bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy
Authors: Aziz Miriam C. , Schneider Patricia N. , Carvill Gemma L.
Published: May 2021

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic SCN1A variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.
Risk of Infection after Deep Brain Stimulation Surgery with Externalization and Local-Field Potential Recordings: Twelve-Year Experience from a Single Institution
Authors: Feldmann Lucia K. , Neumann Wolf-Julian , Faust Katharina , Schneider Gerd-Helge , Kühn Andrea A.
Published: May 2021

Introduction: Deep brain stimulation (DBS) has been an established surgical procedure in the field of functional neurosurgery for many years. The experimental electrophysiological method of local field potential (LFP) recordings in postsurgically externalized patients has made substantial contributions to the better understanding of pathophysiologies underlying movement disorders. As interest in LFP recordings for the development of improved stimulation strategies increases, this study’s aim was to provide evidence concerning safety of this research method, in a major DBS center. Methods: We retrospectively analyzed incidence and infection characteristics in adult patients who underwent two-staged DBS surgery with temporary externalization of leads in our center between January 2008 and November 2019. We focused on whether patients had participated in LFP recordings, and evaluated incidence of infections at 3 months and 1 year after the surgery based on medical records. Infection rates were compared to major DBS studies and reports focusing on the risk of infection due to externalization of DBS leads. Results were visualized using descriptive statistics. Results: Between January 2008 and November 2019, DBS surgery was performed in 528 patients (389/139 patients in the LFP/non-LFP group), mainly for movement disorders such as Parkinson’s disease (308), dystonia (93), and essential tremor (86). Of the patients, 72.9% participated in LFP recordings. The incidence of infections in the acute postsurgical phase (3 months) was 2.46% and did not differ significantly between the LFP group (1.8%) and the non-LFP group (4.32%). The overall incidence after 1 year amounted to 3.6% (19 patients) with no difference between LFP/non-LFP groups. Incidence rates reported in the literature show a large variety (2.6–10%), and the incidence reported here is within the lower range of reported incidences. Discussion/Conclusion: This study demonstrates that DBS is a surgical procedure with a low risk of infection in a large patient cohort. Importantly, it shows that LFP recordings do not have a significant effect on the incidence of infections in patients with externalization. With a representative cohort of more than 380 patients participating in LFP-recordings, this underlines LFP as a safe method in research and supports further use of this method, for example, for the development of adaptive stimulation protocols.
Living Well with Kidney Disease by Patient and Care-Partner Empowerment: Kidney Health for Everyone Everywhere
Authors: Kalantar-Zadeh Kamyar , Li Philip Kam-Tao , Tantisattamo Ekamol , Kumaraswami Latha , Liakopoulos Vassilios , Lui Siu-Fai , Ulasi Ifeoma , Andreoli Sharon , Balducci Alessandro , Dupuis Sophie , Harris Tess , Hradsky Anne , Knight Richard , Kumar Sajay , Ng Maggie , Poidevin Alice , Saadi Gamal , Tong Allison ,   for the World Kidney Day Steering Committee
Published: May 2021

Living with chronic kidney disease (CKD) is associated with hardships for patients and their care-partners. Empowering patients and their care-partners, including family members or friends involved in their care, may help minimize the burden and consequences of CKD-related symptoms to enable life participation. There is a need to broaden the focus on living well with kidney disease and re-engagement in life, including an emphasis on patients being in control. The World Kidney Day (WKD) Joint Steering Committee has declared 2021 the year of “Living Well with Kidney Disease” in an effort to increase education and awareness on the important goal of patient empowerment and life participation. This calls for the development and implementation of validated patient-reported outcome measures to assess and address areas of life participation in routine care. It could be supported by regulatory agencies as a metric for quality care or to support labelling claims for medicines and devices. Funding agencies could establish targeted calls for research that address the priorities of patients. Patients with kidney disease and their care-partners should feel supported to live well through concerted efforts by kidney care communities, including during pandemics. In the overall wellness program for kidney disease patients, the need for prevention should be reiterated. Early detection with a prolonged course of wellness despite kidney disease, after effective secondary and tertiary prevention programs, should be promoted. WKD 2021 continues to call for increased awareness of the importance of preventive measures throughout populations, professionals, and policy makers, applicable to both developed and developing countries.
Abstract 12540: Neural Crest Cell-derived Wnt5a Regulates Planar Cell Polarity in Cranial Second Heart Field Progenitor Cells
Authors: Toubat Omar , De Zoysa Prashan , Choi Jongkyu , Harvey Drayton , Sucov Henry , Subramanyan Ram Kumar
Published: May 2021

Introduction:
Wnt5a is a known regulator of planar cell polarity (PCP) signaling in second heart field (SHF) progenitor cells. It is generally believed that Wnt5a ligands are secreted by the SHF; however, SHF-specific conditional deletion of Wnt5a does not recapitulate outflow tract (OFT) defects observed in global Wnt5a mutants.

Hypothesis:
Given the proximity and interaction between neural crest cells (NCC) and cranial SHF that contributes to the developing OFT, we hypothesize that NCC may serve as an additional source of Wnt5a for SHF progenitors.

Methods:
Wnt5a was conditionally deleted in the neural crest using transgenic Wnt1-cre mice. Embryos were harvested from control and mutant litter mates and immunofluoresence, in situ hybridization, and hematoxylin-eosin stains were performed on histologic sections using standard techniques. India ink injections were performed to evaluate pharyngeal arch artery and outflow tract morphology in whole mount embryos.

Results:
Wnt1-cre driven conditional deletion of Wnt5a in NCC did not impact NCC survival or migration into the developing OFT. However, SHF cells in mutant E10.5 embryos showed altered PCP signaling with reduced phalloidin and laminin expression. The resulting loss in polarized directional movement of the SHF led to reduced incorporation into and elongation of the developing OFT. The shortened OFT was mal-aligned resulting in fully penetrant double outlet right ventricle (DORV) at E14.5. In addition, maturation of pharyngeal arch arteries was also impaired such that all mutants express pharyngeal arch artery defects, including aortic arch abnormalities and aberrant right subclavian artery. In contrast, there was no observed effect on PCP in the more caudal SHF cells, and none of the mutant embryos had inflow tract or venous pole defects.

Conclusions:
Our results demonstrate that NCC are a novel source of Wnt5a. NCC-derived Wnt5a is critically required to regulate PCP signals in the most cranial SHF regulating the development of the OFT and pharyngeal arch arteries.
Abstract 12567: Circulating Factors Induce Cardiomyopathy After Burn Injury
Authors: Wen Jake J ,   Claire B. Cummins,   Bartosz Szczesny,   Ravi S. Radhakrishnan
Published: May 2021

Introduction:
Our previous results
in vivo
indicated PDE5-cGMP-PKG was involved in burn-induced heart dysfunction and PDE5A inhibitor restored the dysfunction. It’s unknown if circulating factors after burn would injure cardiomyocytes.

Hypothesis:
Circulating factors released after burn induce cardiomyopathy.

Methods:
Human cardiomyocytes (AC16) were treated with sham-serum, burn-serum (24 hpb-serum) and burn/sildenafil-serum (24 hpb/SIL). We performed cut-edged biochemistry technologies and Illumina RNA sequencing (RNA-seq) in this study. GraphPad Prism 8.4.2 was used for statistics.

Results:
We found a significant decrease of cGMP level and an increase of cTN1 in 24 hpb-serum group. Treatment with the PDE5A inhibitor Sildenafil completely reversed this change similar to our
in vivo
work. To understand what bioactive molecules would be involved in the alterations by burn injury, human cardiomyocytes (Ac16) were employed to test the cardiomyocyte response to burn-induced circulating factors. We observed that 24 hpb-serum significantly 1) decreased cell viability and cell proliferation; as well as 2) increased cell cytotoxicity, cell apoptosis and cell ROS production. We also found 24 hpb-serum resulted in cell mitochondrial dysfunction by decreasing ATP production and mitochondrial membrane integrity/potential and increasing mitochondrial ROS. Seahorse and O2K approaches confirmed 24 hpb-serum-induced cardiomyocyte mitochondrial dysfunction as evidenced by decreases of mitochondrial basal respiration, proton leak, ATP production, and maximal respiration. 24 hpb/SIL serum rescued 24 hpb serum-induced Ac 16 cell response, at least partially. Advanced bioinformatic analyses identified 1415 upregulated genes and 1091 downregulated genes in 24 hpb-serum group and 776 upregulated genes and 113 downregulated genes restored in 24 hpb/SIL-serum group. We also analyzed and validated the differentially expressed genes.

Conclusions:
Our study not only confirmed burn induced heart dysfunction, but also provided evidence for understanding the pathogenic mechanism of circulating factors released after burn injury and preliminary genomic evidence for the mechanism for cardiomyopathy after burn injury.
Abstract 12623: Vascular Regenerative Capacity: A Window into the Pathobiology of Obesity Paradox
Authors: Mehta Anurag , Meng Qi , Desai Shivang , D'Souza Melroy , Ho Annie , Islam Shabatun , Dhindsa Devinder S , Nayak Aditi , Alkhoder Ayman , Hooda Ananya , Varughese Anil , Ahmad Syed , Mokhtari Ali , Hesaroieh Iraj , Sperling Laurence , Ko Yi-An , Waller Edmund , Quyyumi Arshed A
Published: May 2021

Introduction:
Obese patients (BMI≥30 kg/m
2
) with CAD have better outcomes as compared with non-obese patients, but the underlying pathobiology is unclear.

Hypothesis:
Obesity is directly associated with vascular regenerative capacity, measured as circulating progenitor cell (CPC) count, and this association provides insight into obesity paradox pathobiology.

Methods:
CPCs were enumerated by flow cytometry as CD45
med+
cells expressing CD34+, CD133+, and CXCR4+ epitopes in 672 asymptomatic individuals (50 y, 66% women, 23% Black, 28% obese) and 1,277 patients with CAD (66 y, 39% women, 22% Black, 39% obese). Association of obesity with CPC counts was analyzed using multivariable-adjusted linear regression models. Association of obesity and CPCs with cardiovascular death/myocardial infarction events over 3.5-y follow-up was studied using Kaplan-Meir survival curves and Cox models.

Results:
Obesity was independently associated with 16-34% higher CPC count (CD34+, CD34+/CD133+, and CD34+/CXCR4+) in asymptomatic individuals. This association was not attenuated after adjusting for measures of systemic inflammation, insulin resistance, or insulin secretion. Cardiorespiratory fitness and android fat only partly attenuated the obesity-CPC relationship. In patients with CAD, obesity was independently associated with 8-12% higher CPC counts, and with 30% lower outcome risk. Lower CPC counts were associated with outcome risk in obese patients. Obese patients with high CD34+ count (≥median) were at a lower risk, while obese participants with low counts (<median) were at a similar risk as compared with non-obese patients with high counts. The highest risk was observed in non-obese patients with low counts. Similar results were observed with CD34+/CD133+ and CD34+/CXCR4+ cells.

Conclusions:
Obesity is directly associated with vascular regenerative capacity, and the obesity paradox in CAD is observed in obese patients with high, but not low, CPC counts.
Abstract 12627:
I
Na
Remodeling and Conduction Deficits in a Murine Model of Human
LMNA
-R545H Mutation
Authors: Wu Adonis Z , Wang Cheng , Spoonamore Katie , Everett Thomas , Chen Zhenhui , Field Loren J , Vatta Matteo , Ai Tomohiko , RUBART Michael , Chen Peng-sheng
Published: May 2021

Introduction:
We have identified a
de novo
mutation of
LMNA
(
LMNA
-R545H) in a 34-year-old man with high-grade atrioventricular block. Studies in HEK-293 cells showed that
LMNA
-R545H reduced the amplitude and resulted in a shift in gating kinetics of the voltage-gated sodium current (
I
Na
). These results have not been confirmed in cardiomyocytes.

Hypothesis:
(1)
LMNA
-R545H mutation replicates the electrocardiogram (ECG) phenotypes in vivo and (2) there is downregulation of
I
Na
in cardiomyocytes.

Methods:
We used CRISPR/Cas9 to generate a knock-in mouse model with
LMNA
-R545H mutation. Isolated cardiomyocytes were used for whole-cell voltage-clamp studies of
I
Na
.

Results:
Panel (A) shows P, PR, QTc intervals were significantly prolonged and the standard deviation (SD) of the RR intervals was increased during anesthesia in
Lmna
(R545H+/+)
but not in
Lmna
(R545H+)
mice compared with the wild-type control littermates (WT, N=5-8). In Langendorff perfused hearts, the sinus node recovery time (SNRT) and effective refractory period (ERP) were significantly prolonged in the
Lmna
(R545H+/+)
compared with both WT and
Lmna
(R545H+)
.
Lmna
(R545H+/+)
cardiomyocytes showed decreased
I
Na
current density (-20.1±2.3 pA/pF vs. -30.3±3.9 pA/pF, -40 mV, n=7-8, p<.05, Panel B) and prolonged the recovery time constant from
I
Na
inactivation (τ, 36.3±2.2 ms vs. 22.9±1.6 ms, each n=5, p<.05, Panel C). There were no difference in Nav1.5 protein and mRNA levels between the
Lmna
(R545H+/+)
and WT hearts.

Conclusions:
Homozygous
LMNA
-R545H mutation leads to reduced
I
Na
, prolonged PR and QTc intervals, and increased sinus arrhythmias.
Abstract 12667: Racial Disparities in Emergency Care of Patients With Suspected ACS Undergoing Cardiac CT Angiography: Insights From Romicat II and ACRIN-PA
Authors: Schlett Christopher L , Mayrhofer Thomas , Hallett Travis , Hollander Judd , Ferencik Maros , MILLER Chadwick D , Bittner Daniel , Chang Anna , Janjua Sumbal A , Addison Daniel , Nagurney John t , Uldeson James , Lu Michael T , Truong Quynh A , Woodard Pamela K , Singh Harjit , Bamberg Fabian , Litt Harold I , Hoffmann Udo
Published: May 2021

Introduction:
A disparity in health outcomes between black and white patients with coronary artery disease (CAD) has also been reported with pathophysiological differences in CAD and racial disparities in providing health care as potential explanations.

Hypothesis:
To determine racial disparity in emergency care of patients with suspected acute coronary syndrome (ACS) undergoing cardiac CT angiography (cCTA), which provides knowledge of underlying CAD status.

Methods:
We combined patient level data of the ACRIN-PA 4005 (American College of Radiology Imaging Network, Pennsylvania) and ROMICAT II (Rule Out Myocardial Infarction using Computer Assisted Tomography) trials, which enrolled patients presenting with suspicion of ACS who were randomized to cCTA as a first diagnostic test at 14 US sites. Sample was restricted to subjects with known CAD status based on cCTA. Self-reported race while the race ‘Black’ were defined as “a person having origins in any of the black racial groups of Africa” and the race ‘white’ as “a person having origins in any of the original peoples of Europe, the Middle East, or North Africa”.

Results:
We included 1,191 patients (53% white, 47% black). Pretest probability for ACS was similar (TIMI score, p=0.77) between black and white patients, while black patients had lower presence and extent of CAD (calcium score: 39.3±189.3 vs. 88.2±292.1, p<0.001; obstructive CAD 8.3% vs. 17.5%, p<0.001) and ACS (4.0% vs 6.9%, p=0.03). After accounting for the underlying CAD, black patients were more likely admitted to the hospital (β: 0.29 [95%CI: 0.05-0.54-]) and were more likely to undergo additional testing (β: 0.47 [95%CI: 0.09-0.85]) while remaining management showed no significant differences.

Conclusions:
After adjustment for underlying CAD, among patients in the ED with suspicion of ACS, those who are black received more downstream testing and were more frequently admitted to hospital than white patients.
Abstract 12675: Comprehensive Analysis of Cardiomyopathy and Arrhythmia Genes Yields Unanticipated Molecular Diagnoses
Authors: Callis Tom , Morales Ana , Truty Rebecca , Vatta Matteo , Regalado Ellen , Rojahn Susan , Esplin Ed , Nussbaum Robert
Published: May 2021

Introduction:
Professional societies recommend genetic testing to improve diagnosis and inform management of inherited cardiovascular disease, yet genetic testing is not widely utilized in cardiovascular practice. To reduce barriers to genetic testing and facilitate following of existing guidelines, we initiated a program of sponsored genetic testing with genetic counseling at no cost to patients suspected of having a genetic arrhythmia or cardiomyopathy. Here, we describe unanticipated molecular diagnoses provided by a comprehensive analysis of cardiomyopathy and arrhythmia genes.

Methods:
With IRB approval, de-identified genetic and clinical data provided by ordering clinicians were reviewed from 1,606 individuals referred for testing through the sponsored, no-charge Detect Cardiomyopathy and Arrhythmia genetic testing program between July 2019 and January 2020. Testing consisted of a cardiomyopathy and arrhythmia panel of up to 150 genes detecting single nucleotide, small indel, and exon-level deletion and duplication variants.

Results:
Overall, 20.5% (329/1606) of patients had a pathogenic or likely pathogenic (P/LP) variant identified. The most common reasons for referral were hypertrophic cardiomyopathy (40%), dilated cardiomyopathy (24%), and long QT syndrome (13%). The diagnostic yield was 25% (130/527) among patients whose healthcare provider reported a high or moderate index of clinical suspicion for a genetic cardiomyopathy, of whom 2% (2/130) had P/LP variants only in the arrhythmia gene
KCNQ1
. Conversely, among patients with a high or moderate index of clinical suspicion for a genetic arrhythmia, the diagnostic yield was 20% (28/137), of which 18% (5/28) had P/LP variants only in the cardiomyopathy-associated genes
MYBPC3
(2) and
TTR
(3).

Conclusions:
These data demonstrate that comprehensive genetic testing, without cost as a barrier, identifies clinically-relevant variants in 1 in 5 suspected cardiomyopathy or arrhythmia patients. Notably, genetic testing with a multi-condition panel yielded unanticipated molecular findings likely to change clinical management in up to 18% of genetically-positive patients. These unanticipated findings would have likely been missed by targeted, disease-specific panels.
Abstract 12676: Regular Intake of Pepper Decreases Cardiovascular Mortality: A Meta-Analysis
Authors: Upadhaya Sunil , Madala Seetharamprasad , Tiwari Kanchan
Published: May 2021

Introduction:
Cardiovascular disease is one of the leading causes of morbidity and mortality. Spice consumption has been shown to be beneficial on lipid and fasting glucose profile. However, there is no clear evidence regarding long-term effects of spice consumption.

Methods:
Systematic electronic search of PubMed and EMBASE databases was performed for studies, both randomized and non-randomized, that studied association of pepper consumption with total and cause-specific mortality. A random-effects model was used to calculate hazard ratio (HR).

Results:
Our search identified 4 observational studies (259,184 participants in regular pepper consumption group and 305,563 participants in low or no pepper consumption group). Regular pepper consumption was associated with significant reduction in all-cause mortality (HR: 0.87 [0.84-0.91], I
2
= 25%, p value <0.00001) (Figure 1). In addition, pepper consumption was associated with significant reduction in cardiovascular mortality (HR 0.84 [0.77-0.91], I
2
= 66 %, p value < 0.0001) (Figure 2), mortality related to ischemic heart disease (HR: 0.76 [0.66 -0.87], I
2
= 0%, p value = 0.0001) and cancer (HR: 0.91 [ 0.85-0.97], I
2
= 0%, p value = 0.003). However, stroke related mortality was similar in both groups (HR: 0.78 [0.56-1.10], I
2
= 61%, p value = 0.15).

Conclusions:
This study showed that regular intake of pepper significantly decreases rates of all-cause, cancer-related and cardiovascular mortality.
Abstract 12689: Targeted Exon Sequencing of Lipid-related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia
Authors: Okada Takeshi , Koseki Masahiro , Nishida Makoto , Tanaka Katsunao , Inui Hiroyasu , Kanno Kotaro , Saga Ayami , Ohama Tohru , Kujiraoka Takeshi , Hattori Hiroaki , Yamashita Shizuya , Sakata Yasushi
Published: May 2021

Background:
Familial hypercholesterolemia (FH) is at high risk of premature coronary artery disease (CAD). Japan Atherosclerosis Society (JAS) has published original criteria for FH. Patients are diagnosed clinical FH if at least 2 of the following criteria are satisfied: i) LDL-C ≥ 180 mg/dL, ii) Tendon/ skin xanthomas, iii) History of FH or premature CAD within 2nd degree blood relatives. Although it is easy to apply these criteria for FH-suspected patients, in fact, we are not sure whether other lipid-related genes may be overlapped in addition to those of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9).

Methods and Results:
Ninety-one heterozygous FH (HeFH) patients in Osaka University Hospital, who met the clinical FH criteria of JAS were enrolled after obtaining informed consent. Genomic DNA for each patient was extracted from peripheral blood cells. Targeted exon sequencing was performed to investigate 36 lipid-related genes including conventional FH genes. We have defined pathogenic variants if they fulfilled i) rare protein truncating variants, ii) rare damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 91 HeFH patients (52.9 ± 14.7 years), 41 patients (45.1%) were males. We have identified LDLR pathogenic variants in 61 patients (67.0%) and PCSK9 variants in 1 patient (1.1%). Among these 62 patients, 22 patients (35.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 1 patient, apolipoprotein E4 (APOE4) in 10 patients, ATP-binding cassette subfamily G member 5 (ABCG5) in 2 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 10 patients. As for remaining 29 patients without conventional FH gene variants, 13 patients (44.8%) have pathogenic variants of other lipid-related genes, which include APOE4 in 11 patients, apolipoprotein E5 (APOE5) in 1 patient, and variants of ABCG5 in 1 patient.

Conclusion:
We have identified several variants of lipid-related genes in addition to conventional FH genes in HeFH patients diagnosed according to JAS criteria. These variants may affect the atherogenicity of patients and selection of medication.
Abstract 12692: Overexpression of Myocardial Inducible Nitric Oxide Synthase Exacerbates Cardiac Dysfunction and Beta-Adrenergic Desensitization in Streptozotocin-Induced Diabetic Mice
Authors: Liu Yixi , Cheng Che , Sun Xiaoqiang , Cao Jing , Zhou Peng , Herrington David , Kitzman Dalane , Zhao David , Cheng Heng Jie
Published: May 2021

Background:
Recent evidence links impaired nitric oxide (NO) signaling pathway in the pathogenesis of diabetes-induced cardiac dysfunction. However, the different nitric oxide synthases (NOS) isoforms involved in this pathology are controversial. Recent reports have shown that in failing myocardium, increased inducible NOS (iNOS) contributes to the attenuation of β-adrenergic receptor (AR)-mediated inotropic effect. The alteration and functional significance of cardiac iNOS in diabetic cardiomyopathy (DCM) are unclear. We assessed the hypothesis that increased cardiomyocyte iNOS expression and stimulation may inhibit myocyte contraction, relaxation, [Ca
2+
]
i
transient ([Ca
2+
]
iT
), and depress its response to β-AR stimulation, thereby directly contributing to the functional impairment in DCM.

Methods:
Left ventricular (LV) myocyte protein levels of 3 NOS and myocyte functional responses were evaluated in 2 groups of wild-type female mice (11/group): control and DCM-induced by streptozotocin (STZ) (at 10 weeks after receiving 200 mg/kg STZ, ip). In DCM, we further assessed myocyte contractile and ([Ca
2+
]
iT
) responses to β-AR stimulation by isoproterenol (ISO, 10
-8
M) with and without pretreatment of myocytes with a selective iNOS inhibitor, 1400W (10
-5
M).

Results:
Compared with controls, DCM myocytes had significantly increased iNOS (1.76 vs 1.03) with decreased eNOS (0.29 vs 0.34), but relatively unchanged nNOS (0.17 vs 0.18). These changes were followed by significantly reduced basal cell contraction (dL/dt
max
, 73.8 vs 140.7 μm/s), relaxation (dR/dt
max
, 61.5 vs 121.1 μm/s) and [Ca
2+
]
iT
(0.17 vs 0.20). ISO-stimulated increases in dL/dt
max
(32% vs 59%), dR/dt
max
(30% vs 55%) and [Ca
2+
]
iT
(17% vs 31%) were also significantly reduced. Moreover, in DCM myocytes, pretreatment with 1400W markedly improved myocyte basal contraction (128.0 μm/s) and relaxation (111.7 μm/s). The ISO-induced increases in dL/dt
max
(55%), dR/dt
max
(52%), and [Ca
2+
]
iT
(29%) were also significantly augmented.

Conclusions:
Our findings indicate that myocardial iNOS is activated in diabetic mice and suggest that increased iNOS expression contributes to depressed myocardial contractility, impaired [Ca
2+
]
i
regulation and β-adrenergic hyporesponsiveness.
Abstract 12902: Aerobic Exercise Adherence Among Older People Living With HIV
Authors: Irwin Crista L , Waldrop Drenna , Murden Raphiel , Gary Rebecca
Published: May 2021

Introduction:
HIV+ persons are twice as likely to develop cardiovascular disease (CVD) than non-HIV infected persons. CVD is now a major cause of morbidity and mortality in OPLWH. AHA guidelines recommend moderate to vigorous physical activity (MVPA) of at least 150 minutes per week, but less than 50% of the general population meets this standard. Little is known about exercise adherence among OPLWH over longer study periods.

Hypothesis:
The purpose of this study was to examine preliminary results of adherence to a moderate-intensity exercise regimen among OPLWH randomized to a Let’s Move aerobic exercise intervention (n=76).

Methods:
Participants (mean age 55, +/-5 (65% male, 82.4%AA) were HIV+ persons with at least 2 CVD risk factors. All participants underwent baseline maximal exercise testing (V0
2max
). Based on maximal heart rate obtained, an individualized, moderate-intensity aerobic exercise prescription was calculated at 60-70% of HR reserve. MVPA was measured in both number of steps/week and number of days/week participants met 60-70% max HR for at least 60 minutes/day. Participants wore activity trackers that were remotely monitored by a secure API data collection platform weekly from BL to 3-months. Based on data collected, real-time feedback was provided on exercise performance including follow-up calls using motivational interviewing (MI) counseling methods.

Results:
Mean steps/week over 3 months was 43,993 (SD 33376). 75% (n=57/76) walked at least an average of 30K steps/week over 3 months, 13% (10/76) walked more than 70K steps/week. 77.6% (n=59/76) met the AHA guideline, >150 minutes of MVPA/week. 59% (n=45/76) maintained an average of at least 60% max HR for a minimum of 240 min/week. 57.9% (44/76) participants attained 70% max HR at least 240 min/week.

Conclusions:
OPLWH engaged in a MI supported aerobic exercise program for 3 months exceeded the recommended 150 minutes/week of moderate-intensity exercise by 27.6% more than the general population. HIV+ participants are willing to engage in aerobic exercise which may be a cost-effective approach to reduce CVD risk in this population.
Abstract 12931: Myocardial Regeneration in End-stage Heart Failure After Left Ventricular Unloading
Authors: Pana Tiberiu , Kepinski Ingrid , Fairbourn Adam , Afzal Aneela , Savla Jainy , Mammen Pradeep P , Drazner Mark H , Subramaniam Rathan , Olson Eric N , Drakos Stavros G , Zaha Vlad G , Sadek Hesham A
Published: May 2021

Introduction:
Left Ventricular Assist Devices (LVAD) decrease cardiac mechanical work and metabolic demand and may decrease cardiomyocyte oxidative stress, followed by cell cycle re-entry and cell regeneration. We tested whether LVAD long-term support is associated with myocardial regeneration.

Methods:
Viability fluorodeoxyglucose (18FDG) - positron-emission tomography scans were performed >3 months after LVAD implantation and every 6 months thereafter. 4 patients aged 18-70 with end-stage non-ischemic (NICM, n=3) or ischemic cardiomyopathy (ICM, n=1) were included. Low metabolic activity myocardial regions of interest (ROI) at <15th percentile of relative 18FDG signal intensity were identified on the baseline scan. Global signal and co-registered low-intensity ROIs were analyzed on subsequent scans vs. baseline.

Results:
LV ejection fraction ranged 0-35% at baseline. Two patients (LVAD speed 2660 rotations per minute - RPM, output 3.4-4.1 and 5.6-5.9 liters per minute (LPM), respectively) underwent 2 scans before cardiac transplantation, exhibiting borderline increased global signal (1-4%) and significantly increased 18FDG signal in the baseline low-intensity ROI on the follow-up scan (67.7, 75.7%). The other 2 patients (LVAD parameters: 5600 RPM/ 4.6-5.8 LPM; 9200 RPM/ 4.3-4.8 LPM) exhibited decreased global 18FDG signal (10-16%) and increased signal in the co-registered baseline low-intensity ROIs (1.7-21.5%) (Figure).

Conclusions:
LVAD long-term support is associated with a global decrease in myocardial 18FDG uptake signal over time, and with increased viability signal in baseline low-intensity ROIs, suggestive of myocardial regeneration in metabolically inactive regions. Future research is required to identify patient subgroups that are most likely to exhibit high regeneration potential upon long-term LVAD support.
Abstract 12932: The ABO Blood Group of Donor Hearts Determine the Impact of Cold Preservation Duration on Heart Transplant Outcomes
Authors: TANG Paul C , Haft Jonathan W , LEI IENGLAM , Wang Zhong , Chen Eugene , Abou el ela Ashraf , Pitt Bertram , Aaronson Keith D , Pagani Francis D
Published: May 2021

Background:
Tolerance of donor hearts of different ABO blood types to allograft ischemic time has not been previously examined.

Objectives:
We determined the impact of allograft ischemic time on heart transplant outcomes with differing ABO donor organ types.

Methods:
We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous variables were analyzed with t-test and categorical variables were compared with Chi-squared test. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables.

Results:
Comparing allograft ischemic times <4 hours (hr, n=6579) versus ≥4hr (n=25,875), the odds ratio (OR) for death at 15 years following prolonged allograft ischemic time (≥4hrs) for blood type O, A, B, and AB were 1.106 (P<0.001), 1.062 (P<0.001), 1.059 (P=0.062), 1.114 (P=0.221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for allograft ischemic times ≥4 hours (OR=1.164, P<0.001). Following propensity matching, O donor hearts continued to have worse survival if preserved for ≥4hrs (OR=1.137, P=0.008), but not if allograft ischemic time was <4hrs (OR=1.042, P=0.113). In a matched group with ≥4hrs of allograft ischemic time, patients receiving O donor organs were more likely to experience death from primary allograft dysfunction (2.5% vs 1.7%, P=0.052) and chronic allograft rejection (1.9% versus 1.1%, P=0.021). No difference in death from primary allograft graft dysfunction or chronic allograft rejection was seen with <4hr of allograft ischemic time (P>0.150).

Conclusions:
Compared with non-O hearts, transplantation with O donor hearts stored for ≥4hrs leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when extended cold preservation times are anticipated.
Abstract 12934: Valve, Ventricle, Vessel or Virus: Who is the Shocking Culprit?
Authors: Tyagi Sudhi , Patil Harshal , Miles Robert , Siegel Elizabeth , Allana Salman , Salinger Michael , Mason Peter , Rosenblum Andrew
Published: May 2021

Introduction:
Determining the etiology of dyspnea in patients with structural heart disease can be challenging, especially in the current era with high prevalence of COVID-19. Our case highlights the importance of evaluating bioprosthetic valve function in the setting of a change in clinical status.

Case:
An 82 year old female with surgical coronary revascularization and bioprosthetic aortic valve replacement in 2003 presented with dyspnea. Her evaluation revealed hypoxemia, leukocytosis and a chest x-ray supportive of viral infection when the local prevalence of both COVID-19 and influenza were at their peak. She was admitted to the intensive care unit with impending respiratory failure most likely from an infectious etiology. Echocardiogram revealed an ejection fraction (EF) of 25% and severe prosthetic aortic regurgitation with a pressure half time of 117ms (
Figure
). Six months prior, she had normal EF and normal prosthetic valve function. Interestingly, she lacked a wide pulse pressure, murmur of aortic insufficiency, and other characteristic exam findings of valvular dysfunction. The patient rapidly deteriorated into cardiogenic shock. Following urgent evaluation for transcatheter aortic valve replacement, she had successful valve-in-valve deployment of a 23mm Edwards S3 Ultra valve. Her hemodynamic parameters improved immediately and she was weaned from inotropic support 1 day following valve replacement.

Conclusions:
Evaluation of prosthetic valve function is integral when a patient’s clinical condition changes. In our patient, depressed EF resulting in an elevated left ventricular end-diastolic pressure likely diminished the regurgitant fraction and the expected aortic insufficiency murmur. Periodic evaluation of prosthetic heart valve function is necessary, particularly when the patient’s clinical condition changes. Acute severe aortic regurgitation with cardiogenic shock is fatal without rapid evaluation and valve replacement.
Abstract 12942: Association of Exercise Performance With Hemodynamic and Imaging Parameters in Fontan Patients
Authors: Pierick Alyson R , Kelleman Michael , Stark Megan , Vaiyani Danish , Whitehill Robert , Slesnick Timothy , Petit Christopher
Published: May 2021

Introduction:
The Fontan operation results in hemodynamic, anatomic and functional alterations in single ventricle (SV) heart disease. Studies have shown that SV patients have reduced exercise capacity. We sought to determine hemodynamic and anatomic associations with exercise capacity in our Fontan cohort.

Methods:
We performed a retrospective chart review of all patients born 2002-2012 who underwent Fontan palliation and followed in our Fontan Surveillance Program. Surveillance cardiac magnetic resonance (cMR), cardiac catheterization (cath), and exercise stress test (EST) data were collected. Primary analysis was association of cMR and cath data on EST outcomes including percent-predicted maximum oxygen consumption (ppVO
2
max) and oxygen pulse (ppO
2
Pulse).

Results:
A total of 222 patients were included, 45.5% with a systemic left ventricle (LV). Hypoplastic left heart syndrome was the underlying cardiac diagnosis in 1/3 of patients. The vast majority of the Fontan procedures performed were fenestrated, 44% extracardiac conduits and 42% with a lateral tunnel graft. A total of 185 cMRs, 274 caths, and 136 ESTs were performed. The median respiratory exchange ratio and ppVO
2
max

were 1.11 L/sec and 73% respectively, with a preserved ppO
2
Pulse of 93.5%. Results of correlational analysis are shown in the table. Over serial ESTs, patients with a single RV had a more gradual, but not significant decline in ppVO
2
max than patients with a single LV, r
s
-0.321 and -0.544 respectively (p = 0.28).

Conclusions:
While hemodynamic parameters do not correlate with EST functional endpoints, anatomic factors such as the Nakata index are associated with EST performance. Surveillance of Fontan patients should include regular cMR to assess for subtle changes in ejection fraction, pulmonary artery diameter and differential pulmonary blood flow. Multicenter longitudinal studies with protocolized timing are needed to further elucidate correlates of good exercise capacity.
Abstract 12944: Geographical Variations in Cardiovascular Health in China: A Nationwide Population-based Survey of 74,771 Adults
Authors: Zhang Mei , Shi Yu , Shi Oumin , Zhao Zhenping , Zhang Xiao , Li Chun , Huang Zhengjing , Wang Limin , Li Yichong , Li Xinhua
Published: May 2021

Background:
Cardiovascular disease is the leading cause of death in China.

Objectives:
We aimed to evaluate the levels of cardiovascular health among Chinese adults and to understand the geographic patterns based on a nationally and provincially representative survey.

Methods:
In 2015, a total of 74,771 respondents aged ≥ 20 years with no history of cardiovascular disease were randomly sampled from 298 counties/districts of 31 provinces in mainland China and were interviewed. Seven metrics, including smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose, were determined. Ideal cardiovascular health was defined as the simultaneous presence of all metrics at the ideal level. A score ranging from 0 to 14 was calculated as the sum of all seven metrics for each province. Scores for four health behaviors and four health factors were also calculated.

Results:
The age-adjusted prevalence of ideal cardiovascular health was only 1.13% among Chinese adults above 20 years old in 2015 (0.50% among men and 1.77% among women; 1.63% among urban residents and 0.68% among rural residents). The age-adjusted prevalence varied greatly across provinces, ranging from 0.05% in Qinghai to 2.97% in Heilongjiang. Ideal diet (7.4%) was the least common among seven cardiovascular health metrics and ideal blood pressure (32.2%) was the second least one. We also saw significant heterogeneity among provinces in age-adjusted cardiovascular health score, health behavior score, and health factors score. In all provinces, women had higher scores than men for cardiovascular health, health behaviors and health factors. Differences in cardiovascular health and health behavior scores between urban and rural areas were associated with levels of socio-economic development.

Conclusions:
Strategies for addressing poor cardiovascular health require geographic targeting and localized consideration.
Abstract 12952: Global Longitudinal Strain is Simple, Effective & Sensitive Assessment of Cardiac Chamber Function in Patients With Acute-phase Myocarditis
Authors: Khanna Shaun , Bhat Aditya , Chen Henry H , Gu Kennith , Gan Gary , Tan Timothy C
Published: May 2021

Introduction:
Myocarditis is an inflammatory disease process with growing clinical relevance in the current COVID-19 pandemic. Acute-phase myocarditis is known to result in subclinical changes in left ventricular (LV) function despite normal LV ejection fraction (LVEF), as assessed by myocardial deformation indices. The presence of right ventricular (RV) and left atrial (LA) subclinical dysfunction however has not been well described in current literature.

Hypothesis:
Myocarditis patients have subclinical impairment of LV, RV and LA function as assessed by global longitudinal strain (GLS) on speckle tracking echocardiography.

Methods:
Consecutive patients with clinical diagnosis of myocarditis admitted to our institution during 2013-2018 were assessed (n=76). Patients who did not meet appropriate diagnostic criteria (n=14), had impaired LVEF or prior cardiac disease (n=8) or poor transthoracic echocardiogram images (n=14) were excluded from analysis. Clinical and echocardiographic parameters were compared to age- , gender- and risk factor- matched controls. GLS was performed by two independent observers using vendor independent software (TomTec Arena, Germany v4.6).

Results:
The final cohort consisted 40 patients with myocarditis (age 44.3±16.7, 60% male) and 40 matched controls (44.5±16.6, 60% male). No significant differences in baseline clinical characteristics were observed between groups. No differences in LVEF, indexed LV mass, RV fractional area change, indexed LA volume or TR pressure gradient (p>0.05 for all) were demonstrated between the two groups. Patients with myocarditis had a lower mean LV strain (GLS%: -16.4±2.9 vs -19.7±2.7, p=0.0001), a lower mean RV Free Wall Strain (FWS) (GLS%: -22.1±4.1 vs -26.2±6.9, p=0.03) and a lower mean LA reservoir strain (GLS%: 27.5±4.6 vs. 33.7±6.3, p<0.0001) when compared to controls.

Conclusions:
Our results demonstrate the presence of significant subclinical global myocardial dysfunction despite normal traditional echocardiographic indices, in patients with acute-phase myocarditis. Routine assessment of GLS may identify such patients for early targeted cardiac therapy.
Abstract 12962: Prognostic Value of Simultaneous Hybrid
18
F-fluorodeoxyglucose Positron Emission Tomography/magnetic Resonance Imaging in Cardiac Sarcoidosis
Authors: Kiko Takatoyo , Oikawa Masayoshi , KOBAYASHI ATSUSHI , YOSHIHISA Akiomi , Yamaki Takayoshi , Takeishi Yasuchika
Published: May 2021

Background:
Cardiac magnetic resonance imaging with late gadolinium enhancement (LGE) and
18
F-fluorodeoxyglucose (FDG) positron emission tomography (PET) are widely used modalities for the diagnosis of cardiac sarcoidosis. The aim of this study was to examine the prognostic value of simultaneous hybrid
18
F-FDG PET/MRI in cardiac sarcoidosis.

Methods:
Forty-three consecutive patients with suspected cardiac sarcoidosis underwent cardiac FDG PET/MRI. The patients were categorized based on the presence or absence of LGE and/or FDG uptake in the myocardium. The end points were defined as composite of all-cause death, sustained ventricular tachyarrhythmia, hospitalization due to decompensated heart failure and a decline of left ventricular ejection fraction more than 10%.

Results:
During the median follow-up of 3.7 ± 1.3 years, there were 16 (33%) adverse events. Accumulated event rate was higher in the LGE positive group than in the LGE negative group (log-rank, P < 0.001, Figure A) Additionally, the FDG positive group showed higher adverse event rate than the FDG negative group (P < 0.001, Figure B). Furthermore, adverse event rate was highest in the both PET- and LGE-positive group among 4 groups (P < 0.001, Figure C). In the Cox proportional hazard analysis adjusted for other potential confounding factors, the presence of LGE and the presence of FDG uptake were independent predictors of adverse events (LGE: HR 11.1, 95% CI 1.3-92.4, P = 0.013; FDG: HR 4.4, 95% CI 1.4-13.2, P = 0.007) in cardiac sarcoidosis.

Conclusion:
Simultaneous cardiac PET/MRI with FDG identifies patients at higher risk for adverse events in patients with cardiac sarcoidosis.
Abstract 12969: Potential of Targeted Nanotherapy for Vascular Inflammation With Gold Nanoparticles
Authors: Kosuge Hisanori , Nakamura Maki , Oyane Ayako , Taninaka Atsushi , Shigekawa Hidemi , Chikamori Taishiro , Aonuma Kazutaka
Published: May 2021

Introduction:
Inflammation contributes to progression of both atherosclerosis and abdominal aortic aneurysms (AAA). Gold nanoparticles (GNPs) have imaging and therapeutic properties, as they can ablate cells through optical excitation. We have shown that GNPs are taken up by vascular macrophages and can be used to detect murine carotid atherosclerosis and AAA with computed tomography (CT). In this study, we evaluated GNPs for optical ablation of macrophages in vitro and ex vivo.

Methods:
Mouse macrophage cells were incubated with or without 100 or 200 μg/ml of GNPs (15 nm) for 24 hours. Ten million cells with or without GNPs were exposed to near-infrared (NIR) laser light (830 nm, pulse width 200 femtosecond) for 10-20 minutes at 400-437 mW. After optical excitation, cells were incubated for 24 hours, and the viability was measured by MTT assay. Male apoE-deficient mice were subject to continuous angiotensin II infusion via subcutaneously implanted osmotic mini-pumps (N=4). After 2 weeks, mice were injected with GNPs (10 mg/mouse) via tail vein. At 48 hours post-injection, aortas were excised. Excised aortas were scanned with micro-CT imaging system and exposed to the laser for 20 minutes at 364 mW. After optical ablation, the sections of aortas were stained with anti-caspase-3 antibody.

Results:
With the higher dose of GNPs (200 μg/ml), cell viability was significantly reduced by in vitro optical excitation for 10 minutes (Figure 1, left; p<0.05). With the lower dose of GNPs (100 μg/ml), cell viability was significantly reduced by 20-minutes excitation, although 10-minutes excitation was not sufficient to reduce cell viability (Figure 1, right; p<0.003). Ex vivo CT imaging showed the accumulation of GNPs in adventitia of aorta (Figure 2). Ex vivo optical excitation showed minimal apoptosis induction of macrophages in adventitia.

Conclusion:
Optical excitation of GNPs causes macrophage ablation and has potential for targeted nanotherapy of vascular inflammation.