bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 21015: Coronary Inflammation in Humans Drives Spatial Changes of Perivascular Adipose Tissue Composition Detectable by a Novel Computed Tomography-Based Technology
Authors: Antonopoulos Alexios S , Oikonomou Evangelos K , Sanna Fabio , Sabharwal Nikant , Thomas Sheena , Herdman Laura , Margaritis Marios , Shirodaria Cheerag , Kampoli Anna-Maria , Akoumianakis Ioannis , Petrou Mario , Sayeed Rana , Krasopoulos George , Psarros Constantinos , Ciccone Patricia , Brophy Carl M , Digby Janet , Kelion Andrew , Uberoi Raman , Anthony Suzan , Alexopoulos Nikolaos , Tousoulis Dimitris , Achenbach Stephan , Neubauer Stefan , Channon Keith M , Antoniades Charalambos
Published: March 2022

Background:
Non-invasive detection of vascular inflammation remains an unmet goal. We hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation can be quantified using a new computed tomography angiography (CTA) methodology.

Methods:
In Arm 1, human PVAT adipocytes were cultured +/- inflammatory cytokines (n=7) or co-cultured with vascular tissue (+/-Angiotensin-II, n=6) to assess the effects of vascular inflammation on PVAT differentiation. In Arm 2, AT explants (epicardial, subcutaneous and thoracic AT) from 453 cardiac surgery patients were used in histology and gene expression studies to relate the ex vivo images with in vivo CT scan information (n=105) on the biology of the explants. In Arm 3, in 267 patients undergoing diagnostic CTA, PVAT attenuation (Fat Attenuation Index (FAI) defined as the average CT attenuation of AT), was analysed around the proximal right coronary artery. In Arm 4, PVAT FAI around unstable (culprit) and stable coronary plaques was calculated in 22 CAD patients undergoing CTA.

Results:
In Arm 1, Angiotensin-II (A) and proinflammatory cytokines (B) prevented lipid accumulation and adipocyte differentiation in cultured PVAT. In Arm 2, adipocyte size by histology was inversely correlated with FAI in vivo (C). Both FAI of AT explants (not shown) and FAI in-vivo (n=105) were negatively associated with epicardial AT differentiation as assessed by FABP4 expression (D). In Arm 3, PVAT FAI change over distance from RCA wall was significantly different in CAD compared to no CAD patients (E). In Arm 4, PVAT FAI was significantly increased around unstable plaques (F).

Conclusions:
Human vessels exert paracrine effects on surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can then be monitored using a CT imaging approach. This novel methodology can be implemented in clinical practice to detect unstable plaques in the human coronary vasculature.
Abstract 21016: Left Atrial Dysfunction Persists After Transapical but Not Transfemoral Transcatheter Aortic Valve Replacement and is Associated With Worse Outcomes
Authors: Fahim Mirette A , Pislaru Sorin V , Pellikka Patricia A , Nkomo Vuyisile T , Eleid Mackram F , Greason Kevin L , Pislaru Cristina
Published: March 2022

Introduction and Aims of The Study:
The relief of outflow obstruction after transcatheter aortic valve replacement (TAVR) is expected to improve cardiac output, LV systolic and diastolic function and to regress left ventricular (LV) mass. The impact of these changes on left atrial (LA) reservoir, conduit and contractile function remains unknown. Our aims were to compare LA functions in patients with transfemoral (TF) vs transapical (TA) TAVR and test whether they have an impact on patient outcomes.

Methods:
Retrospective analysis of LA deformation by speckle tracking strain echocardiography in 54 patients with TA TAVR and 54 TF TAVR, matched for age, sex and STS score. Measurements were performed pre TAVR and 1 month and 1 year post TAVR. Follow up data was available up to 5 years.

Results:
At baseline, there were no significant differences between the TF and TA groups with regard to patient age (81 ± 8 vs 82 ± 8 years), male gender (44% vs. 44%) or STS score (8.3 ± 4.4 vs 9.7 ± 4.5, respectively). LV filling pressures (E/e’) at baseline and 1 month were higher in TA vs. TF group (see table). LV global longitudinal strain (GLS) were similar at baseline and improved at 1 month only in the TF group (p=0.0001), while in the TA group it showed an improvement only at 1 year. LA reservoir, conduit and contractile functions improved within 1 month post TAVR in the TF group. In contrast, despite similar baseline LA functions in both groups, no improvement was observed in the TA group (see Table). At Cox proportional hazard analysis, lower LA reservoir function predicted major adverse events (death, cardiac rehospitalization or stroke) even after adjusting for age, gender and group allocation (p=0.034; risk ratio per unit decrease in LA function 1.04).

Conclusion:
These findings suggest that patients with TA TAVR have poor (if any) recovery of LA functions post TAVR. Presence of a stiff LA, best reflected by a persistently reduced LA reservoir strain, may contribute to the excess morbidity seen in TA patients.
Abstract 21027: Prognostic Evaluation and Risk Assessment in Scleroderma Patients With Newly Diagnosed Pulmonary Arterial Hypertension
Authors: Mercurio Valentina , Diab Nermin , Damico Rachel L , Kolb Todd M , Mathai Stephen , Hassoun Paul M
Published: March 2022

Introduction:
Systemic sclerosis related pulmonary arterial hypertension (SScPAH) is characterized by a worse prognosis in comparison to idiopathic pulmonary arterial hypertension (IPAH). The estimated mortality risk reported in the current European guidelines for pulmonary hypertension has been evaluated mostly in IPAH patients. The aim of this study was to explore the ability of the risk assessment proposed in the guidelines to predict long-term mortality in SScPAH patients.

Methods:
The study population constituted patients diagnosed with SScPAH and prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Program from 2000-2016. Patients with assessment of WHO functional class, 6-minute walking distance (6MWD), and right heart catheterization measurements at diagnosis were included in the analysis. A Cox proportional hazards model was used to examine the adjusted hazard ratio (HR) of mortality for each of the following four low-risk criteria: WHO functional class I-II, 6MWD >440m, right atrial pressure <8mmHg, and cardiac index ≥2.5L/min/m
2
. A Kaplan-Meier curve was plotted to describe overall survival at 5 years.

Results:
151 patients (mean age 61.2, 84.8% female) were included in the analysis. Over a mean follow-up period of 4.9 years, 87 patients (57.6%) died. In Cox proportional hazards multivariate analysis, the HR (95%CI) of mortality compared to the presence of no low-risk criteria was 0.65 for one criterion (0.37-1.15), 0.34 for two (0.17-0.68), 0.16 for three (0.06-0.44), and 0.10 for four (0.01-0.78). Figure 1 describes the 5-year survival according to the number of criteria.

Conclusion:
Our study highlights that only a small proportion of SScPAH patients are diagnosed at an early stage of PAH disease, suggesting the need of more intense PAH screening programs for this population. Current guidelines for risk assessment in IPAH patients can also be helpful in SScPAH patients, particularly in identifying patients at higher risk of mortality.
Abstract 21032: Effect of Financial Incentives on Cardiac Testing Rates
Authors: Masoudi Fredrick , Moghtaderi Ali , Black Bernard , Magid David , Schilsky Samantha , Viragh Timea
Published: March 2022

Introduction:
In 2006, the Federal government concluded that overpayment was driving rapid growth of office-based cardiac stress testing. In response, the Centers for Medicare and Medicaid Services (CMS substantially reduced payments for Medicare fee-for-service (MFFS) office-based stress tests between 2007 and 2010, while at the same time holding constant or increasing payment for the same outpatient tests performed on hospital campuses.

Objective:
To compare changes in the rate and location of stress testing among MFFS and MA patients before and after the introduction of reduced MFFS office-based stress test payments.

Methods:
Cross-sectional study from 2005-2014 comparing the rate and location of stress tests for a random 5% sample of MFFS patients compared to patients enrolled in three large MA health plans that are paid on a capitated basis, and were not subject to these payment changes.

Results:
While overall stress testing rates decreased between 2005 and 2014 for both groups, the decline was greater for MA patients than MFFS patients. However, outpatient testing shifted from the lower-cost office setting to a higher-cost outpatient hospital setting for MFFS patients and to a lesser extent for MA patients.

Conclusion:
Our findings suggest that changes to the MFFS office - hospital payment differential had little effect on overall testing rate but shifted the location of outpatient testing to the hospital resulting in increasing testing costs for MFFS patients.
Abstract 21052: Risk-Benefit Ratio May Not Justify a Further Decrease in Threshold for Pulmonary Valve Replacement Late After Tetralogy of Fallot Repair: An Experience With 2579 Patients
Authors: Hickey Edward J , Roche Susan L , Silversides Candice , Oechslin Erwin , Crean Andrew , Colman Jack , Benson Lee , Horlick Eric , Osten Mark , Heggie Jane , Pham-Hung Eric , Van Arsdell Glen , Caldarone Christopher A , Honjo Osami , Wald Rachel
Published: March 2022

Background:
Recommended thresholds for pulmonary valve replacement (PVR) in asymptomatic patients after tetralogy of Fallot (TOF) repair are continually decreasing. We studied the natural history versus outcomes after PVR in various categories of indexed right ventricular end-diastolic volume (RVEDVi).

Hypothesis:
We hypothesized that the benefit of PVR would not be outweighed by the risk at lower RVEDVi thresholds.

Methods:
Acquisition of all repeated measure datapoints and cross-sectional review in 2579 patients (born 1924 - 2011), including 7553 echos, 2579 MRI scans and all interventional data. Analysis was via parametric competing risks techniques and time-related regressions adjusted for repeated measures.

Results:
Survival was 95%, 81% and 73% at age 20, 40 and 60 years respectively. Freedom from PVR (N=516, mean age 25 years) was 87%, 66% and 45% at 20, 40 and 60 years after repair. Overall, survival after PVR was 98%, 95% and 87% at 1, 10 and 20 years. PVR-free survival in all 345 patients with MRI RVEDVi > 150 was 95% at 15 years. Comparative survival showed no survival advantage with PVR versus natural history for RVEDVi 150-160, 160-170, 170-180 (table); these categories had excellent PVR-free survival approaching 100% at 10 years. Patients with RVEDVi > 200 had late survival decrements with PVR or without. PVR resulted in a large and significant reduction in RVEDVi (mean 40 ml/m
2
, P<.0001), after which RVEDVi remained stable (P=.10). Patients with RVEDVi 150-160, 160-170 or 170-180 had similar reductions in RVEDVi after PVR to comparable levels (table). 35% of children transitioning to adult care had RVEDVi > 150 ml/m
2
.

Conclusions:
Lowering the RVEDVi threshold for PVR does not appear to offer a clear survival advantage and offers small differences (if any) to RV geometry, risks potential procedure-related morbidity and would mean intervening on many teenagers with repaired TOF who could otherwise anticipate intervention in later life.
Abstract 21074: Long-Term Clinical and Angiographical Outcomes in 25 Patients With Buerger’s Disease Treated With Endovascular Therapy
Authors: Park Yoonjee , Rha Seung-Woon , Her Ae-Young , Kim Yong Hoon , Choi Byoung Geol , Choi Se Yeon , Byun Jae Kyeong , Mashaly Ahmed , Jang Won Young , Kim WooHyeun , Choi Jah Yeon , Park Eun Jin , Na Jin Oh , Choi Cheol Ung , Lim Hong Euy , Kim Eung Ju , Park Chang Gyu , Seo Hong Seog , Oh Dong Joo
Published: March 2022

Background:
Thromboangiitis Obliterans (TAO), commonly Buerger’s disease, is associated with high risk of adverse outcomes, particularly higher amputation rate despite all the effort. The role of endovascular therapy (EVT) in TAO has been questioned owing to the technically challenging distal distribution of lesions and high rate of restenosis.

Methods:
Among 765 consecutive patients (pts) with significant peripheral artery disease (PAD) who underwent endovascular therapy (EVT) from Jan 2004 to June 2016, we identified 25 patients diagnosed as TAO with critical limb ischemia (CLI) who underwent EVT . Various clinical, coronary and peripheral angiographic characteristics and 5-year clinical outcomes were examined.

Results:
The prevalence of TAO among PAD pts undergoing EVT was 3.27% (23 males; 3.86% and 1.18% among total male and female, respectively). The mean age was 48.6 ± 16.8 (SD) and 23 (92%) had a history of smoking. Pts commonly presented with lower limb wounds, gangrene, claudication, diabetic foot and resting pain in deceasing order [N(%): 15(60), 11(44), 9(36), 5(20) and 1(4)], with 77.4% of limbs higher than Rutherford grade 2. A total 25 pts, 31 limbs and 81 lesions were treated with stent or balloon angioplasty [24 (29.6%) and 53 (65.4%) lesions, respectively], achieving clinical success in 73 (90.1%) lesions. Over half lesions were chronic total occlusions (56, 69.1%) and distributed peripherally (Table). Although nearly half patients underwent repeated procedures, limb salvage was achieved in most patients after 5 years.

Conclusion:
TAO is known for its poor prognosis in terms of limb salvage and peripherally located lower extremity lesions which are technically difficult to approach. Our experience with 25 patients with 81 lesions show promising long-term limb salvage outcomes following repetitive EVT with optimal medical therapy.
Abstract 21087: Coronary Reperfusion Ameliorates the Deleterious Effect of Mechanical Unloading on Infarct Size and Interstitial Fibrosis After Acute Myocardial Infarction
Authors: Bello Sean O , Singh Charanjit , Punjabi Prakash , Perbellini Filippo , Terracciano Cesare
Published: March 2022

Background:
Contemporary studies show that myocardial fibrosis worsens after mechanical unloading with left ventricular assist devices (LVADs). The exact mechanism underlying this phenomenon remains unknown. Mechanical unloading has however been associated with a reduction in microvascular lumenal diameter in the failing heart, suggesting a link with negative auto-regulatory effects on the collateral circulation. We hypothesise that coronary reperfusion after myocardial infarction ameliorates the deleterious effect of mechanical unloading on infarct size and interstitial fibrosis.

Methods:
Syngeneic male Lewis rats weighing 200 to 300g were studied. Myocardial infarction – acute (AMI) and chronic (CMI) - was induced by LAD ligation. Two groups were generated: a permanent ligation group (AMI and CMI) and a reperfusion - coronary circulation restored after 90 minutes - group (AMI/R and CMI/R). In each group hearts were either loaded (L) or unloaded (U). In the loaded subgroup, rats were recovered after coronary ligation. In the unloaded subgroup, the infarcted hearts were explanted after 90 minutes and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart transplantation. Hearts were explanted on day 2, day 7, and 16wks. The recipient’s heart acted as control. Histological analysis and western blotting for αSMA and TGF-β1 (markers of fibrosis) were completed.

Results:
Ninety rats were studied. There was a significant increase in infarct ratio (IR) - infarct size/area at risk-, and interstitial fibrosis (IF) after mechanical unloading in the permanent ligation group at day 2 (AMI-L vs AMI-U p = 0.0073 (IR) and p = 0.0012 (IF)) and day 7 (AMI-L vs AMI-U p = 0.0166 (IR) and p = 0.0363 (IF)). After coronary reperfusion, there was no increase in IR or IF with mechanical unloading. At 16wks however, this protective effect of reperfusion was lost (CMI/R-L vs CMI/R-U p = 0.004 (IR) and p = 0.0024 (IF)). The expression profiles of αSMA and TGF-β1 correlated with the results above.

Conclusion:
These data suggest an association between the revascularisation of a less auto-regulated vessel and amelioration of the deleterious effect of mechanical unloading on the extracellular matrix with implications for LVAD induced recovery.
Abstract 21098: Variables From the CMS Heart Failure Readmission Model Poorly Predict 30-Day Rehospitalization Risk in Heart Failure Patients From a Large Academic Hospital System
Authors: Perez Antonio L , Chagin Kevin , Milinovich Alex , Tang W.H. Wilson , Kattan Michael , Starling Randall C
Published: March 2022

Introduction:
Predicting 30 day readmission risk in patients with acute heart failure (HF) remains challenging. As part of the Hospital Readmissions Reduction Program, the Centers for Medicare and Medicaid Services (CMS) has implemented a claims-based 30 day readmission risk model to stratify US hospitals for its HF penalty algorithm, with a reported c-statistic of 0.61. The variables used in this model may be useful in hospitals for predicting readmission risk and informing population health efforts.

Methods:
We evaluated the discriminatory power of variables from the CMS HF readmission risk model to predict 30 day readmission in patients part of the Cleveland Clinic Heart Failure Registry (n=29,749 hospitalizations), which contains data from all admissions from 2010 to present with a primary diagnosis of HF to all Cleveland Clinic Health System hospitals. The CMS model contains 37 variables including history of HF, ACS, COPD, renal failure (RF) and drug/alcohol abuse.

Results:
Twenty one percent of our cohort experienced all cause 30 day readmission (n=5109). The median age was 74 (IQR 63-84) and 48% were female. Based on billing codes from the year prior to a HF admission, there was no significant difference in the rates of ACS, RF, active cancer, CVA, dementia and COPD between patients who did and did not experience a 30 day readmission (p>0.05). Using 2010-13 admissions (n=19,904) and 37 variables from the CMS HF readmission model, we derived a 30 day all cause readmission predictive model. We validated this model using 2014-15 admissions (n=9,845). This model had poor discriminatory power in the derivation and validation cohorts (c-statistic=0.51 for both). In a parallel analysis, a bootstrapped model using the entire cohort was created, with a c-statistic of 0.53. The discriminatory power did not improve when the cohort was limited to patients ≥ 65 years (validation c-statistic=0.51).

Conclusion:
A prediction model derived using claims-based variables from the CMS HF readmission model poorly predicts 30 day all cause readmission in a large hospital system-based cohort, with a validated c-statistic of 0.51. The applicability of CMS’ readmission risk stratification approach to clinical care and local population management efforts in HF is likely limited.
Abstract 21129: Arterial Anatomy and Functional Performance in Peripheral Artery Disease: Cardiovascular Cell Therapy Research Network Patients With Intermittent Claudication Injected With ALDH Bright Cells: CCTRN PACE
Authors: Ambale Venkatesh Bharath , Fujii Tomoki , Perin Emerson , Murphy Michael P , Yang Phillip C , Henry Timothy D , Moye Lemuel A , Bettencourt Judith L , Ebert Ray F , Lima Joao A
Published: March 2022

Introduction:
Claudication is characterized by the presence of a stenosis or occlusion of arteries in the lower extremities that limits walking endurance compared with healthy individuals. Magnetic Resonance (MR) based assessments of leg arterial anatomy may enable improved understanding of the underlying causes of functional impairment.

Hypothesis:
The severity of stenosis in the lower extremity arteries and collateral vessel density is associated with functional impairment.

Methods:
A total of 82 participants with claudication and infrainguinal PAD were recruited across 9 US sites as part of the National Heart, Lung, and Blood Institute-sponsored CCTRN PACE clinical trial. Baseline (pre-treatment) data for 78 participants were used for this analysis. Functional performance was assessed by treadmill test measures of peak walking time (PWT) and claudication onset time (COT). Contrast-enhanced time-resolved magnetic resonance angiography was used to assess maximum stenosis of the superficial femoral artery (SFA) in each leg. The extent of arterial collateralization at the thigh (nTC) and calf (nCC) was measured by counting the number of vessels that bypassed a stenosis and reconstituted the main conduit vessel. Linear regression was used to evaluate the association between PWT and COT as the dependent variable and maximum stenosis, nTC and nCC as independent variables.

Results:
The participants were 66±9 years old, 27% female. The mean pre-exercise ankle brachial index in the more symptomatic leg was 0.61± 0.12. Participants were primarily Rutherford 2 (54%) and 3 (44%). At baseline, mean PWT was 5.0±2.6 min, COT was 1.6±0.9 min, nTC was 3.4±3.3 and nCC was 1.1±1.9. The maximum thigh stenosis was ≥75% in 77/78 and 99-100% in 66/78 participants. In linear regression models, maximum stenosis and nTC were not associated with PWT or COT. The nCC was associated with the COT (beta=0.08, p=0.008), and weakly associated with PWT (beta= 0.16, p=0.07). The association with COT remained after adjustment for thigh stenosis and nTC (beta=0.08, p=0.01).

Conclusions:
In patients with claudication and significant SFA stenosis, calf collateralization was associated with superior functional performance.
Abstract 21144: Gene-Based Risk Stratification for Cardiac Disorders in
LMNA
Mutation Carriers in Japan
Authors: Nishiuchi Suguru , Aiba Takeshi , Makiyama Takeru , Nakajima Kenzaburo , Yagihara Nobue , Ishikawa Taisuke , Onoue Kenji , Murakoshi Nobuyuki , Watanabe Ichiro , Ohkubo Kimie , Watanabe Hiroshi , Ohno Seiko , Doi Takahiro , Shizuta Satoshi , Minamino Tohru , Saito Yoshihiko , Oginosawa Yasushi , Nogami Akihiko , Aonuma Kazutaka , Kusano Kengo , Makita Naomasa , Shimizu Wataru , Horie Minoru , Kimura Takeshi
Published: March 2022

Introduction:
Mutations in
LMNA,
which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance (CCD), atrial fibrillation, and malignant ventricular arrhythmias (MVAs). Although the type of
LMNA
mutations have been reported to be associated with susceptibility to MVAs, the gene-based risk stratification for cardiac complications remains unexplored.

Hypothesis:
We hypothesized that truncation mutations might be associated with poor prognosis in
LMNA
mutation carriers, due to CCD, MVAs, and heart failure.

Methods:
The multicenter cohort included 77
LMNA
mutation carriers (49 male, mean age: 45+/-17 yrs old) in 45 families from 7 institutions in Japan. All cause mortality and cardiac disorders were retrospectively analyzed.

Results:
Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families, in which 71 (92%) were phenotypically affected, and showed CCD (81%), lower left ventricular ejection fraction (LVEF<50%; 45%), atrial arrhythmias (AAs: 58%), and MVAs (26%). During the follow-up period (median 47 months), 9 (12%) patients died due to end-stage heart failure (n=7) or suddenly (n=2), but not differ between the the type of mutations. On the other hand, the onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of CCD (41+/-12 vs. 51+/-10 yrs old; p=0.004) and LVEF<50% (47+/-12 vs. 56+/-7 yrs old; p=0.07) compared to those with missense mutations. In addition, the truncation mutation was found to be at risk for the early onset of CCD (Odds ratio [OR]=3.55, 95%CI:1.1-12.3, p=0.04) and the occurrence of AAs (OR=5.18 [1.4-20.4], p=0.01), LVEF<50% (OR=3.92 [1.0-16.6], p=0.04), and MVAs (OR=12.8 [1.9-259], p=0.006), as estimated using multivable analyses. However, no significant difference was observed in each cardiac phenotype between probands vs. relatives and male vs. female.

Conclusions:
The truncation mutations were associated with earlier manifestation of cardiac phenotypes in
LMNA
-related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification in
LMNA
mutation carriers.
Abstract 21146: Late Pregnancy is Associated With a Decrease in Global Circumferential Strain and Tumor Necrosis Factor Receptor 2
Authors: Moazeni Shayan , Umar Soban , Methangkool Emily , Pham Sheshanna , Mahajan Aman , Eghbali Mansoureh
Published: March 2022

Background:
The hearts of pregnant women and rodents undergo physiological hypertrophy with preserved function. Recently, we have demonstrated that the hearts of late pregnant (LP) rodents are more prone to ischemia reperfusion injury compared to non-pregnant (NP) rodents. Currently, measurements such as ejection fraction (EF) are not sensitive enough to determine subclinical myocardial dysfunction. However, speckle-tracking echocardiography (STE), a novel imaging tool, has been demonstrated to assess myocardial function with greater sensitivity. Tumor Necrosis Factor Receptor 2 (TNFR2), a membrane receptor that has been implicated in cardioprotection and has been demonstrated as marker for subclinical myocardial dysfunction in patients. Thus, we hypothesized that global circumferential strain (GCS) measured by STE can detect subclinical myocardial dysfunction in pregnancy that is associated with a decrease in TNFR2 in rats.

Methods:
LP (20 days pregnant) and NP female Sprague-Dawley rats were used for the study (n=14). Left ventricular EF (LVEF, %), fractional shortening (FS, %), heart rate (HR, bpm), and GCS (%) were obtained using echocardiography (Visualsonics, Vevo 2100) (n=7/group). GCS was obtained with STE and was measured in triplicates. Total ventricular weight (VW) was recorded and LV was isolated to measure LV hypertrophy (LV/VW) (n=6/group). TNFR2 expression was measured using qPCR.

Results:
LP rats showed slightly reduced but insignificant LVEF (LP: 67.65+/-1.41% vs. NP: 71.35+/-1.52%, P=0.10) and FS (39.07+/-0.90 % vs. 42.643+/-1.76 %, P=0.09) compared to NP rats. Additionally, no difference in HR between LP and NP rats were found (352.50+/-16.36 bpm vs. 333.75+/-4.78 bpm, respectively, p=0.314).However, hearts from LP rats had evidence of hypertrophy evident by an increase in LV/VW compared to NP (0.57+/-0.03 g vs. 0.48+/-0.02 g). LP rats had a significantly reduced GCS compared to NP rats (-27.50+/-1.40 % vs. -34.375+/-1.95 %, p<0.01) and reduced TNFR2 expression compared to NP.

Conclusions:
Our results demonstrate that late pregnancy is associated with a decrease in GCS with no significant change in EF and a decrease in TNFR2, which may be a subclinical marker for myocardial dysfunction.
Abstract 21155: Outcomes of Transcatheter Aortic Valve Replacement in High or Extreme Risk Patients With Severe Bicuspid Aortic Valve Stenosis
Authors: Pineda Andres M , Rymer Jennifer , Wang Alice , Koweek Lynne H , Plichta Ryan , Williams Adam , Kiefer Todd L , Wang Andrew , Gaca Jeffrey , Hughes Chad , Harrison John K
Published: March 2022

Introduction:
Although TAVR has been performed in patients with bicuspid aortic valves (BAV), these patients were excluded from all the US pivotal trials and therefore their postoperative outcomes are not clearly defined.

Hypothesis:
Patients with BAV undergoing TAVR may achieve similar outcomes when compared with trileaflet aortic valve (TAV) stenosis.

Methods:
We retrospectively evaluated the outcomes of high or extreme risk patients with BAV stenosis at our institution between April 2011 and November 2016, and compared them with those of patients with TAV stenosis. Chi-square and the Mann-Whitney U tests were used to compared the groups, and a Kaplan-Meier analysis was performed to estimate long-term survival. The study was approved by the Duke University Hospital Institutional Review Board.

Results:
TAVR was performed in a total of 567 eligible patients, from which 50 (8.8%) had BAV and 517 (91.2%) TAV disease. Patients with BAV were younger (median age 70 years [64-74] vs. 81 [75-86], p<0.001), had higher prevalence of COPD (52.0% vs. 30.8, p=0.002), lower prevalence of coronary artery disease (64.0% vs 76.8, p=0.036), higher BMI (median 28 kg/m
2
[25-35] vs. 27 [24-31], p=0.046) and lower STS PROM score (median 4.6% [3.0-7.7] vs. 6.7 [4.4-9.9], p=0.004) when compared with those with TAV. Overall, self-expanding and balloon-expandable TAVR devices were used in 58.4% and 41.3% of the cases, and transfemoral access was used in 86.8%. Patients with BAV had a higher mean aortic valve gradient postoperatively (median 12 mmHg [10-15] vs. 10 [7-13], p<0.001). There were no differences in the procedural characteristics or in the incidence of any of the postoperative adverse outcomes between the groups, including moderate to severe paravalvular regurgitation (4.0% vs. 3.5, p=0.541), stroke (2.0% vs. 1.5, p=0.567), and 30-day all-cause mortality (6.0% vs. 1.5, p=0.064). The 2-year survival (82.0% vs. 83.4, p=0.476) was similar between the groups.

Conclusions:
This initial experience suggests that TAVR can be performed in patients with severe BAV stenosis at high or extreme risk for traditional surgical aortic valve replacement achieving similar short-term clinical outcomes and mid-term survival compared with patients with TAV.
Abstract 21158: Ultra-Short Caloric Restriction Prior to Cardiac Arrest and Resuscitation Leads to Improved Survival and Neurological Outcome in a Rodent Model
Authors: Azadian Matine , Bazrafkan Afsheen , Abbasi Hamidreza , Zaher Shuhab M , Alcocer Juan , Badiyan Ramin , Otarola Ieeshiah , Tian Guilian , Akbari Yama
Published: March 2022

Introduction:
Caloric restriction (CR) has been widely shown to have both cardioprotective and neuroprotective properties. However, nearly all studies have investigated chronic CR with mechanisms linked to the upregulation of SIRT-1 and BDNF. Minimal to no focus has been placed on the potential benefits of transient CR in models of brain injury, including stroke. Furthermore, the effects of transient CR in cardiac arrest-induced global cerebral ischemia have not been evaluated. We investigated the effects of overnight (~14-hour) CR on survival and neurological outcome in a rodent model of cardiac arrest (CA).

Methods:
Adult male Wistar rats (n=28) were divided into 75% CR (n=14) and non-CR (n=14) groups 14hrs prior to rats undergoing intubation, mechanical ventilation, cannulation of femoral vessels, and 8 minutes of asphyxial CA followed by cardiopulmonary resuscitation (CPR). Blood glucose was measured before CA. We conducted neurological deficit scale (NDS) behavioral testing at 4hrs, 24hrs, 48hrs, and 72hrs post-CA. The NDS score ranges from 0 (dead) to 80 (normal). Rats were euthanized after 72hrs and tissue was collected for protein analysis via Western blot.

Results:
CR, in comparison to no-CR, resulted in significant reduction of mortality (0% vs. 28.6%; Kaplan-Meier log-rank test, p< 0.05). Of those that survived, NDS scores improved significantly in the CR group at 4hrs (32.8±6.1 vs. 24.5±3.3; p<0.05), 24hrs (66.5±8.4 vs. 57.0±7.9; p< 0.05), 48hrs (73.1±4.7 vs. 61.3±12.5; p< 0.05), and 72hrs (76.3±3.3 vs. 73.14±12.2; p< 0.05). CR also significantly lowered pre-CA glucose levels (151.0±22.1 vs. 220.7±17.5; p< 0.05). Western blot analysis yielded no significant difference in BDNF and SIRT-1 expression in brain regions of CR vs. non-CR rats.

Conclusions:
Our results demonstrate that ultra-short CR (~14 hours) significantly improves survival and neurological outcome after CA/CPR. Interestingly, these improvements appear to be independent of BDNF or SIRT-1 pathways, commonly linked to chronic CR. While ultra-short CR improved glycemic control in rats, further investigation into the underlying molecular mechanisms are imperative to explore potential translational and therapeutic implications, including for patients at high risk of CA.
Abstract 21177: Seamless Gene Correction of
LDLR
in Familial Hypercholesterolemia Induced Pluripotent Stem Cells Mediated by CRISPR/Cas9 and
PiggyBac
Authors: Wei Rui , Yang Jiayin , Tse Hung-Fat
Published: March 2022

Introduction:
Familial hypercholesterolemia (FH) is an autosomal disorder, characterized by elevated circulating lipoproteins and high risk of premature coronary heart disease. Mutations in low-density lipoprotein receptor gene (LDLR) is one of the major causes. Induced pluripotent stem cell (iPSC) technology helps us generate cell model with patient-specific genetic background. In this study, we aimed to correct LDLR mutation in iPSCs reprogrammed from an FH patient, using CRISPR/Cas9 and
piggyBac
.

Methods:
Patient-specific iPSCs were generated from an FH patient with heterozygous duplication of “TGCTGGC” (c.2108_2114dup, p.Ala705fsX14) in exon 14 of LDLR. CRISPR/Cas9 targeting the mutation site and
piggyBac
were employed to correct the mutation via homologous recombination. Corrected iPSCs were subjected to karyotype analysis, and a series of tests of pluripotency, then differentiated into hepatocyte-like cells (iHeps) to assess the LDLR function
in vitro
and
in vivo
.

Results and conclusions:
We designed two sgRNAs which showed high cutting efficiency in the target site. Co-delivery of CRISPR/Cas9 and
piggyBac
in FH iPSCs facilitates the integration of donor constructs in the target site with high efficiency. Then, the drug selection cassette was removed by hyPBase expression vectors. After two rounds of genetic manipulation, we achieved a seamless genetic correction in iPSCs, which showed retain full pluripotency and normal karyotypes. In addition, the corrected iPSCs can be differentiated into functional iHeps efficiently, and these iHeps showed restored function of LDLR, characterized by recovery of LDL receptor expression levels and the capacity of LDL uptake. Our study highlights the feasibility of using CRISRP/Cas9 and
piggyBac
to generate seamless, genetically corrected patient-specific iPSCs, and functional iHeps. These genetically corrected cells are not only ideal models for disease modeling, but also the potential source for autologous cell replacement therapies.

Acknowledgment:
This work was supported by the Shenzhen Science and Technology Council Basic Research program (JCYJ20150331142757383), the Hong Kong Research Grant Council Theme Based Research Scheme (T12-705/11).
Abstract 21189: High Diastolic Blood Pressure (DBP) and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction (HFpEF) and Hypertension (HTN): Findings From Medicare-Linked OPTIMIZE-HF Registry
Authors: Dooley Daniel J , Lam Phillip H , Fonarow Gregg C , Ahmed Ali
Published: March 2022

Background:
According to 2017 update of 2013 ACCF/AHA HF guideline, systolic BP (SBP) should be lowered to <130 mmHg in euvolemic patients (pts) with HFpEF and persistent HTN. However, little is known about the role of high diastolic BP (DBP) on outcomes in these patients.

Methods:
Of the 10482 hospitalized pts with decompensated HFpEF (EF >40%) discharged alive, 2652 had HTN, defined as SBP ≥140 or DBP ≥90 mmHg at both admission and discharge. Of these, 289 had a discharge DBP ≥90 mmHg. Propensity scores for DBP ≥90 mmHg, estimated for each of the 2652 pts, were used to assemble a cohort of 263 pairs of pts, with a discharge DBP ≥90 and <90 mmHg, balanced on 40 baseline characteristics including discharge SBP. The 526 matched pts (52% women, 24% African American) had mean (±SD) age of 74 (±13) years, EF of 56 (±8) %, and discharge DBP of 84 (±13) mmHg.

Results:
During 6 (median, 3) years of follow-up, all-cause mortality occurred in 73% and 61% of matched pts with a discharge DBP ≥90 vs <90 mmHg, respectively (HR, 1.36; 95% CI, 1.10-1.67; p=0.004;
Figure
). HF readmission occurred in 54% and 43% of matched pts with DBP ≥90 vs <90 mmHg, respectively (HR, 1.37; 95% CI, 1.06-1.75; p=0.015). There was no association with all-cause readmission (HR, 1.05; 95% CI, 0.86-1.26).

Conclusion:
About 1 in 10 hospitalized patients with HFpEF and HTN had a discharge DBP ≥90 mmHg, which was associated with a higher risk of mortality or morbidity.
Abstract 21190: A New Biologic Targeting mAKAPβ Diminishes Post-Ischemic Systolic Dysfunction and Heart Failure
Authors: Martinez Eliana C , Li Jinliang , Thakur Hrishikesh , Kapiloff Michael S
Published: March 2022

Introduction:
Heart failure (HF) morbidity and mortality remain significant, mandating the continued development of new therapeutics. The scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) is a regulator of pathological remodeling. Our unpublished data show that induction before myocardial infarction (MI) of cardiac myocyte-specific mAKAPβ gene deletion decreases infarct size and preserves cardiac function long-term in mice. To develop a therapeutic providing the benefit of mAKAPβ targeting, we designed a new gene therapy vector, a self-complementary, serotype 9 adeno-associated virus (scAAV) that expresses a mAKAP-specific small hairpin RNA (shRNA) under the control of the cardiac troponin T promoter. We have tested whether post-MI suppression of mAKAPβ expression in the cardiomyocyte as provided by this new biologic prevents HF.

Methods:
MI was induced by permanent ligation of the left coronary artery in adult C57BL/6 mice. Mice with ejection fraction (EF) ≤40% 2 days post-MI and sham-operated controls were randomized and injected the following day with 5x10
11
vg I.V. of either mAKAP- or control-shRNA scAAV.

Results:
EF pre-treatment was 31.7% and 32.8% for mAKAP-MI (n=10) and control-MI (n=6) cohorts, respectively. mAKAP-shRNA treatment resulted in amelioration of systolic dysfunction as evidenced by normalization of EF from day 2 to weeks 2, 4 and 8 post-MI, while control-MI mice displayed progressive EF deterioration. At 8 weeks post MI, EF for the mAKAP-MI cohort was comparable to mAKAP- and control-Sham animals (44.3±3.3% vs. 54.6±1.7% & 54.5±2.0%), whereas it was markedly higher than for control-MI animals (18.0±4.3%, P<0.0001). mAKAP-MI mice also had a greater left ventricular (LV) anterior wall thickness in systole (0.9±0.1mm vs. 0.5±0.1mm, P<0.05) and decreased LV end-systolic-volumes than control-MI mice (72.1±8.6μL vs. 137.3±26.3μL, P<0.01). In addition, treatment with mAKAP-shRNA attenuated the development of pulmonary edema (a sign of HF), as wet lung weight for mAKAP-MI mice was less than for control-MI mice (7.7±0.2 vs. 10.6±1.2mg/mm tibial length, P<0.01).

Conclusion:
Inhibition of mAKAPβ expression using a novel gene therapy vector ameliorates post-MI cardiac dysfunction and prevents the development of HF.
Abstract 21198: Human Atrial Natriuretic Peptide Levels in Combination With Plasma Brain Natriuretic Peptide Levels Predict Cardiac Function in Patients With Light-Chain Amyloidosis
Authors: Koyama Jun , Kuwahara Kouichirou
Published: March 2022

Introduction:
Plasma brain natriuretic peptide (BNP) levels are known to be a predictor of cardiac dysfunction in patients with systemic light-chain amyloidosis (AL). There is no data about the clinical significance of human atrial natriuretic peptide (h-ANP) levels in combination with BNP.

Hypothesis:
Plasma h-ANP levels in combination with plasma BNP levels provide additional information about the cardiac function in patients with AL.

Methods:
We prospectively examined 100 consecutive, untreated patients with biopsy-proven systemic AL amyloidosis with data of BNP and h-ANP. Patients were divided into 4 groups by h-ANP (median value, 29pg/mL) and BNP (median value, 68pg/mL) levels. We assessed diastolic wall strain (DWS) calculated from M-mode in left ventricular (LV) posterior wall (PW) as the following equation {(LVPWs - LVPWd)/LVPWs} (s, at end-systole; d, at end-diastole), standard 2-dimensional echocardiography, Doppler flow measurements, and LV global longitudinal strain (GLS) by speckle tracking echocardiography. Plasma levels of h-ANP and BNP were measured on the day of echocardiography.

Results:
In the group with both higher level of h-ANP and BNP, the DWS was significantly lower than the other 3 groups. This group showed significantly higher values in the ratio of trans-mitral early to late diastolic flow velocity, the ratio of pulmonary venous diastolic to systolic ratio, the septal E/e’, and GLS compared with the other 3 groups.

Conclusions:
Plasma h-ANP levels in combination with BNP levels provide useful information about cardiac function in patients with AL.
Abstract 21201: Stent Length Remains an Important Risk for Recurrent Events in Women With or Without Diabetes Mellitus After New Generation DES PCI: From the WIN DES Collaboration
Authors: Chandrasekhar Jaya , Baber Usman , Sartori Samantha , Sarin Michele , Stone Gregg , Leon Martin , Stefanini Giulio , Sharma Madhav , Vogel Birgit , Farhan Serdar , Sorrentino Sabato , Ge Zhen , Windecker Stephan , Serruys Patrick , Von Birgelen Clemens , Smits Pieter , Kimura Takeshi , Wijns William , Kastrati Adnan , Kandzari David , Chieffo Alaide , Galatius Soren , Mehran Roxana
Published: March 2022

Introduction:
New Generation drug eluting stents (DES) have overcome the limitations of bare metal stents and first generation DES resulting in lower risk of ischemic events in women.

Hypothesis:
We sought to compare increasing total stent length per patient for 3-yr outcomes in DM and non-DM women after percutaneous coronary intervention (PCI) with new generation DES.

Methods:
The WIN-DES collaboration is a pooled database of women undergoing PCI with coronary stents in 26 randomized trials. We compared total stent length per patient treated with new generation DES in quartiles (Among DM - Q1: 8-18mm, Q2: 18-24mm, Q3: 24-38mm and Q4: 38+mm; among non-DM Q1: 8-18mm, Q2: 18-24mm, Q3: 24-36mm and Q4: 36+mm). 3-yr outcomes were analyzed in a time to event manner and adjusted using multivariable methods. Major adverse cardiovascular events (MACE) were defined as a composite of death, myocardial infarction (MI) or target lesion revascularization (TLR).

Results:
The study sample comprised 5403 patients, of which 31.8% (n = 1719) had DM. In both DM and non-DM groups, patients in Q4 had greater prevalence of B2/C type and calcified lesions with smaller stent diameter compared to others. 3-yr MACE increased from Q1-Q4 in DM and non-DM patients, albeit DM patients experienced higher event rates (
Figure
). After multivariable adjustment, findings were unchanged, and increasing stent length remained associated with greater risk of 3-yr MACE in DM (p-trend=0.003) and non-DM (p-trend <0.0001) patients. No interaction was observed between DM status and stent length for any outcomes.

Conclusions:
Despite the use of new generation DES, increasing total stent length per patient was associated with greater risk of MACE in both DM and non-DM women undergoing PCI. Women with DM experienced worse outcomes, and a greater risk of TLR regardless of total stent length. Meticulous attention to stent optimization and post PCI pharmacotherapy is needed to mitigate long-term adverse outcomes in women.
Abstract 21202: 5-Aminolevulinic Acid Combined With Sodium Ferrous Citrate Ameliorates Post Cardiac Ischemia/Reperfusion Injury via Regulating Inflammatory Cytokines
Authors: Oimatsu Yu , Kaikita Koichi , Ishii Masanobu , Izumiya Yasuhiro , Tsujita Kenichi
Published: March 2022

Post ischemia/reperfusion injury (I/R) reduces beneficial effect of restoration of coronary flow in the setting of acute myocardial infarction. Heme oxygenase-1 (HO-1) is inducible enzyme, and plays a crucial role in reaction against for oxidative stress, inflammatory, and apoptosis. Previous studies reported that HO-1 could reduce the infarct size after ischemia/reperfusion injury (I/R). 5-aminolevulinic acid (5-ALA) is known to be a naturally occurring metabolic precursor of heme, and 5-ALA combined with ferrous iron can induce HO-1 in various cells. In this study, we investigate the protective effect of 5-ALA pretreatment after I/R using mice model. Male C57/BL 6J mice (8-12 weeks of age and weighing 21-26 g) were pretreated with 100 mg/kg 5-ALA/HCL and 157 mg/kg sodium ferrous citrate or placebo 48, 24, 1 h before I/R, and underwent 50 minutes of left coronary artery occlusion followed by 24 h reperfusion. Infarct area (IA), area at risk (AAR), and area of left ventricle (LV) were determined by 5% Evans blue and 1% triphenyltetrazolium chloride (TTC) double staining after 24h reperfusion (Figure [A]). Pretreatment of 5-ALA group significantly reduced IA/AAR compared to the placebo group (34.0% [28.1 - 37.6%] VS 51.7% [45.8 - 54.0%], p= 0.001, n=6, Figure [B and C]). Real time PCR assay after 24h reperfusion showed that expression of mRNA of TNF-α (p=0.040), IL-1β(p=0.024), MMP-9 (p=0.011) and BNP (p=0.046) were significantly lower in 5-ALA group than that in placebo group. These findings suggested that 5-ALA pretreatment regulated inflammatory reaction after I/R. The beneficial effect of 5-ALA could be related with HO-1 induction. In conclusion, pretreatment of 5-ALA combined with ferrous iron could play a protective role after I/R by attenuating inflammatory reaction.
Abstract 21213: Cardiac Secreted Beta-2 Microglobulin Promotes Fibrosis Involving Epidermal Growth Factor Receptor Signaling During Pressure Overload
Authors: Li Yang , Gong Hui
Published: March 2022

Plasma Beta-2 microglobulin (β2M) level is inversely associated with glomerular filtration rate (GFR) and ejection fraction (EF) in patients with chronic kidney disease. However, few studies have evaluated roles of β2M in cardiac remodeling induced by hypertension. The present data showed that serum β2M level was increased in patients with hypertension as compared to control group, and it was significantly higher in patients with chronic heart failure than in those with hypertension. Serum β2M level was related to diastolic dysfunction in patients with hypertension and heart failure. During 4 weeks after transverse aortic constriction (TAC) in mice, β2M level in serum or heart tissue increased progressively in time-dependent manner. Cardiomyocyte but not fibroblast secretory β2M was rapidly increased after mechanical stretch (MS)
in vitro
. Exogenous β2M showed pro-fibrotic effects and enhanced migratory capability in cardiac fibroblasts. Conditional medium (CM) from mechanical stretched cardiomyocytes showed the similar effects in fibroblasts, but these effects were partly abolished by CM from β2M-downregulated-cardiomyocytes subjected to MS. In vivo, AAV9 mediated-knockdown of cardiac β2M greatly improved the cardiac fibrosis and dysfunction induced by TAC. Further analysis indicated that β2M promoted the phosphorylation of p38, smad2/3 and epidermal growth factor receptor (EGFR) in fibroblasts, and inhibition of EGFR attenuated p-p38 and p-smad2/3 levels, and significantly inhibited pro-fibrotic effects in cardiac fibroblasts treated with β2M. The present data demonstrated the importance of β2M as a paracrine pro-fibrotic mediator associated with hypertension or heart failure. It suggests that inhibition of β2M may have the therapeutic potential for the prevention of cardiac fibrosis or the progression of heart failure associated with hypertension.