leaflets in Barlow’s and MMR exhibit distinct gene expression patterns, suggesting different pathophysiologic mechanisms are involved in the leaflet remodeling processes. Understanding such adaptive mechanisms can potentially provide therapeutic opportunities.
Abstract 18923: S-Nitroso Human Serum Albumin versus Inhaled Nitric Oxide for the Treatment of Pulmonary Hypertension in a Chronic Right Ventricle Volume Overload Model
Authors: Rungatscher Alessio , Hallström Seth , Linardi Daniele , Milani Elisabetta , Tessari Maddalena , Luciani Giovanni Battista , Mazzucco Alessandro , Faggian Giuseppe
Published: April 2024

Background:
The study aimed to compare the acute overall hemodynamic and oxidative stress effects of intravenous S-NO-human serum albumin (S-NO-HSA) infusion and inhaled nitric oxide (iNO) in a chronic left-to-right shunt-induced pulmonary arterial hypertension model.

Methods and Results:
Male Wistar rats underwent surgical creation of aorto-caval fistula (Qp/Qs> 2.0). After 10 weeks they were randomly treated with human serum albumin (HSA) (controls; n. 25), S-NO-HSA (0.5 μmol/kg/h; n. 30) or iNO (20 ppm; n. 35) for 60 minutes.

Right ventricular contractility, right ventricular-vascular coupling and ventricular interdependence were assessed in vivo at different preloads by biventricular conductance catheters prior and after 60 minutes treatment. Heart and lung biopsies were obtained to determine oxidative stress by oxidized to reduced glutathione (GSSG/GSH) ratio and high-energy phosphates content.

Both S-NO-HSA and iNO led to a significant reduction in right ventricular afterload expressed by effective pulmonary arterial elastance (Ea) (from 1.3 ±0.2 to 0.5 ±0.3 and 0.4 ±0.2 respectively; P< 0.001). Only S-NO-HSA significantly improved right ventricle diastolic function (slope of end-diastolic pressure-volume relation) and contractility indicated by end-systolic elastance (Ees). Therefore a significant increase in the efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA but not iNO treatment (from 0.33 ±0.15 to 0.98 ±0.21; P< 0.005 and from 0.35 ±0.16 to 0.45 ±0.18; P< 0.1 respectively) with significant increase in left ventricular stroke volume (58 ±7 vs 18 ± 9 %; P< 0.003).

S-NO-HSA compared to iNO improved right ventricle phosphocreatine content (27.08 ±11.35 vs. 8.41 ±1.80 nmol/mg protein; P<0.001) and myocardial energy charge (0.85 ±0.03 vs. 0.78 ±0.03; P<0.01). Both S-NO-HSA and iNO decreased lung and right ventricular GSSG/GSH ratio (P<0.001).

CONCLUSIONS:
S-NO-HSA is more effective than iNO in treating pulmonary hypertension, improving right ventricle diastolic function and right ventricular-arterial coupling with a positive effect on ventricular interdependence. This results in superior energetic reserve of the heart, despite similar reduction of lung and right ventricular oxidative stress.
Abstract 18933: Cardiac Magnetic Resonance 4D Flow: An in vitro Validation of Bioprosthetic Mitral Valve Flow Volume Quantification
Authors: Ghosn Mohamad G , Jackson Matthew S , Maragiannis Dimitrios , Chin Karen , Igo Stephen R , Shah Dipan J , Little Stephen H
Published: April 2024

Background:
Phase contrast cardiac magnetic resonance imaging allows for the simultaneous acquisition of morphology in 3D (x, y, and z directions) and time-resolved blood flow velocities (known as 4D flow MRI). The clinical applications of this methodology continue to be developed. For this study, we sought to evaluate the methodology and accuracy of 4D flow MRI for the quantification of diastolic flow volume across bioprosthetic mitral valves (BMV) in a controlled and reproducible in vitro system.

Methods:
BMV of 3 sizes (27, 29, and 31 mm) were consecutively mounted in an MRI compatible flow loop. Flow conditions within the flow loop were set using control software that programmed a pump to generate pulsatile, physiologic ventricular ejection and filling characteristics. Diastolic flow volumes of ~70, 90, and 110 ml/beat were tested for each valve at a beat rate of 70 bpm. An in-series ultrasonic flow transducer (UFT) was used to measure flow (L/min) by which diastolic flow volumes were determined. The acquisition of 3D cine (4D flow) phase contrast velocity data was acquired in a 1.5 Tesla MRI scanner (Siemens) and flow measurements were determined “offline” at 3 locations within the valve; valve base, leaflet tips, and midway between the base and the tips.

Results:
When 4D flow volume measurements were compared to UFT diastolic flow volumes, the average difference was -0.2 ± 3.0 ml/beat. For all flow condition tested (n=8), the 4D flow measurements were strongly correlated to the reference standard flow meter, regardless of measurement location within the bioprosthesis (Pearson correlation, r=0.98, 0.99, and 0.99 for the base, mid, and tips location, respectively. P<0.001).

Conclusion:
4D flow MRI can be used to directly assess bioprosthetic mitral valve diastolic inflow volume, with considerable accuracy compared to reference standard measure. The imaging plane chosen for trans-valvular flow analysis did not affect the accuracy of the 4D flow measurements.
Abstract 18940: Application of the HeartMateII Risk Score in Patients With Continuous Flow Left Ventricular Assist Devices
Authors: Thomas Sunu S , Nahumi Nadav , Han Jason , Lippel Matthew , Yuzefpolskaya Melana , Colombo Paolo , Takayama Hiroo , Naka Yoshifumi , Uriel Nir , Jorde Ulrich P
Published: April 2024

Background:
Survival with left ventricular assist device (LVAD) therapy is dependent on appropriate patient selection. The Heart Mate II Risk Score (HMRS) was recently derived and validated in clinical trial patients to predict 90 day mortality following implantation of a continuous flow LVAD. The aim of this study was to test the validity of the HMRS in our patient population.

Methods:
We performed a retrospective analysis of patients implanted with HeartMate II (Thoratec, Pleasanton, CA) LVADs from March 31, 2004 to September 20, 2012. Patients were stratified according to HMRS profiles (HMRS Low < 1.58; < 1.58 HMRS Medium < 2.48; HMRS High > 2.48) calculated using age, albumin, creatinine, international normalized ratio (INR) and center volume. Outcome was defined as survival at 90 days post-device implantation.

Results:
HeartMate II LVADs were implanted in 205 patients. Pre-operative data from 201 patients were categorized into HMRS Low (n=101; 1.04 (0.64-1.31)), HMRS Medium (n=73; 1.98 (1.78-2.25)), and HMRS High (n=27, 3.07 (2.70-3.43)); p<0.0001. Kaplan Meier survival estimates at 90 days (HMRS Low 91.0 ± 2.9%; HMRS Medium 91.7 ± 3.2 %; HMRS High 88.7 ± 6.1%), and at one year (HMRS Low 85.5 ± 3.8%; HMRS Medium 79.3 ± 5.5%; HMRS High 82.4 ± 8.4%) following LVAD implantation were not statistically different, p=0.43, Figure. HMRS discrimination to predict 90 day mortality by receiver characteristic curve analysis was poor, AUC=0.56.

Conclusion:
The HMRS successfully stratifies patients according to pre-operative clinical characteristics. In our HeartMate II LVAD population, the HMRS demonstrated poor discrimination for 90 day mortality. HMRS generalizability may be limited.
Abstract 18958: High Pre-Operative Right Atrial Pressure to Pulmonary Capillary Wedge Pressure Ratio is Not Associated With Right Ventricular Dysfunction After LVAD Implantation
Authors: Cogswell Rebecca J , Masri S. Carolina
Published: April 2024

Background:
High RA pressure (RAP) to pulmonary capillary wedge pressure (PCWP) ratio has been associated with right ventricular (RV) failure after left ventricular assist device (LVAD) placement. This predictor has performed variably in external validation sets and RV failure after LVAD remains difficult to predict. We sought to determine the relationship between pre-operative RA:PCWP ratios and post-LVAD hemodynamic measures of RV function.

Hypothesis:
A high pre-operative RAP:PCWP ratio will be associated with RV dysfunction by invasive hemodynamics (high RAP, low cardiac index) after LVAD implantation.

Methods:
Right heart catheterization and other hemodynamic variables were collected both pre and post (within 48-72 hours) LVAD implantation on a cohort of 69 patients with end stage systolic heart failure. Patients were divided into 3 groups based on pre-operative RAP:PCWP ratios and pre and post-op hemodynamic data was analyzed by group.

Results:
Pulmonary vascular resistance (PVR) was higher and pulmonary artery capacitance (PAC) was lower in patients with the highest pre-operative RAP:PCWP ratios. There was no difference in post-LVAD RA pressure, cardiac index, or PCWP between RAP:PCWP groups (Table). In fact, higher pre-operative RAP to PCWP ratios were associated with the larger decreases in RA pressure post LVAD, with each 0.1 increase in pre-operative RAP:PCWP ratio being associated with a 1.7 mm Hg decrease in RA pressure post LVAD (p < 0.0001).

Conclusions:
High pre-operative RAP:PCWP ratios were associated with the largest drop in RA pressure after LVAD implantation. While high RAP:PCWP ratios have previously been associated with RV failure, in the presence of increased RV afterload, this seemed to predict a favorable hemodynamics response and should not preclude LVAD implantation.
Abstract 18962: Impact of Angina on Cardiovascular Outcomes in Patients With Stable Ischemic Heart Disease: A Post-Hoc Analysis From the COURAGE Trial
Authors: Acharjee Subroto , Sidhu Mandeep S , Hartigan Pamela M , Teo Koon K , Spertus John A , Maron David , Weintraub William S , Boden William E
Published: April 2024

BACKGROUND:
Previous data on the prognostic value of angina on clinical outcomes in patients with stable ischemic heart disease (SIHD) has been conflicting. We studied the impact of presence and severity of angina on clinical outcomes among participants in the COURAGE trial.

METHODS:
Based on presence or absence of angina at baseline, 2,280 patients with SIHD were divided into 2 subgroups. Those with angina were further stratified based on angina severity determined by Canadian Cardiology Society (CCS) class. Hazard ratios for clinical outcomes were calculated using the group with silent ischemia (CCS = 0) as referent.

RESULTS:
Table 1 shows cumulative event rates and hazard ratios among study participants after 4.6 years of follow-up. Although presence or absence of angina did not have any impact on clinical outcomes, patients with CCS III angina did have a significantly higher rate of death/MI/ACS, largely due to greater ACS (unstable angina) events.

CONCLUSIONS:
Patients with SIHD on optimal medical therapy had similar rates of “hard” cardiovascular endpoints regardless of presence or severity of angina. Those with severe (CCS III) angina at baseline had higher incidence of unstable angina with negative biomarkers, a finding that merits further investigation in future clinical trials.
Abstract 18966: Right Ventricular Dysfunction is Common in Patients With Breast Cancer Experiencing Cardiotoxicity During Adjuvant Trastuzumab Therapy
Authors: Calleja Anna , Poulin Frédéric , McDonald Michael , Delgado Diego H , Thavendiranathan Paaladinesh
Published: April 2024

Background:
Cardiotoxicity (CTOX) during cancer chemotherapy is commonly identified using a threshold reduction in left ventricular ejection fraction (LVEF) from pre-therapy values. Right ventricular (RV) dysfunction is not considered in the definition of CTOX. We examined the hypothesis that RV dysfunction will be present in a subset of patients experiencing CTOX.

Methods:
We retrospectively analyzed echocardiograms (echo) performed in consecutive breast cancer patients referred to a heart function clinic for management of CTOX during adjuvant trastuzumab therapy. All patients had an echo performed during the first clinical visit and were not on cardio-protective therapy. RV function was assessed using fractional area change (FAC) and global longitudinal peak systolic strain (VVI software, Siemens, Figure) using a 4 chamber view. Ten healthy volunteers were used as controls for RV strain measurements.

Results:
A total of 27 female pts (age 53 ± 12yrs) were included. Mean 2D biplane LVEF was 53.5 ± 9.3% with 13/27 having an LVEF <55%. The mean RV FAC for all patients was 39.6 ± 9.0%, with 7/27 (26%) having an abnormal FAC (<35%). LVEF was normal in 4 of these 7 patients. Including all 6 RV segments mean RV global longitudinal strain was -17.1 ± 7.4% versus -25.4 ± 2.2% in controls (p=0.001). Limiting the analysis to the 3 RV lateral wall segments, the mean longitudinal strain in patients was -22.9 ± 3.6% versus -30.0 ± 3.3% in controls (p=0.007). Using a strain cut off value of -23.5% for the lateral wall (2SD below mean for normal), 9/20 (45%) with normal FAC had had abnormal RV peak systolic longitudinal strain.

Conclusion:
Amongst patients referred for management of CTOX, 26% had significant RV systolic dysfunction. However, and additional 45% of the patients had subclinical RV dysfunction based on a reduced RV longitudinal strain. RV dysfunction should be considered as an important parameter in the assessment of patients referred for the assessment of cardiotoxicity.
Abstract 18971: Changes in HDL Quality Rather Than Macrophage Function Mediate the Atheroprotective Phenotype in Usf1 Knockout Mice
Authors: Soronen Jarkko , Laurila Pirkka-Pekka P , Kaiharju Essi , Van Eck Miranda , Kovanen Petri , Jauhiainen Matti
Published: April 2024

We previously demonstrated that allelic variants of Usf1 are associated with myriad metabolic phenotypes in human populations and the knockout of Usf1 in mice leads to a favorable metabolic phenotype. Here, we have studied the role of macrophages and HDL particles in the development of atherosclerosis in the Usf1 -/- mice.

A mouse strain of double knockout of Usf1 and Ldlr (Usf1 -/- Ldlr -/-) was generated, and mice along with their Usf1 +/+ Ldlr -/- littermates were fed with a high fat diet diet for 20 weeks. The double knockouts displayed a three-fold reduction in their atherosclerotic lesion area as demonstrated by the aortic longitudinal section based en face technique.

To study the potential mechanisms behind the attenuated lesion development in the Usf1 -/- mice, we knocked down USF1 by constitutive expression of shRNA from human monocyte cell line (THP1). We differentiated monocytes into macrophages and loaded them with acetylated LDL for 48 hours. We observed no change in cholesterol efflux from USF1 knockdown macrophages to wild type mouse serum or HDL when compared to efflux from control cells expressing non-targeting shRNA. Furthermore, we performed bone marrow transplantation of Usf1 -/- and wild type bone marrow to Ldlr -/- mouse background. After 12 weeks of western diet we saw no change in atherosclerotic lesion development in the aortic root area in the mice with Usf1 -/- bone marrow compared to the mice with wild type bone marrow, indicating a macrophage independent mechanism for the atheroprotection in Usf1 -/- mice.

The Usf1 -/- mice displayed both elevated cholesterol (p<0.001) and phospholipids (p<0.001) in their serum both on western and regular chow diet. Interestingly, cholesterol efflux from wild type THP1 macrophages to Usf1 -/- serum and HDL was significantly increased (p<0.05 and p<0.001, respectively) compared to serum and HDL from the wild type mice indicating that not only increased serum HDL concentration but also changes in HDL particle quality in the Usf1 -/- mice have properties increasing cholesterol efflux.

Our study establishes the atheroprotective role for Usf1 deficiency that could be in part due to the favorable changes HDL particle quality rather than macrophage specific effects in the Usf1 -/- mice.
Abstract 18977: Trends in Use of Thrombolytic Therapy Among Fee-For-Service Medicare Beneficiaries With Acute Pulmonary Embolism
Authors: Bikdeli Behnood , Wang Yun , Minges Karl , Nallamothu Brahmajee K , Kim Nancy , Desai Mayur , Masoudi Frederick A , Spertus John A , Goldhaber Samuel Z , Krumholz Harlan M
Published: April 2024

Background:
Thrombolytic therapy may improve the outcomes of select patients with acute pulmonary embolism (PE); however, it has historically rarely been used in older adults. Contemporary national trends in use of thrombolytic therapy among elderly patients with PE are not known.

Methods:
Using the inpatient Medicare Standard Analytic Files, we identified all Fee-For-Service patients aged ≥65 years old with a principal discharge diagnosis of PE between 1999 and 2010 and also identified those who received thrombolytic therapy. We used the Vital Status Files to determine rates of 30-day and 1-year mortality and fitted mixed-effects models to calculate adjusted mortality.

Results:
During the study period, there were 545,131 patients with a principal discharge diagnosis of PE, of whom 7158 (1.3%) received thrombolysis. The number of PE patients undergoing thrombolysis increased from 380 in 1999 to 840 in 2010 (P<0.001 for linear trend), in large part owing to increased utilization among patients 65-74 years. The proportion of patients with PE receiving thrombolysis changed from 12 per 1000 in 1999 to 16 per 1000 in 2010 (p=0.09 for linear trend). In-hospital mortality rates among patients receiving thrombolysis ranged between 15% and 21.2% in the study period. Adjusted 30-day and 1-year mortality rates ranged between 17.9% to 23% and 26.1% to 31.4% across the years.

Conclusions:
Recent trials (e.g., PEITHO) suggest thrombolysis may confer benefits in PE, even among older adults. We observed more widespread use in older age groups in recent years, but thrombolysis is still rarely applied for elderly patients compared with other age groups.