bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16510: Acute Use Impairs Vascular Function in Exclusive Juul Users (the Jive Study)
Authors: Majid Sana , Keith Rachel J , Fetterman Jessica L , Weisbrod Robert M , Vargees Comreen , Nystoriak Jessica , Thomas Tabitha L , Stokes Andrew , Blaha Michael J , Srivastava Sanjay , Robertson Rose M , Bhatnagar Aruni , Hamburg Naomi M
Published: May 2021

Introduction:
The use of pod-based electronic cigarettes such as JUUL has especially increased among youth and young adults. Due to its popularity and high nicotine delivery as salts, JUUL warrants assessment of its cardiovascular effects.

Hypothesis:
JUUL use alters vascular function.

Methods:
In the JUUL Impact on Vascular Effects (JIVE) Study, we evaluated endothelial function and blood pressure (BP) in healthy young adults aged 18-40 who were either tobacco nonusers (N=23), exclusive combustible cigarette users (N=17) or exclusive JUUL users (N=15).

Results:
As shown in the figure, no differences were noted in baseline brachial artery FMD across the 3 groups. Both JUUL and combustible cigarette users had higher systolic and diastolic BP compared to nonusers (P<0.01). Following 10-minute structured use, JUUL decreased FMD more than nonuse (P<0.01) and was similar to combustible cigarette use (P=0.30 vs JUUL). These differences persisted in models adjusted for age, race and sex. Additionally, JUUL use induced an acute rise in systolic BP (6 ± 6mmHg) that differed from nonuse (0.3 ± 5 mmHg, P=0.001) but was similar to combustible cigarette use (8 mmHg, P=1.0). Urinary cotinine and nicotine levels were higher in combustible cigarette and JUUL users following acute exposure (general linear model adjusted for urinary creatinine with overall P<0.01, combustible cigarette vs nonusers P<0.01, JUUL vs nonusers P<0.01).

Conclusions:
Our results indicate that acute and chronic JUUL use are associated with higher BP, and acute use with a decrease in endothelial function similar to acute combustible cigarette use, thereby suggesting that JUUL alters vascular function both chronically and upon acute exposure in healthy young adults. Further studies are needed to evaluate the long-term impact of JUUL use on vascular health.
Abstract 16514: Impact of Chronic Obstructive Pulmonary Disease on Outcomes in Heart Failure With Preserved Ejection Fraction: An Analysis of PARAGON-HF
Authors: Mooney Leanne , Jhund Pardeep S , Anand Inder S , Desai Akshay S , Maggioni Aldo P , Rouleau Jean L , Swedberg Karl B , Van Veldhuisen Dirk J , Zile Michael R , Solomon Scott , McMurray John J
Published: May 2021

Background:
Little is known about the prognostic significance of chronic obstructive pulmonary disease (COPD) in patients with heart failure and preserved ejection fraction (HFpEF).

Purpose:
To evaluate the association between COPD and outcomes in the Prospective Comparison of ARNI and ARB Global Outcomes in HFpEF trial (PARAGON-HF).

Methods:
We assessed the relationship between the presence of COPD and the composite of time to first heart failure hospitalization or CV death, components of that composite, and all-cause death in PARAGON-HF using Cox proportional hazard models. Outcomes were adjusted for other prognostic variables including age, sex, comorbidities, LVEF, NT-proBNP and NYHA class.

Results:
Among 4791 participants, 670 patients (14%) had COPD. Patients with COPD were older, less likely to be female, had a worse functional class, lower LVEF, higher creatinine and markers of systemic inflammation, including neutrophil count and neutrophil/lymphocyte ratio. Compared to patients without COPD, those with COPD had a lower baseline KCCQ-CSS and were more likely to experience a clinically significant decrease in KCCQ-CSS during follow-up. COPD was associated with higher adjusted risks of the composite outcome (hazard ratio 1.50, 95%CI 1.29-1.75), heart failure hospitalization (1.54, 1.30-1.83), CV death (1.42, 1.10-1.82) and all-cause death (1.52, 1.25-1.84), all p<0.01. In comparison to the other common comorbidities, COPD was associated with the highest risk of all-cause mortality (Figure).

Conclusion:
In HFpEF, patients with COPD have worse functional class, quality of life and outcomes than those without COPD, and COPD is associated with a higher risk of death than other comorbidities
Abstract 16550: Community Perception and Treatment of Sore Throat Among Children in a Rheumatic Heart Disease Endemic Setting
Authors: Nalubwama Hadija , ATALA JENIFER , KANSIIME ROSEMARY , Sarnacki Rachel , Ndagire Emma , Okello Emmy , Watkins David
Published: May 2021

Introduction:
Although Group A Streptococcal (GAS) pharyngitis (sore throat) can be treated, its complications -- acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain significant public health problems in low- and middle -income countries. Examining community perceptions and health seeking behavior for sore throat in these settings could translate into effective ARF/RHD prevention strategies.

Objective:
To develop a local explanatory model of sore throat health seeking behavior that can be used in designing ARF/RHD preventive interventions

Methods:
This focus group discussions-based qualitative study was conducted in 3 districts of Uganda (Lira in the north, Wakiso in central and Mbarara in the west). Overall, 50 participants were included in these discussions about sore throat in children. Thematic analysis was done on transcribed and translated audio recordings.

Results:
Perception of sore throat, treatment practices and challenges/barriers to seeking proper care for sore throat were major topics discussed during the focus group discussions. Across the 3 districts, sore throat was perceived to be a common and serious problem within the community. Although the majority of participants could not tell the exact cause of sore throat, they believed that poor hygiene could be a related factor. Variable methods of treatment were used across all districts. However, traditional medicine use and practices were more common in Lira and Wakiso districts while there was more trust in modern medicine in Mbarara district. Improvement in a child’s symptoms was the most common reason for stopping treatment. Individual, societal and health system factors such as distance to health facility, long waiting time and lack of medicines influenced care givers’ decisions to seek proper care for sore throat.

Conclusions:
Our findings show interplay between care givers’ knowledge, beliefs and preferences and the health care system as major determinants of caregivers’ behavior to seek proper care for pharyngitis. Community ARF/RHD educational programs in Uganda should emphasize the consequences of untreated or poorly treated pharyngitis and the importance of seeking proper care and treatment.
Abstract 16554: Sphingosine-1-Phosphate Activates the Mitochondrial Unfolded Protein Response in the Pulmonary Vasculature
Authors: Lockett Angelia D , Vlasak Grace , Natarajan Viswanathan , MacHado Roberto F
Published: May 2021

Introduction:
Aberrant activation of pathways that promote pulmonary arterial smooth muscle (PASMC) and endothelial cell (PAEC) proliferation causes vascular remodeling and increased vascular resistance that leads to the deadly disease Pulmonary Arterial Hypertension (PAH). Sphingosine-1-phosphate (S1P) induces PASMCs proliferation and disruption of its signaling mitigates vascular remodeling and PAH. Mitochondria regulate proliferation and can promote or inhibit it in a signal dependent manner. The mitochondrial unfolded protein response (UPR
mt
) is a mechanism by which mitochondria preserve cell survival due to stress. Mitochondria are important mediators of PASMC proliferation and PAH development as both mitochondrial (mt) fission and aerobic glycolysis contribute to disease progression. Studies in C. elegans suggest a link between regulation of mt fission and activation of the UPR
mt
as suppression of fission leads to S1P dependent activation of the UPR
mt
.

Hypothesis:
We hypothesized that S1P stimulation leads to activation of the UPR
mt
to promote proliferation of hPASMCs and hPAECs.

Methods:
hPASMCs were stimulated with S1P (1 μM) for up to 24h. Cell extracts were analyzed by immunoblotting for proteins (eIF2α, ATF-5, HSP70 and Lonp1) that regulate the UPR
mt
. Mitochondrial dynamics was assessed by immunoblotting or immunofluorescence for mediators of fission (Drp-1) and fusion (mitofusin-2). SPHK1, the lipid kinase that catalyzes S1P generation, was overexpressed in hPAECs followed by immunoblotting for UPR
mt
and mt fission activation. PCNA expression was assessed to measure cell proliferation.

Results:
S1P stimulation of hPASMCs enhanced proliferation and caused rapid and sustained activation of the UPR
mt
as phosphorylation of eIF2α and expression of ATF-5 and HSP70 were increased. S1P also enhanced mt fission in hPASMCs as Drp-1 phosphorylation was increased concomitant with decreased mitofusin-2 expression. Overexpression of SPHK1 in hPAECs increased proliferation and activation of both the UPR
mt
and mt fission.

Conclusions:
S1P promotes functional and phenotypic changes of mitochondria that leads to activation of pathways that promote PASMC and PAEC proliferation which could contribute to vascular remodeling in PAH.
Abstract 16555: The Relationship of Preeclampsia and Maternal Region of Birth and Duration of Residence in Non-US Born Black Women
Authors: Sharma Garima , Boakye Ellen , Creanga Andreea A , Vaught Arthur J , Zakaria Sammy , Mehta Laxmi S , Blumenthal Roger S , Hong Xiumei , Ogunwole Serena M , Ji Yuelong , Wang Xiaobin
Published: May 2021

Introduction:
Preeclampsia is a risk factor for cardiovascular disease (CVD) and disproportionately effects black women. Few studies have explored the prevalence of CVD risk factors and preeclampsia risk in non-US-born black women. We investigated the differential risk of preeclampsia by maternal birth country and duration of stay in US-born vs non-US-born black women residing in US.

Methods:
We analyzed data from 2967 black women (US-born and non-US-born) in the Boston Birth Cohort (1998 - 2016). Maternal sociodemographic characteristics and key CVD risk factors (hypertension, obesity, diabetes, smoking) were characterized in the two groups. We performed multivariate logistic regression to investigate the prevalence of preeclampsia by maternal birth country and the duration of stay in the US (<10 years and ≥ 10 years) after controlling for explanatory variables. In all analyses, US-born black women were used as the reference group.

Results:
Of the study group, 40.5% were non-US-born (42% Caribbean, 36% from Sub-Saharan Africa and 21% from other regions). US-born black women were younger and had higher baseline prevalence of obesity (BMI≥ 30Kg/m2), multiparity, pregestational diabetes, smoking, maternal stress, lower educational level, and single marital status. As compared to US-born black women, non-US-born women had a 26% lower risk of preeclampsia. When further categorized by their duration of residence in the US, the prevalence of preeclampsia in non-US-born women with duration of stay <10 years was 8.5%, compared to 9.3% in those with duration of stay beyond 10 years (Figure).

Conclusions:
As compared to US-born blacks, the prevalence of CVD risk factors and preeclampsia is lower in non-US-born blacks. The "healthy immigrant effect” which typically results in health advantages for foreign born women, tends to wane with increasing duration of US residence (≥ 10 years). Further research on the impact of CVD risk factors on preeclampsia is needed.
Abstract 16563: FOXO1 Induces Cardiomyocyte-KLF5, Which Drives Oxidative Stress and Diabetic Cardiomyopathy
Authors: Kyriazis Ioannis D , Hoffman Matthew K , Gaignebet Lea , Lucchese Anna Maria , Wang Chao , Bannister Thomas , Christofidou-Solomidou Melpo , Oka Shinichi , Sadoshima Junichi , Koch Walter J , Goldberg Ira J , Yang Vincent W , Bialkowska Agnieszka , Kararigas Georgios , Drosatos Konstantinos
Published: May 2021

Introduction:
Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice.

Hypothesis:
KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM).

Methods and Results:
Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC-
Foxo1
-/-
mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA-
Klf5
), which we generated, recapitulated cardiomyopathy without T1D. Moreover,
Pparα
-/-
mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA-
Klf5
mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA-
Klf5
with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA-
Klf5
mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity.

Conclusions:
In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.
Abstract 16564: Location of Persistent Atrial Fibrillation Drivers Based on Body Surface Mapping: A Systematic Review and Metanalysis
Authors: Sarkar Abdullah , Tellez Mauricio , Saifman Shane , Weitz Daniel
Published: May 2021

Introduction:
Body Surface Mapping (BSM) is a non-invasive electrocardiogram-based mapping system that is used to identify localized drivers in patients with persistent Atrial Fibrillation (AF). Mapping of local drivers is becoming increasingly important in guiding treatment of atrial fibrillation but may not be readily available. We conducted a systematic review to determine the most prevalent atrial regions of AF driver activity identified with BSM.

Methods:
Electronic literature searches were performed across PubMed, Google Scholar, Cochrane, CINAHL, Web of science, EMBASE databases up to January 2019, for studies that utilized BSM to identify and report localized focal and rotor (reentrant) driver activity. Prevalence of drivers, as a percentage, were recorded for every region according to the Bordeaux Biatrial Schema. Random-effects model was used to calculate weighted averages with the corresponding 95% confidence interval (CI).

Results:
Total of 468 unique studies were identified and reviewed. 4 prospective cohort studies were included in the final analysis—of which 3 were single-center and 1 was multi-centered; totaling 336 patients. The mean age was 62.8 (±5.41) and 73% were males. The three most prevalent regions with persistent AF foci activity were region 1 (left pulmonary veins and left appendage): 59% (CI 48-71), followed by region 4 (upper half of right atrium and appendage): 31% (CI 12-54), and region 2 (right pulmonary veins and posterior interatrial groove): 19% (CI 7-34). The three most prevalent regions of persistent AF rotor activity were region 3 (inferior and posterior left atrium): 71% (CI 32-98), region 1: 70% (CI 21-100), and region 2: 70% (CI 25-99).

Conclusion:
In patients with persistent AF, majority of localized drivers seem to originate from specific atrial regions based on BSM.
Abstract 16565: Intramyocardial Tbx18 Gene Delivery in a Radiopaque Medium Enables Real-Time Assessment of Gene Transfer, and is Compatible With Biological Pacemaker Function
Authors: Kim Nam Kyun , Lee Ki Hong , Langberg Jonathan , Beyersdorf Jared , Fernandez Natasha , Shin Minji , Santangelo Philip , Cho Hee
Published: May 2021

Introduction:
The efficacy and specificity of myocardial gene transfer depends on retention of the injectate at the site of gene delivery. However, no direct method exists to confirm myocardial retention of a biologic delivered via an intracardiac transvenous catheter. We tested feasibility of a radiographic contrast media as a gene delivery vehicle, and fluoroscopic assessment of intramyocardial retention as well as proper function of a transgene.

Methods and Results:
Synthetic mRNA expressing GFP in saline was mixed with an iodine-based radiopaque contrast agent, iopamidol, at 2, 5, 20, 30 and 40%. The minimum content of iopamidol that allowed unequivocal radiographic identification ex vivo was 20%. To validate functional expression of the transgene, GFP mRNA was injected focally into the left ventricular apex of the rat heart upon thoracotomy at 0, 2, 5 or 20% iopamidol solution. On day 5, the hearts were harvested and examined for GFP expression, which illustrated comparable and focal GFP expression in all animals. To test whether gene delivery in a contrast media is compatible with intended disease-modifying activity, we employed TBX18 gene transfer via the right femoral vein in a porcine model of complete heart block. We have previously demonstrated that TBX18 could convert ventricular myocytes to pacemaker cells, and create de novo ventricular pacing in situ. Intracardiac delivery of TBX18 or GFP (n=6 or 2 pigs, respectively) mRNA dissolved in 20% iopamidol to the high His bundle region revealed clear, real-time visualization of the injectate in all pigs. In one of the 8 pigs, the injectate diffused rapidly into the ventricular circulation, which necessitated a repeat injection. The maximum heart rate of TBX18-injected pigs was faster than that of GFP-injected pigs upon β-adrenergic stimulation at 77±12 vs. 43±13 BPM at week 2 (
P
=0.08), and at 93±19 vs. 48±3BPM at week 4 (
P
<0.05), respectively.

Conclusion:
Radiographic contrast agent can serve as an effective gene delivery vehicle, allowing real-time and non-invasive assessment of the retention of intramyocardial gene delivery. This approach may be generalizable to other focal gene therapy applications, and minimize suboptimal gene delivery.
Abstract 16575: Synthetic TBX18 mRNA Induces Durable Reprogramming of Cardiac Myocytes to Pacemaker Cells
Authors: Wolfson David W , Zureick Nadine , Fernandez Natasha , Beyersdorf Jared , Sheng Christina , Park Sung Jin , Santangelo Philip , Cho Hee
Published: May 2021

Introduction:
Adenoviral gene delivery of transcription factor, TBX18, has been proven to reprogram ordinary cardiomyocytes to pacemaker cells, and provide ventricular pacing in the rodent and porcine heart. Yet host innate immune response to recombinant viral therapies remains a hurdle to overcome for successful translation. Somatic cell reprogramming does not require persistent expression of the reprogramming factors after arriving at the final cell fate. We hypothesized that brief expression of synthetic TBX18 mRNA suffices to convert chamber cardiomyocytes to induced pacemaker cells, thus obviating issues inherent to adenoviral gene therapy.

Methods:
Synthetic mRNAs were
in vitro
transcribed as previously described. Neonatal rat ventricular myocytes (NRVMs) were used as an
in vitro
platform to test pacemaker reprogramming by TBX18 mRNA. GFP or fLuc encoded mRNA was used as controls in all experiments.

Results:
Three days after synthetic TBX18 mRNA transfection, Hcn4 transcript level increased >6-fold compared to control. After two weeks, genes enriched in the pacemaker tissue, e.g., Shox2, Hcn4, and Tbx3, continued to be expressed higher in TBX18-NRVMs compared to control by >4.2-fold. The level of endogenously expressed, rat Tbx18 increased by 50% in NRVMs transfected with synthetic human TBX18 mRNA, which point to long-term reprogramming. To identify and lineage-trace reprogrammed pacemaker cells in real time, we cultured ventricular cardiomyoytes from transgenic mouse line Hcn4

(
GFP/+
)

, in which
de novo
pacemaker cells expressing Hcn4 contain eGFP fluorescence. Twelve days after synthetic mRNA or adenoviral gene transfer of TBX18 or GFP control, a significantly higher number of Hcn4

(
GFP/+
)

cells were observed in both mRNA and adenoviral TBX18-treated wells compared to their respective controls. TBX18 mRNA-transfected NRVM monolayers exhibited >2-fold slower conduction velocities compared to fLuc-transfected myocytes. In line with slow conduction velocity in the induced pacemaker myocytes, expression of ventricular gap junction protein, Cx43, decreased significantly compared to control.

Conclusions:
Together, the data indicate durable nodal pacemaker cell reprogramming with transient expression of synthetic TBX18 mRNA.
Abstract 16596: Immune Evasion by Human Neonatal Cardiac Mesenchymal Stem Cells Demonstrates Therapeutic Application in Myocardial Infarction
Authors: Gunasekaran Muthukumar , Mishra Rachana , Saha Progyaparamita , Shah Aakash , Davidson Lauren , Arfat Yasir M , Abdullah Mohamed , Fu Xuebin , Li Deqiang , Sharma Sudhish , Kaushal Sunjay
Published: May 2021

Immune rejection of transplanted stem cells is a major stumbling block in designing effective therapy for myocardial infarction. Human neonatal cardiac mesenchymal stem cells (nMSCs) showed superior cardiac functional recovery compared to adult MSCs in immune competent rat MI model. However, molecular mechanisms underlying immune evasion by transplanted nMSCs in the infarcted myocardium remain unexplored. In this investigation, we demonstrate for the first-time the expression, regulation and function of CD47 in human nMSCs and its novel mechanism of immune evasion increases its regenerative potential in rat MI model. Transplanted nMSCs showed significant increased cell retention, reduced phagocytosis and CD68
+
cells compared to aMSCs in rat MI model. Comparative proteomic analysis by LC-MS/MS on nMSCs and aMSCs showed that CD47 higher in nMSCs. Increased CD47 expression in nMSCs inhibited phagocytosis compared to aMSCs
in vitro and in vivo
. Further, CD47 blockade in nMSCs using anti-CD47, siRNA and shRNA lentiviral based approaches increased
in vitro
,
in vivo
phagocytosis, CD68
+
cells and reduced cell retention and MI recovery
in vivo
. Microarray analysis and validation showed miR-34a was significantly higher in aMSCs than nMSCs. To unravel CD47 regulation in aMSCs, we performed target scan analysis that predicted miR-34a binds on CD47. Further, miR-34a over expression in nMSCs reduced CD47 expression, increased
in vitro
and
in vivo
phagocytosis and reduced cell retention and MI recovery. In conclusion, increased CD47 expression in nMSCs inhibit phagocytosis by CD47/SIRPα immune regulatory axis to demonstrates its immune evasion potential and its therapeutic applications in myocardial infarction.
Abstract 16607: Age-induced Endoplasmic Reticulum Stress in the Heart: Role of Increased Very Long-chain Ceramides
Authors: Chen Qun , Kovilakath Anna , Allegood Jeremy , Cowart Lauren A , Lesnefsky Edward J
Published: May 2021

Introduction:
Mitochondrial function is impaired in aged hearts. Increased endoplasm reticulum (ER) stress contributes to the mitochondrial dysfunction observed during aging. Ceramides (CRMD) are sphingolipid metabolites that contribute key roles in cell signaling. Increased CRMD can lead to ER stress. Ceramide synthase enzymes (CerS) generate chain length specific CRMD with the CerS isoform 2 (Cers2) forming very long chain CRMD of ≥ 20 carbon acyl chain lengths.

Hypothesis:
An increase in CRMD content during aging contributes to age-related ER stress.

Methods:
Male mice (3, 18, 24 mo.) from the NIA colony were studied. Cardiac mitochondria (MITO), mitochondrial associated membranes (MAM), and ER were isolated from mouse hearts. CRMD content was measured using LC-MS. The contents of CerS enzymes were measured by immunoblotting in myocardial homogenates.

Results:
ER stress increased progressively during aging with increased contents of cleaved ATF6 and CHOP, indicators of increased ER stress, evident at 18 and 24 mo. (Panel A) (all data mean±SEM; *p<0.05 vs. 3 mo., † p<0.05 vs. 18 mo.). Aging increased very long-chain CRMD (≥C20) in ER (Panel B) at 18 and 24 mo. Similar CRMD trends were observed MAM (Panel C), shared membrane domains where ER and MITO interact. The content of CerS2 was increased at 24 mo. compared to 3 mo. (Panel D, n=4 each age). In contrast, the contents of CerS isoforms 4 and 5, that generate shorter chain CRMD (<C20) were unchanged (not shown). CRMD contents in MITO were unaltered with age (not shown). Thus, increased generation of very long chain CRMD in the ER is the likely mechanism of increased ER stress in the aged heart.

Conclusion:
Aging increased ER CRMD content by enhancing the formation of very long chain CRMD in ER by an increase in CerS2 content, concomitant with the onset of ER stress. The increase in age-induced ER stress, in turn, leads to mitochondrial dysfunction in the aged heart.
Abstract 16617: Multimodality Imaging Approach in Delivery and Tracking of a Novel Imageable Hydrogel in a Chronic Porcine Infarct Model
Authors: Melvinsdottir Inga H , Lee Shin-rong , Avendano Ricardo , Midgett Dan , Liu Yi-Hwa , Thorn Stephanie , hawley christi , Mamarian Marina , Uman Selen , Humphrey Jay D , Duncan James , Burdick Jason A , Sinusas Albert J
Published: May 2021

Introduction:
Left ventricular (LV) remodeling is a known complication from myocardial infarction (MI). Intramyocardial hydrogel (HG) delivery can potentially prevent LV remodeling post MI. We evaluated the feasibility of using multimodality imaging approach to assess the delivery and response to an imageable HG in a chronic porcine MI model.

Methods:
Nine Yorkshire pigs subjected to 90 min balloon occlusion and reperfusion were randomized 5 days post MI to delivery of HG (n=5) or controls (n=4).
99m
Tc-Tetrofosmin was injected during the occlusion to assess risk area (RA). The imageable HG (Hyaluronic Acid/Gelatin modified with Aldehydes and Hydrazides, with 100 mg/mL iohexol) was delivered intramyocardially in a 3x3 grid 5 days post-MI after assessing MI region with Hybrid
201
Tl SPECT/CT. Contrast cineCT angiography was performed at baseline, 5 days post MI and 1 hour and 1 week post thoracotomy to assess LV geometry, HG location and CT intensity expressed as Hounsfield units (HU).

Results:
The average RA was 16.7% LV with no difference between the groups (p=0.44). The HG was delivered to the MI region with guidance of SPECT/CT. The HG was visible with cineCT post-delivery within perfusion defect (MI: 154 ± 26 HU; remote 82 ± 20 HU, p<0.0001), but it was not visible 1 week post-delivery (MI: 79 ± 12 HU; remote 80 ± 14 HU, p=0.94). The wall thickening of the MI region dropped by 33% in both groups (p=0.99) at 5 days post MI. After HG delivery wall thickening increased by 33% in the HG group but decreased by 31% in the control group (HG: 2.42 ± 0.33 mm; Control: 1.25 ± 0.31 mm, p=0.041). After similar increase in end diastolic volume (EDV) 5 days post MI (p=0.43), the EVD was significantly reduced post HG delivery in the HG group (6.0 ± 2.0 ml reduction) compared to the control group (6.3 ± 4.4 ml increase, p=0.042).

Conclusions:
Multimodality imaging is a feasible method to guide and track the delivery of a novel imageable HG. Intramyocardial HG delivery was associated with decreased LV remodeling.
Abstract 16623: Interim Acute and 30-day Results of the Flash Registry
Authors: Toma Catalin
Published: May 2021

Introduction:
FLASH, a prospective multi-center all-comers registry, is designed to evaluate real-world outcomes in pulmonary embolism (PE) patients treated with the FlowTriever System (Inari Medical, Irvine, CA). The FlowTriever System is designed to extract large PE thrombus without a need for thrombolytic drugs.

Methods:
FLASH will enroll up to 500 patients who will be evaluated through 6 months. The primary endpoint is a major adverse events composite of device-related death and major bleeding at 48 hours, and periprocedural device or procedure-related AEs. Secondary endpoints include changes in acute hemodynamics, utility measures, and longer-term clinical outcomes. Acute data in 203 patients and 30-day data in 170 patients has been analyzed.

Results and Conclusion:
This analyzed cohort included 10% high-risk and 90% intermediate-risk PE patients. The mean RV/LV ratio was 1.54±0.47, sPESI was 1.54±1.06, concomitant DVT was present in 72% and elevated biomarkers in 97% of patients. The primary endpoint occurred in 2 patients (1%) both were major bleeds (non-ICH). There were no periprocedural device related injuries or clinical deteriorations. No deaths (0% mortality) were reported at 48 hours. Significant on-table improvement in hemodynamics were seen, including an average reduction in mean PA pressure of 20% (6.1 mmHg, p<0.0001) and a reduction in heart rate from a pre-procedure high of 111.9±16.9 bpm to 90.5±16.6 bpm (p<0.0001). Patients with low cardiac index (<2l/min/m
2
) experienced an 18% on table improvement (0.3 l/min/m
2
, p<0.0001). At 30-day follow-up, one patient had died, unrelated to the procedure (0.6% mortality) and 10 patients were readmitted (1 related, 9 unrelated to the procedure). Dyspnea significantly improved from a pre-procedure Modified Medical Research Council Dyspnea Scale average grade of 2.6±1.4 to 0.76±1.1 at 30 days, and 0.54±1 at 6 months (p<0.0001). In conclusion, early results demonstrate excellent safety with immediate improvements in hemodynamics and low 30-day mortality. Data analysis is ongoing and additional results will be presented at the conference.
Abstract 16636: Cardiac Microstructural Associations With Metabolic Syndrome Differ by Sex
Authors: Salto Gerran , Kwan Alan C , Osypiuk Ewa , Stantchev Plamen , Kim Elizabeth H , Hiremath Pranoti , Cheng Susan
Published: May 2021

Background:
Alterations in the orientation and integrity of myocardial fibers can be assessed using ultrasonic image analysis. The ability to detect such microstructural abnormalities may shed light on sex differences in the progression from metabolic risk factors to overt cardiac disease.

Methods:
In a community-based cohort of N=2510 adults (age 66±9 years, 56% women) without overt cardiovascular disease, we evaluated whether a novel echocardiography-based assessment of left ventricular myocardial microstructure, the signal intensity coefficient (SIC), could detect tissue-level alterations that are associated with metabolic risk factors, such as body mass index (BMI) and the metabolic syndrome.

Results:
In multivariable models adjusting for age and BMI, women had a significantly greater degree of cardiac microstructural alteration (coeff 0.15; s.e. 0.06, P=0.007) in the presence of metabolic syndrome, whereas this association was only borderline significant in men (coeff 0.11; s.e. 0.06, P=0.07) (

Figure

). Notably, there was no sex-specificity in the associations of either age or BMI with cardiac microstructure.

Conclusion:
A novel index of myocardial tissue alteration is significantly associated with presence of metabolic syndrome, even after adjusting for body size, and more prominently in women than in men. Further research is needed to examine the extent to which cardiac microstructural abnormalities may mediate the metabolic risks for cardiac disease, particularly in women.
Abstract 16648: Covid-19 at the ICU: A Multiorgan Challenge
Authors: Markl Andreas A , Schnupp Steffen , Mischke Thomas , Breuer Georg , Brachmann Johannes , Mahnkopf Christian
Published: May 2021

Introduction:
About 5% of all COVID-19 patients require intensive care, mostly because of respiratory failure. Little is known about concomitant multi-organ manifestation under these circumstances.

Methods:
Retrospective observational study using routine data sets of 13 COVID-19 patients requiring mechanical ventilation in the Regiomed Hospital Coburg, Germany, between March 1
st
and June 15
th
, 2020.

Results:
Of 13 patients eligible for this study, all were intubated and ventilated mechanically, with signs of infiltration in chest radiographs. 4 suffered from renal failure and needed dialysis; 3 of these patients died, but none without renal failure. Proteinuria was found in all and microhematuria in all but one patients tested (n=11). All developed metabolic alkalosis (BEmax 9.75±0.99, mean ±SEM), and 6 afterwards polyuria (6.75 ±2.45l per day); both conditions resolved in all surviving patients but 1 spontaneously and were not related to prior renal failure. Liver enzymes were elevated in all patients (γGT 506 ±78U/l), but bilirubin levels only in 4; 2 of these died shortly after. Bacterial superinfection was found in 8 patients, and in all 3 ones finally dying. Rhabdomyolysis affected 12 patients (CKmax 1604±542U/l) and resolved later. All patients had slightly elevated troponin T (0.059 ±0.013ng/ml), and 7 had elevated nt-pro-BNP levels (3566±2359pg/ml), indicating cardiac COVID-19, and elevated d-dimer levels (18.1 ±6.68mg/dl) representing disseminated intravascular coagulation. No thromboembolic was observed. The need of catecholamines was low (<1mg/h norepinephrine), as long as there was no septic complication.

Conclusions:
Our data indicate that severe COVID-19 is a multi-organ disease, even though ARDS is the leading problem; renal involvement - together with bacterial superinfection - seems to be a major risk factor for unfavorable disease development. Especially metabolic alkalosis and polyuria without overt renal failure have not been studied yet and require close clinical attention.
Abstract 16656: Drug Eluting Balloon Versus Percutaneous Transluminal Angioplasty Below the Knee Intervention for Critical Limb Ischemia: A Meta-analysis of Randomized Controlled Trials
Authors: Khalid Muhammad , El Iskandarani Mahmoud , Ramu Vijay , Donovan Michael , Forrest Terry , Helton Thomas
Published: May 2021

Introduction:
Studies have shown decrease rates of restenosis and target lesion revascularization (TLR) with drug eluting balloon (DEB) in diabetic patients with critical limb ischemia (CLI).

Hypothesis:
The aim of this meta-analysis to compare the efficacy of DEB versus Percutaneous transluminal angioplasty (PTA) below the knee peripheral intervention.

Methods:
Electronic databases including MEDLINE, ClinicalTrials.gov and the Cochrane Library were searched for all randomized controlled trials (RCTs) published until April 2020 comparing outcomes of DEB vs PTA in patients with CLI below the knee. End points were major amputation, major adverse events (MAEs), all-cause mortality, target lesion revascularization (TLR), myocardial infarction, and cerebrovascular accidents (CVA). The risk ratio (RR) with 95% confidence interval (CI) were computed and p <0.05 was considered as a level of significance.

Results:
A total of 4 RCTs (n=655) were included in the final analysis. There were no differences of major amputation (RR: 1.30; CI: 0.68-2.46; p=0.43), MAEs (RR: 0.86; CI: 0.60-1.23; p=0.41), all-cause mortality (RR: 0.91; CI: 0.69-1.19; p=0.48), TLR (RR: 0.65; CI: 0.30-1.44; p=0.29), MI (RR: 1.71; CI: 0.57-5.14; p=0.34) and CVA (RR: 0.66; CI: 0.19-2.26; p=0.50) between the 2 groups [Figure 1].

Conclusions:
There were no significant differences of major amputation and TLR for DEB versus PTA . Major adverse cardiac, cerebrovascular events and all-cause mortality were not statistically different for drug coated balloon versus PTA in the management of below knee critical limb ischemia. Further studies needed to confirm these findings.
Abstract 16657: Guideline Recommended Statin Therapy and Sex Based Cardiovascular Disease Outcomes: Data From a Multi-site Healthcare Network Primary Prevention Cohort
Authors: Saeed Anum , Zhu Jianhui , Thoma Floyd W , MARROQUIN Oscar C , Countouris Malamo E , Aiyer Aryan , Gulati Martha , Berlacher Kathryn , Michos Erin D , Nasir Khurram , Mulukutla Suresh R
Published: May 2021

Introduction:
Statin therapy has been shown to reduce ASCVD morbidity and mortality. Evidence on statin utilization per the ACC/AHA cholesterol guidelines and outcomes are limited in primary prevention cohorts of women. We investigated statin use outcomes per 10-year ASCVD risk in a large healthcare system stratified by sex.

Methods:
Statin prescription in patients without CAD (MI or revascularization) or ischemic stroke were evaluated (2013-2019). Risk categories per the ASCVD risk were defined as:
Borderline
(5%-7.4%),
Intermediate
(7.5%-19.9%) or
High
(≥20%). Guideline-directed statin intensity (GDSI), at time of first event, was defined as: “at least moderate” for
Intermediate
and
high
-risk groups. Cox regression hazard ratios (HR) [95% CI] were calculated for statin use and outcomes (MI, stroke and composite ASCVD events) stratified by gender. Interaction terms (age ≥75y and sex) were applied.

Results:
Among 159,100 women (out of 282,298 patients; mean age ~51y), 15,153 (9.5%), 26,697 (16.8%) and 10,583 (6.7%) were categorized as borderline, intermediate and high risk, respectively. Only 9,277 (35%) intermediate and 4,893 (46%) of high-risk women received any intensity of statin. High risk women (vs men) on GDSI, had lower association with CAD events (HR 0.8 [0.7-0.9]) and increased stroke risk (HR 1.2 [1.1-1.4]) (
Table).
Intermediate and high-risk women (on <GD statin or no statin) had higher stroke risk than those on GD statin
(p for interaction <0.001
). Older women (≥75y) on “no statin” (vs GD statin) had independently increased risk of CAD (HR 1.30[1.1-1.6])
(p interaction <0.001)
.

Conclusions:
In a real-world primary prevention cohort, women on statin therapy had significantly improved ASCVD outcomes and lower mortality. However, approximately one-fourth of statin-eligible women were not prescribed any statin therapy. Further research can develop healthcare system strategies to optimize under-treatment of women for ASCVD prevention.
Abstract 16665: Intracoronary Administration of Neonatal Cardiac Mesenchymal Cells Promotes Cardiac Functional Recovery in a Porcine Model of Acute Myocardial Infarction
Authors: Abdullah Mohamed , Morales David , Shah Aakash M , Levy Lauren , Saha Progyaparamita , Mishra Rachana , Sharma Sudhish , Kaushal Sunjay
Published: May 2021

Background:
The strong regenerative potential of neonatal mesenchymal stem cells (nMSCs) in animal MI models when compared to adult MSCs have been attributed to their paracrine secretions. This study determines the therapeutic potential of nMSC-based therapies in a translationally relevant animal large model.

Methods:
Yorkshire Pigs underwent a 60-minute coronary occlusion followed by reperfusion. Pigs were randomized for intracoronary administration of 10 million nMSCs (n=4), 20 million nMSCs (n=4), 2 mg/kg of TCM (n=4), 10 million nMSCs plus 2 mg/kg TCM (n=5), or placebo (n=4). The infarct size was quantified 48 hours post-infarction. Separate (10 million nMSCs plus 2 mg TCM treated and control) groups were allowed to survive for 28 days, and cardiac MRI (cMR) was performed on post- operative days 7 and 28.

Results:
After 48hrs, increasing the dose of nMSCs (20 million vs 10 million nMSCs) showed more decrease in infarct size (74+0.03% vs 83.2+0.05%,
p
=0.25). 2 mg TCM reduced the infarct size in comparison to control (60.8+ 0.09% vs 91+0.03%,
p=
0.02). Combination of 10 million nMSCs plus 2 mg TCM achieved the greater reduction of infarct size from 91+ 0.03% to 56+0.02% (
p
=0.0002). At 28 days, infarct percent mass to the left ventricle mass was significantly smaller in the combination of 10 million nMSCs and 2mg TCM than control group (3.98+1.7 % vs 13.63 + 3.9%,
p
=0.003). These combination treated animals showed an increase in stroke volume (+ 10 mL vs - 1.7 mL,
p=
0.002) and preserved LV dimensions and ejection fraction by day 28 as compared to day 7. None of the treatment groups showed any end-organ damage. The infarct zone for treated animals showed enhanced angiogenesis and reduced fibrosis, inflammation and apoptosis. Anti-apoptotic signaling molecules related to MAPK pathway are being investigated.

Conclusions:
Intracoronary infusion of nMSCs-TCM is safe, promotes the strongest cardiac and vascular regeneration by decreasing scar and improving LV function in pigs after AMI. These results provide the rationale for a subsequent translation of a combination allogenic product of nMSCs-TCM to clinical trials.
Abstract 16691: The Effect of Socioeconomic Status: Patients in the Lowest Quartile of Income May be Subject to Worse Outcomes After Major Cardiac Surgery
Authors: Chao Joshua C , Deng Xiaoyan , Okoh Alexis K , Soliman Fady K , Baxi Jigesh , Volk Lindsay , Suhotliv Amy , Ady Justin W , Russo Mark J , Lee Leonard Y
Published: May 2021

Introduction:
Racial disparities in cardiac surgery (CS) are well documented, but socioeconomic status (SES)’s role, independent of race and other factors, requires further study. Our purpose is to investigate effects of low SES on patient outcomes after CS.

Methods:
National Inpatient Sample 2010-15, was queried. Adult patients undergoing coronary artery bypass grafting (CABG), surgical aortic valve replacement (SAVR), mitral valve repair (MVRR) or replacement (MVRT) were identified. Patient & hospital characteristics, charges, and outcomes of patients in the lowest quartile of income by zip code (low SESP) and highest (high SESP) were compared, per procedure. Multivariable analysis was used to determine effects of SES on outcomes; primary was in-hospital mortality (death).

Results:
Number of procedures, low v. high SESP: CABG (30,799).
Abstract 16805: Assessing Correlation and Agreement in Activated Clotting Time (ACT) Measurement Using Hemochron Signature Elite
Authors: Aggarwal Ankita , Jain Anubhav , Bhardwaj Arjun , Choksi Nishit
Published: May 2021

Introduction & Hypothesis:
ACT is the preferred mode of assessing degree of anti-coagulation during cardiac catheterization. Studies have shown significant variability in ACT measurement with different company analysers. We aimed to assess correlation and agreement between two instruments of the same company, Hemochron Signature Elite.

Method:
Paired samples were collected before and after heparin administration for each patient. Each paired sample was collected and entered into the two instruments tagged A & B using the same syringe and at the same time.

Results:
A total of 46 samples were included in the study. There was a significant correlation between the two instruments (r= 0.92, p- value 0.02). However, the two devices had significant discordance with a mean bias of 11.1 , 95% CI 0.77 to 24.9 and limits of agreement -35.8 to 58.1. Mean ACT between the two devices was significantly different (231 vs 248, p-value 0.01). Inter-device reliability was 30%. There was a more than 10% difference in about 30% of the paired samples and more than 20% difference in 9% of the samples.

Conclusion:
Significant correlation but discordance exists in ACT measurement even between the same type of device. This may affect clinical decision making during cardiac procedures and need further investigation.
Abstract 16813: The Prevalence and Predictors of Pacing-Induced Cardiomyopathy (PICM) in Younger Patients
Authors: Li Dan L , Yoneda Zachary , Issa Tariq Z , Montgomery Jay A , Shoemaker Ben B
Published: May 2021

Background:
Pacing-induced cardiomyopathy (PICM) has been increasingly recognized as a cause of heart failure in patients with pacemakers. Thus far, clinical trials and observational studies of PICM have largely included elderly patients with mean age > 70 years. The prevalence and predictors of PICM in younger patients (age ≤ 59 years) after pacemaker implantation are not known.

Methods:
We retrospectively studied the prevalence and predictors of PICM in younger adults (18-59 years) who received single ventricular chamber or dual chamber pacemakers at Vanderbilt University Medical Center from 1986-2015. Patients without documented ventricular pacing burden, and patients with baseline left ventricular ejection fraction (LVEF) < 30% were excluded. PICM was defined as LVEF drop of ≥ 10% and LVEF < 50% during follow up in the setting of significant right ventricular pacing (≥ 20%), without alternative explanations for cardiomyopathy. Univariate and multivariable Cox proportional hazards regression models were utilized to study the factors associated with hazard of developing PICM.

Results:
A total of 325 patients were included in the study. 182 patients had high ventricular pacing (≥ 20%), which was associated with pre-existing atrial fibrillation (AF) and reduced baseline LVEF in addition to atrioventricular block (AVB) in the multivariate analysis. During the median follow up duration of 11.5 (Interquartile range 7 - 17) years, 38 patients (11.7%) developed PICM (1.3 per 100 patient-year). The median time to the development of PICM was 5 (Interquartile range 2 - 10) years. Older age (HR 2.5 for age ≥ 50 years, P = 0.013), reduced baseline LVEF (HR 2.4, P = 0.022), and AVB (HR 2.7, P = 0.007) were associated with an increased risk of PICM in the multivariate analysis. Furthermore, pre-existing AF was associated with an increased risk of PICM in patients without pre-implant AVB (HR 8.8 compared to the absence of both AF and AVB, P = 0.039).

Conclusion:
The incidence of PICM in young patients was low in this cohort of younger patients. Older age, baseline reduced LVEF, and AVB were associated with an increased risk of PICM in the young patient cohort. AF was associated with an increased risk of PICM in a subset of patients without pre-existing AVB at implant.
Abstract 16827: miR-34a Expression in Cardiac Neonatal Mesenchymal Stem Cells is Essential for Heart Regeneration
Authors: Mishra Rachana , Gunasekaran Muthukumar , Saha Progyaparamita , Fu Xuebin , Arfat Yasir M , Abdullah Mohamed , Davidson Lauren , Shah Aakash , Sharma Sudhish , Kaushal Sunjay
Published: May 2021

Advancing chronological age negatively impacts the functional activity of stem cell-based therapies. Despite the early promise stem cell mediated differentiation into selected cellular lineages when injected in the chosen organ, stem cell’s functional unit is the secretome that is directly modulated by chronological aging. However, the precise mechanism driving the secretome potency is unknown. Here we show a single miRNA, influenced by aging, drives the potency of the stem cell secretome at multiple cellular levels by increasing exosome production and directly increasing the levels of independent stem cell paracrine factors. We show differential miRNA microarray analysis of cardiac neonatal mesenchymal stem cells (nMSCs) and adult MSCs (aMSCs) identified miR34a among the top ten differentially expressed miRNAs present in aMSCs but not nMSCs. We demonstrated that miR34a singly inhibits the aMSC’s regenerative abilities in the acute myocardial infarct model by decreasing the secretome potency when compared to nMSCs in knockdown studies of miR-34a. Moreover, overexpression of miR-34a in nMSCs reversed the strong regenerative properties of nMSCs by decreasing their secretome potency. Mechanistically, miR-34a regulates the secretome potency firstly by decreasing Heat Shock Factor 1 (HSF1) levels that directly decreases exosome production and alters the exosome cargo to a less-regenerative phenotype, and secondly by directly inhibiting transcriptional levels of critical stem cell paracrine factors. These results implicate the miR34a-HIF1 pathway as a critical pathway controlling the secretome of MSCs impacted by advancing chronological age. Our findings further advance miRNA-based therapeutic approaches to cardiac repair and heart regeneration by indicating how to improve the quality of secretome of transplanted stem cells.