bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 10686: Lack of Normal Blood Pressure Awareness Among Cardiology Clinic Patients
Authors: Mahdi Mohammed , Nagra Arshdeep
Published: March 2022

Introduction:
Hypertension is a condition of elevated blood pressure associated with significant morbidity and mortality. Normal blood pressure is defined as systolic blood pressure of <120 mm Hg and diastolic blood pressure of <80 mm Hg. Uncontrolled hypertension and patient awareness of hypertension remain large public health challenges.

Hypothesis:
We hypothesized that a significant number of patients have poor awareness of what is normal blood pressure. Patient’s unawareness of this definition could be a significant contributor to poorly controlled hypertension. Thus, we set out to assess the awareness level for normal blood pressure readings amongst patients visiting a cardiology clinic.

Methods:
This is an observational study of randomly recruited patients from a cardiology clinic located in Trenton, New Jersey. After patient consent, a questionnaire written in both English and Spanish was given to each patient. The questionnaire was in the form of a multiple-choice question with options to identify normal blood pressure reading as less than either 170/90, 140/90, 160/100, or 120/80 mmHg.

Results:
A total of 252 patients were recruited. The sample was made up of 57% women and 40% men, with a mean age of 62.7 years. Patients’ primary spoken language was English among 81% of the sample, Spanish among 13%, and other languages among 6%. The race/ethnicity of patients surveyed were Black/African American in 50% of the sample, White/Caucasian in 24%, Hispanic in 16%, Asian in 4%, and other in 6%. Among those surveyed, 35% of patients were unable to identify the normal blood pressure values, with 22% identifying “normal” blood pressure as 140/90 mm Hg, 7% identifying 160/100 mm Hg, and 6% identifying 170/90 mm Hg.

Conclusions:
Health illiteracy is common among patients with at least one cardiac problem and might be associated with poor outcome. Mass education regarding normal blood pressure values could aid in better hypertension awareness and management.
Abstract 10688: The Association of Atrial Cardiomyopathy with Ischemic Stroke is Minimally Explained by Atrial Fibrillation: The Atherosclerosis Risk in Communities (aric) Study
Authors: Maheshwari Ankit , Norby Faye L , Inciardi Riccardo M , Wang Wendy , Zhang Michael J , Soliman Elsayed Z , Alonso Alvaro , Johansen Michelle C , Gottesman Rebecca F , Solomon Scott , Shah Amil M , Chen Lin Y
Published: March 2022

Introduction:
Atrial cardiomyopathy, characterized by abnormalities in left atrial (LA) size and function, is a risk factor for atrial fibrillation (AF) and ischemic stroke. We aimed to determine if 2D-echocardiographic (2DE) LA strain and volumetric parameters are independently associated with ischemic stroke and the extent to which AF mediates this risk in the ARIC study, a community-based cohort study.

Methods:
We included 4817 ARIC participants (mean age 75; 59% women; 22% Black) and who had 2DE in 2011-13. We evaluated LA volume index (maximum, minimum), LA emptying fraction (total, passive, active), LA strain (reservoir, conduit, contractile). Incident ischemic strokes (2013-2019) were physician adjudicated after review of medical records. AF was ascertained from hospitalization discharge codes and 2-week ambulatory rhythm monitoring in 2016-17. We used multivariable Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals (CI) of LA parameters for stroke and performed mediation analyses to quantify the indirect effect of AF in these associations.

Results:
After a median follow-up of 5.9 years, each SD increment in LA reservoir stain, LA conduit strain, LA contractile strain, total LA emptying fraction, and active LA emptying fraction was associated with a percent (95% CI) decrease in stroke risk of 27 (14-38), 19 (4-32), 17 (4-29), 19 (6-31), and 14 (1-26), respectively. Greater left atrial minimum, but not maximum volume index was associated with higher stroke risk. The proportion of these associations which was mediated by AF ranged from 3-36%. Our findings remained unchanged in sensitivity analysis excluding participants with AF and on anticoagulants.

Conclusions:
The associations of LA strain and volumetric parameters with stroke are minimally mediated by AF. Future research should determine whether LA strain and volumetric analysis can guide anticoagulation for stroke prevention in people independent of AF status.
Abstract 10689: C-src Contributes to Mitochondrial Ca
2+
Uniporter Increase and Arrhythmic Risk in Ischemic Cardiomyopathy
Authors: Xie An , Kang Gyeoung-Jin , Kim Eun Ji , Polina Iuliia , Feng Feng , Jhun Bong Sook , O-uchi Jin , Dudley Samuel C
Published: March 2022

Introduction:
We have described previously an arrhythmic mechanism in nonischemic heart failure (HF) involving an increased mitochondrial Ca
2+
uptake that results in QT prolongation and lethal arrhythmias during cardiomyopathy. This arrhythmic mechanism is associated with mitochondrial Ca
2+
uniporter (MCU) tyrosine phosphorylation (p-Tyr).

Hypothesis:
Here, we determined which kinase was responsible for MCU phosphorylation in ischemic cardiomyopathy.

Methods:
Ischemic HF was induced in wild type FVB/NJ mice for three weeks by ligated left anterior descending coronary artery. Western blot, immunoprecipitation, fluorescence resonance energy transfer (FRET) and patch-clamp techniques were employed in isolated mouse cardiomyocytes.

Results:
When compared to sham hearts, the protein level of p-Src increased significantly in ischemic HF mouse hearts. In a heterologous expression system, c-Src could bind MCU and tyrosine phosphorylate MCU. This phosphorylation was blocked by a c-Src inhibitor, PP1. Overexpression of constitutive active c-Src (Src-Y527F) significantly increased MCU inward current at -160 mV. Downregulation of C-terminal Src kinase (CSK), a regulatory kinase inversely related to c-Src activity, increased p-Src, enhanced mitochondrial and SR contact, and facilitated mitochondrial Ca
2+
uptake in ischemic HF mouse cardiomyocytes. Protein expression of CaMKII, PyK2, and p-PyK2 did not change during ischemic HF. MI activated c-Src by S-nitrosylation of caveolin-1 with subsequent release of the kinase. c-Src activation was associated with APD prolongation and arrhythmia following myocardial infarction in mice. Human heart tissue showed that ischemic HF patients had significantly increased p-Src associated with increased QTc prolongation and arrhythmia.

Conclusions:
During ischemic HF, c-Src activation directly increased MCU current that contributed to QT prolongation and arrhythmic risk in ischemic cardiomyopathy.
Abstract 10691: Single Cell Florescence Imaging in Hypertrophic Cardiomyopathy Reveals a Proarrhythmic Substrate: Implications for Arrhythmogenesis and Antiarrhythmic Therapy
Authors: Moreno Jonathan , Bhagavan Druv , Damiano Ralph , Li Allie , Cresci Sharon , Huebsch Nathaniel , Silva Jonathan R
Published: March 2022

Introduction:
Hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality and remains the leading cause of sudden death in young people. Despite 5 decades of research, there is no disease modifying therapy for HCM. The cellular mechanisms leading to a proarrhythmic substrate are not yet fully elucidated but may be patient-specific. Here, we present single cell electrophysiology results of adult cardiomyocytes isolated from a cohort of HCM patients who underwent septal reduction therapy with surgical myectomy.

Methods:
Freshly isolated surgical specimens from HCM patients were enzymatically digested into single ventricular myocytes and compared to discarded wild-type (WT) donor hearts as controls. Myocytes displayed characteristic rod-shaped morphology, clear sarcolemmal ultrastructure, and intact plasma membranes without significant inclusions. After Ca
2+
readaptation and labeling with both a voltage and Ca
2+
sensitive fluorescent dye, cells were field stimulated at various pacing frequencies to obtain voltage and Ca
2+
tracings. APD restitution, response to drug therapy, and baseline data was compared to patient’s clinical data including electrocardiography, pathology, and multimodality imaging.

Results:
As compared to WT controls, HCM myocytes displayed significantly prolonged APD and Ca
2+
transients, as well as steeper APD restitution at all pacing frequencies tested. These results correlated with clinical QTc prolongation which was evident in HCM patients’ baseline ECGs that was not seen in controls. Despite genetic diversity in HCM samples, the HCM specimens appeared to share a common proarrhythmic phenotype. Finally, pathologic analysis of the myectomy specimens revealed evidence of myocyte hypertrophy, fibrosis, and cellular disarray, consistent with the clinical diagnosis of HCM.

Conclusions:
The single cell electrophysiology of HCM is markedly different than WT controls and displays a proarrhythmic phenotype. Single cell fluorescence imaging of a patient’s myocytes is a promising approach to elucidate patient specific electrophysiologic signatures and predict precision therapies for these patients.
Abstract 10694: Relationship of Serum Triglycerides with Incident End Stage Renal Disease Across Urine Albumin-to-Creatinine Ratio Subgroups and Chronic Kidney Disease Stages
Authors: Arif Yousif , Soohoo Melissa , Rizk John , Hashemi Leila , Marroquin Maria , Hsiung Jui-Ting , Edward Jessica , Streja Elani
Published: March 2022

Background:
Studies investigating serum triglycerides (TG) and renal outcomes including ESRD were mixed, and often these studies were unable to account for potential confounding for MetS components. It remains unclear how these relationships may present in patients with diabetic kidney disease and in consideration of albuminuria, or UACR.

Methods:
We studied 138,675 US diabetic veterans, with data on serum TG and UACR from 2004-2006 and follow-up until 2014. Using Cox models adjusted for clinical characteristics and laboratory markers (including UACR, body mass index, hemoglobin A1c and high-density lipoprotein), we evaluated the relationship of baseline TG with time to ESRD. All models were stratified by baseline CKD stage and baseline albuminuria stage ascertained at time of TG measurement.

Results:
The cohort was 65±11 years old, and included 28% with CKD 3A-5, and 4% with UACR >300 mg/g. The median[IQR] of TG was 146[99,217] mg/dL. In non-albuminuric patients, we observed a linear relationship between TG and transition to ESRD among non-CKD patients, yet a U-shaped relationship for CKD 3A-3B (ref: TG 120-<160 mg/dL). The relationship with TG ≥ 240 mg/dL diminished across CKD stages, where it was attenuated for CKD 4/5 patients (p-trend =0.05). In microalbuminuria patients, a trend towards an elevated risk of ESRD transition for TG ≥ 240 mg/dL was observed in CKD 3A and 4/5 only. Finally, patients with macroalbuminuria and elevated TG did not have a clear pattern in risk of ESRD across CKD stages (p-trend= 0.73). [Figure]

Conclusion:
In patients with diabetes and CKD, high TG levels predicted ESRD in CKD 3A non-albuminuria patients and in CKD 3A and 4/5 in patients with microalbuminuria. These associations were independent of glycemic control, MetS components, and medications including lipid-lowering drugs. These findings highlight the importance of investigating the impact of lipid modulating therapies specifically among patients with diabetic kidney disease.
Abstract 10695: Early Overnutrition in Rats Induces Premature Cardiac Alterations Independently of Blood Pressure: Leptin-TRH Pathway Involvement
Authors: Aisicovich Maia , Rosati Macarena Luz , Schuman Mariano , Giardina Graciela L , Landa MarÃa Silvina , Garcia Silvia
Published: March 2022

Animal models are an interesting tool to evaluate future consequences of early nutritional insults. We described in adult mice that: leptin induces cardiac cTRH, leading to cardiac damage regardless of blood pressure in hyperleptinemic Agouti. Conversely, cTRH in the ob/ob lacking leptin is similar to control and even do not have Left Ventricular Hypertrophy (LVH). Moreover, leptin restitution induces cTRH and later LVH. Also, in C57BL/6 a 3-week subanorexigenic leptin dose induced cTRH and sequent LVH. All this suggests that heart damage in obesity depends on the novel leptin-cTRH pathway. Plus, Leptin directly induces TRH in cell culture (Aisicovich 2019, AHA) To further investigate the impact of early dietary interventions in childhood, we studied rat litter size reduction, a model with a reported increase in body weight, fat, leptin, insulin and cholesterol levels (Stefanidis A, 2012) We hypothesize that leptin rise increases cTRH leading to cardiac damage, independently of hypertension. On postnatal day 4, Wistar rat litters of 11 pups at birth were adjusted to 4 male pups (overnourished ON) or 11 (control C). At weaning, we individualized rats with free access to water and standard diet up to 7 weeks old. The rise in body weight, food consumption, and fat in ON vs C (p<0.02 n=10 ANOVA) confirmed the model. There weren’t any blood pressure differences between groups, still LVH index increased (heart weight/tibia length) (p< 0.01 n=6) in ON vs C. As expected, in ON the higher leptin increased cTRH mRNA (p< 0.01 n=6) as protein [WB (p=0.05 n=3) IHQ (p<0.04 n=6)] vs C. According to cTRH actions, hypertrophic and fibrotic markers TGF-B and Collagens 1 and 3 mRNA increased (p<0.01, n=6) confirmed by IHQ and Sirius red staining (p< 0.01 n=6) Also, echocardiogram showed increases in LV end-diastolic (0.26±0.08 vs 0.61±0.07 ml
p
<0.01) and end-systolic (0.02±0.02 vs 0.11±0.01 ml
p
<0.01) volumes, and decreases in LV ejection fraction (94.5±2.2 vs 83.3±1.9 %
p
<0.01) and SF (54.4±2.6 vs 45.0±2.3 %
p
<0.02) This could be restored by cTRH inhibition as demonstrated in the cardiac infarct model (Schuman ML, 2021)
Our results point out that early overnutrition induces evident cardiac damage already at 7 weeks, independently of blood pressure and mostly driven by the leptin-TRH pathway.
Abstract 10700: Inverse Relationship Between Cerebral Blood Flow and Systemic to Pulmonary Collateral Flow in Fontans Adjusting for Brain Injury: What Goes up Must Come Down - and Visa Versa
Authors: Fogel Mark A , Donnelly Elizabeth , Crandell Ian , Hanlon Alex , Raevsky Allie , Whitehead Kevin K , Harris Matthew A , Partington Sara , Biko David M , Flynn Thomas , Nicolson Susan , Felix Wehrli , Licht Daniel , Vossough Arastoo
Published: March 2022

Introduction:
Single ventricle patients develop aortopulmonary collaterals (APC) whose flow (APCF) has been shown, in a cross-sectional study, to be inversely proportional to cerebral blood flow (CBF). Serial longitudinal CBF and APCF data in Fontan patients taking into account brain injury (BI) has never been reported. Decreased CBF may adversely impact neurodevelopmental outcome.

Methods:
A prospective longitudinal cohort of 27 Fontan patients (age 10
+
1.9 years, 74% male) underwent cardiac and brain MRIs 3-9 months after Fontan and 6.0
+
1.86 years afterwards to measure CBF, APCF and to assess BI (grouped into focal brain injury (FBI), generalized insult (GI) and hemorrhage). CBF was measured using jugular venous flow and APCF was measured by the difference between aortic flow and caval return. A multivariate linear regression model was used to assess the relationship between change in APCF and change in CBF controlling for time since Fontan, sex, and changes in BI.

Results:
Demographics, flow and BI data are shown in table 1. A strong inverse relationship was found between CBF and APCF when CBF was indexed to aortic flow and APCF was indexed to BSA (R^2 = 0.72, P<0.01). Overall, CBF decreased by 9
+
11% and APCF decreased by 0.73
+
0.67 l/min/m^2 (12% when indexed to aortic flow). CBF and APCF were significantly and inversely related when adjusting for time since Fontan, sex, and change in the visibility of BI on MRI. Each one unit increase in APCF was associated with an 8% decrease in CBF. Change in CBF was smaller for those with longer times since Fontan and was larger for males. Change in CBF was larger for those whose FBI or GI became less visible, but smaller for those whose hemorrhages became less visible. See table 2.

Conclusion:
CBF and APCF are inversely related across serial imaging, adjusting for time from Fontan, sex and BI. This may adversely impact neurodevelopment. As APCs can be embolized, this may be a modifiable risk factor. A large scale trial is warranted.
Abstract 10708: Cannabidiol Loaded Nanoparticles Exhibit an Anti-Fibrotic Effect in a Mouse Model of Non-Ischemic Heart Failure
Authors: Krishnamoorthi Muthu Kumar , Sanaee Forughalsadat , Lavasanifar Afsaneh , Bolton Anthony , Youker Keith , Bhimaraj Arvind
Published: March 2022

Introduction:
Cannabidiol (CBD) is being studied in a spectrum of ailments including cardiovascular disorders. It is also clinically prescribed for certain diseases. However, the hydrophobicity of CBD has been reported to contribute to low oral bioavailability. Here we use a polymeric nanoparticle formulation of CBD (nCBD) to overcome this limitation and evaluate its potential in heart failure (HF).

Methods:
HF was induced in 3-month old C57BL/6J mice with drinking water containing 1% NaCl and 0.3 mg/mL of L-NAME. After 1-week, subcutaneous osmotic pumps were implanted to deliver angiotensin-II at a rate of 0.7mg/kg/day for 4 weeks. nCBD was prepared using co-solvent evaporation of poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-b-PBCL) and pharmaceutical-grade CBD. nCBD (1 mg/kg) was injected 2 times per week subcutaneously in HF mice and Control mice. At week 5, Masson’s trichrome and H & E staining was performed to evaluate severity of fibrosis and cardiomyocyte (CM) size respectively using Cell Sense Dimension Software from Olympus.

Results:
PEO-b-PBCL nanoparticles localized in both interstitial and replacement fibrotic regions in the heart of our HF mice. HF mice with nCBD treatment displayed less fibrosis when compared to HF mice without treatment as shown in a representative image of fibrosis staining (Figure A). Histological quantification depicted that fibrosis area was higher in HF mice and was significantly (p<0.0001) reduced in HF mice exposed to nCBD (Figure B). Treatment of HF mice with nCBD also influenced CM size. Normal mice had a mean CM size of 12.33±2.07 μm. This increased to 21.17±2.88 μm in HF mice without treatment. However, nCBD treatment significantly (p<0.0001) decreased CM size to a mean value 14.76±2.71 μm (Figure C).

Conclusion:
Our results show that nCBD has an anti-fibrotic and anti-hypertrophic effect in a mouse model of non-ischemic heart failure.
Abstract 10712: Observational Findings of PULS Cardiac Test Findings for Inflammatory Markers in Patients Receiving mRNA Vaccines
Authors: Gundry Steven R
Published: March 2022

This clinic has been using the PULS Cardiac Test (Predictive Health Diagnostics Co., Irvine, CA) a clinically utilized measurement of multiple protein biomarkers, which generates a score predicting the 5 yr risk (percentage chance) of a new Acute Coronary Syndrome (ACS) called the PULS Score. The score is based on changes from the norm of multiple protein inflammatory biomarkers including IL-16, a proinflammatory cytokine, soluble Fas, an inducer of apoptosis, and Hepatocyte Growth Factor (HGF) which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue, among other markers. Elevation above the norm increases the PULS score, while decreases below the norm lowers the PULS score. The PULS score has been measured every 3-6 months in our patient population for 8 years. Recently, with the advent of the mRNA COVID 19 vaccines (vac) by Moderna and Pfizer, we tracked the changes of the PULS score and three of the inflammatory markers it measures in all of our patients consecutively receiving these vaccines.

This report summarizes those results. A total of 566 pts, aged 28 to 97, M:F ratio 1:1 seen in a preventive cardiology practice had a previously scheduled PULS test drawn from 2 to 10 weeks following the 2
nd
mRNA COVID shot and was compared to the pt’s PULS test drawn 3 to 5 months previously pre-shot. Each vac pt’s PULS score and inflammatory marker changes were compared to their pre-vac PULS score, thus serving as their own control. There was no comparison made with unvaccinated patients or pts treated with other vaccines.

Baseline IL-16 increased from 35+/-20 above the norm to 82 +/- 75 above the norm post-vac; sFas increased from 22+/- 15 above the norm to 46+/-24 above the norm post vac; HGF increased from 42+/-12 above the norm to 86+/-31 above the norm post vac. These changes resulted in an increase of the pre vac PULS score of predicted 11% 5 yr ACS risk to a post vac PULS score of a predicted 25% 5 yr ACS risk, based on data which has not been validated in this population. No statistical comparison was done in this observational study.

In conclusion, the mRNA vacs numerically increase (but not statistically tested) the markers IL-16, Fas, and HGF, all markers previously described by others for denoting inflammation on the endothelium and T cell infiltration of cardiac muscle, in a consecutive series of a single clinic patient population receiving mRNA vaccines without a control group.
Abstract 10714: The Role of Interleukin-6 in Heart Failure and Its Subtypes: Results from Mendelian Randomization and Mediation Analysis
Authors: Liu Chang , Hui Qin , Charest Brian , Aragam Krishna , Wang Zeyuan , Cho Kelly , Wilson Peter W , Casas Juan P , Gaziano Michael M , Phillips Lawrence S , Joseph Jacob , Sun Yan V
Published: March 2022

Introduction:
Heart failure (HF) increases morbidity, mortality, and costs, with complex pathogenic mechanisms. Interleukin-6 (IL-6) is a key cytokine and immune regulator with broad impact on inflammation – a critical component of HF pathophysiology. Circulating levels of IL-6 receptor (IL-6R) determines the activity of the IL-6 signaling pathway. We aim to estimate the causal effect of the IL-6R on HF and two clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) in a Mendelian Randomization (MR) framework including mediators.

Hypothesis:
Plausible causal associations between IL-6R and HF, HFrEF and HFpEF are mediated by body mass index (BMI) or coronary artery disease (CAD).

Methods:
Two-sample MR analyses were conducted using genetic association results for composite HF, HFrEF and HFpEF among >300,000 MVP participants of European ancestry. Thirty-four independent genetic variants within 250 kb from the IL6R gene associated with plasma IL-6R levels were used as genetic instrumental variables. We estimated the direct effect of IL-6R levels on HF and subtypes, and the indirect effect mediated through BMI and CAD.

Results:
Causal effects of IL-6R on composite HF, HFrEF and HFpEF were estimated as odds ratios (OR): 0.97 (CI 0.96-0.99, p=0.02), 0.96 (CI 0.93-0.98, p=0.003) and 1.00 (CI 0.97-1.03, p=0.89), respectively. Mediation analyses for composite HF and HFrEF showed significant mediation effects by CAD, with ORs 0.98 (CI 0.97-0.99) and 0.98 (CI 0.96-1.00), respectively. No mediation effect of BMI was identified.

Conclusions:
These findings support a causal role of IL-6 signaling in composite HF and HFrEF, but not HFpEF. Although the IL-6 signaling pathway plays a role in both BMI and CAD, the effect of IL-6 signaling on composite HF and HFrEF may be mediated through by CAD. Our findings demonstrate the role of IL-6 signaling in HF and its difference between HF subtypes, which may lead to more specific therapeutic targets for HF.
Abstract 10715: The Quality of Coronary Artery Bypass Grafting on YouTube
Authors: Nus Bradley , Wu Kylie , Sledge Trey , Torres Grant , Kamma Sai , Janumpally Sanjana , Gilani Syed
Published: March 2022

Objective:
YouTube, the second most accessed site on the internet, has become a widespread source of healthcare information for patients. Videos for Coronary Artery Bypass Grafts (CABG) have accrued tens of millions of views on the platform, yet their educational quality is unknown. This study investigates the level of bias and misinformation in videos regarding CABG procedures on YouTube.

Methods:
YouTube was searched for various terms such as “Coronary Bypass Graft Procedure.” After applying exclusion criteria, 73 videos were assessed. Two independent reviewers rated the material with the Global Quality Scale (GQS; 5 = high quality, 3 = low quality) to judge educational value. A ratio of view count to days since upload was applied to assess video popularity. Source, modality, and date of upload were recorded for each video as well.

Results:
An average GQS score of 2.95 was found, indicating poor educational quality amongst the 73 YouTube videos for CABG procedures. Videos uploaded by physicians (56 or 76.7%) had a significantly higher average GQS score than those not uploaded by physicians (p<0.001). In grouping cohorts by modality, physician-led presentations (24 or 32.9%) produced the highest average GQS score of 3.35; conversely, patient-friendly delivery methods (18 or 24.7%) yielded the lowest average GQS score of 2.36 (p<0.001) (Fig 2.). Neither view ratio nor days since upload significantly correlated with educational quality of the video.

Conclusion:
Although Coronary Artery Bypass Graft videos are readily available on YouTube, they often contain considerable biases and misleading information. With online sources for healthcare education now commonplace, physicians must be aware of the vast quantities of low-quality videos patients often encounter when weighing different treatment options. Further analysis of CABG videos on YouTube may allow physicians to ameliorate this gap by producing videos that are not only high quality, but highly viewed on the platform.
Abstract 10719: Deep Learning to Estimate COVID-19 Mortality Risk from Chest Radiographs
Authors: Raghu Vineet , Cheng Alexander , Singh Sanjana , Li Matthew D , Zinzuwadia Aniket , Kalpathy-Cramer Jayashree , Lu Michael T
Published: March 2022

Introduction:
Management of coronavirus disease 2019 (COVID-19) requires accurate assessment of risk of future cardiopulmonary complications. Deep learning can extract complex relationships between medical imaging and clinical outcomes.

Hypothesis:
A deep learning model can predict 30-day mortality from COVID-19 based on a chest radiograph image.

Methods:
A deep learning model (CXR-CovRisk) was developed to estimate 30-day mortality risk using a single chest radiograph image (chest x-ray or CXR). The model was developed using 1,738 patients with PCR-confirmed coronavirus disease 2019 (COVID-19) from four Boston-area hospitals between March 1, 2020 and April 24, 2020. CXR-CovRisk was tested on 903 consecutive patients with confirmed COVID-19 between April 25, 2020 and June 15, 2020. CXR-CovRisk was compared to two published deep learning models (PXS and COVID-GMIC) and a clinical risk factor-based severity score for discrimination of 30-day mortality. The continuous risk score was converted to three risk groups: Low, Medium, and High based on development dataset probability quantiles. Results are provided for the independent testing set only

Results:
CXR-CovRisk had high discrimination for 30-day mortality (AUC = 0.839, 95% CI [0.79,0.89]), which was higher than when using a deep learning lung disease severity score (PXS AUC 0.750 [0.70,0.80], p < 0.001) or the output of a model trained for 96-hour mortality prediction (COVID-GMIC 0.755 [0.70,0.81], p = 0.003). CXR-CovRisk had added value to the clinical risk-factor based severity score (Clinical Severity Score AUC 0.799 [0.76,0.84] vs. Combined AUC 0.872 [0.84,0.90], p < 0.001). Among outpatients not admitted to the hospital, the CXR-CovRisk High-risk group had a high rate of subsequent hospital admission and 30-day mortality (composite event rate 11/26, 42.3%), higher than the medium-risk (30/179, 16.8%, p=0.005) and low-risk groups (17/172, 9.9%, p < 0.001).

Conclusion:
A deep learning model, CXR-CovRisk, can estimate 30-day mortality risk from a chest radiograph image.
Abstract 10720: Outcomes of Ultrasound Assisted Catheter Directed Thrombolysis Compared to Anticoagulation Alone in Patients with Intermediate Risk Pulmonary Embolism: A Meta-Analysis
Authors: Goel Mishita , Oberoi Mansj , Choksi Nishit , kumar sarwan
Published: March 2022

Purpose:
USCDT is evolving as a popular treatment for PE. Studies have shown that USCDT causes significant reduction in RV strain and pulmonary hypertension risk. However, impact of these treatment modalities on clinical outcomes remains unclear. We conducted meta-analysis of observational studies to assess safety and mortality outcomes of USCDT compared with systemic anticoagulation alone in patients with submassive PE.

Methods:
Systematic literature search was performed using PUBMED database. Studies published from January 2008-December 2020 were identified using search terms “catheter thrombolysis” and “pulmonary embolism”. Outcomes included mortality and bleeding. Meta-analysis was performed using Review-Manager version-5.4. Effect size was measured using random effects with 95%-confidence interval.

Results:
5 retrospective observational studies with 985 patients were included. Meta-analysis was performed for both mortality and major bleeding outcomes. Mortality rate was significantly greater in the anticoagulation group as compared to the USCDT group (odds ratio=3.08, 95%CI 1.62-5.87). There was no statistically significant difference in major bleeding rates between anticoagulation and USCDT groups (Risk-ratio=0.68, 95%CI 0.25-1.83). Heterogeneity was not significant among the five studies for mortality or bleeding outcome (I
2
=0%, p=0.82; I
2
=18%, p=0.30, respectively).

Conclusions:
USCDT, in addition to its known therapeutic efficacy, is associated with better mortality outcomes and no significant difference in major bleeding risk when compared to systemic anticoagulation.

Clinical Implications:
USCDT can be utilized over systemic anticoagulation alone in patients presenting with submassive PE for better outcomes.
Abstract 10724: Long-Term Mortality After Acute Coronary Syndromes Among Patients with Normal, Mid-Range or Low Ejection Fraction
Authors: Furtado Remo , Juliasz Marcela G , CHIU FELIPE Y , Bastos Livia B , Dalcoquio Talia F , Lima Felipe G , Rosa Renato , Caporrino Cesar A , Bertolin Adriadne , Soffiatti Carla , Ribeiro Andre S , Andrade Maria C , Giraldez Roberto , Baracioli Luciano , Nicolau Jose C
Published: March 2022

Introduction:
Left ventricle ejection fraction (LVEF) is a well-established marker for survival after acute coronary syndromes (ACS). While there has been strong association between low ejection fraction (i.e., LVEF < 40%) and mortality, the long-term prognostic impact of mid-range EF (LVEF 40-49%) after ACS remains less clear.

Methods:
This was a retrospective study enrolling consecutive patients admitted with ACS included in a single tertiary center databank. LVEF was assessed by echocardiography during index hospitalization. Patients were divided in the following categories according to LVEF: normal (LVEF ≥ 50%), mid-range (40-49%) and low (< 40%). The endpoint of interest was all-cause death after hospital discharge. A multivariable Cox regression model was used to adjust for confounders. The model was adjusted for age, sex, race, history of diabetes mellitus, prior HF, arterial hypertension, dyslipidemia, smoking, STEMI versus non-ST elevation ACS, prior MI, prior PCI, prior CABG, creatinine and Killip class at admission

Results:
A total of 3200 patients were included (1,952 with normal EF; 659 with mid-range EF and 589 with low EF); mean age was 63.5 ± 12.4 years (63.2±12.3, 63.9±12.7 and 64.2±12.4 years, respectively for normal, mid-range and low EF; p = 0.14); 2216 (69.3%) were male and 1257 (39.3%) presented with STEMI. The median follow-up time was 5 years, and the maximum follow-up time was 17.8 years. Overall results are shown in the Figure 1. In a sensitivity analysis using a different definition for mid-range EF (36-54%), results remained similar (data not shown).

Conclusion:
In ACS patients discharged alive from hospital, mid-range EF measured in the acute phase was associated with increased long-term mortality compared to patients with normal EF. This magnitude of effect was similar to that observed for patients with low EF. These data reinforce the need to consider anti-remodeling therapies also for ACS patients who have LVEF in the mid-range.
Abstract 10725: Prevalence and Impact of Recurrent Rejection on Graft Loss in Pediatric Heart Transplant Recipients: A Pediatric Heart Transplant Society Multi-Institutional Analysis
Authors: Amdani Shahnawaz , Kirklin James K , Cantor Ryan , Koehl Devin , Lal Ashwin K , Chau Peter , Curren Valerie , Edelson Jonathan , Parent John J , Bostdorff Hannah , BURNETTE Ali L , Lamour Jacqueline M
Published: March 2022

Introduction:
Rejection remains a significant cause of graft loss after heart transplantation. The current prevalence of recurrent rejection and its impact on graft loss after pediatric heart transplantation is unknown.

Methods:
All pediatric heart transplants between 1/2000-6/2020 in the Pediatric Heart Transplant Society database were included. Rejection was defined as a clinical event determined by biopsy, echocardiogram or clinical findings that resulted in augmentation of immunosuppression. Recurrent rejection was defined as ≥ 2 episodes of rejection after heart transplant. Freedom from recurrent rejection in the early (2000-2009) and current (2010-2020) era were compared. Multiphase parametric hazard modeling was utilized to understand the effects of each additional episode of rejection on graft loss in addition to identifying other risk factors.

Results:
Of 6342 heart transplants during the study period, 3921 (62%) had 0, 1386 (21%) had 1 and 1035 (17%) had ≥2 rejection episodes. In the current era, recurrent rejection is less frequent [468/4206 (11.1%) vs. 567/2136 (26.5%); p<0.001] (Figure A). Recurrent rejection increased probability of graft loss in both the unadjusted and multivariate adjusted analysis (HR 1.68; 95% CI 1.61-1.75, p<0.001) (Figure B and Table). Other risk factors for graft loss after pediatric HT are outlined in the Table.

Conclusions:
Currently, recurrent rejection is experienced by 1 in 10 pediatric HT recipients. Each additional episode of rejection post-HT confers an increasing risk for graft loss. Identifying risk factors for recurrent rejection is paramount to improving graft longevity.
Abstract 10727: Results from First-in-Human Clinical Trial of RP-A501 (AAV9:LAMP2B) Gene Therapy Treatment for Danon Disease
Authors: Greenberg Barry , Eshraghian Emily , Battiprolu Pavan , Ricks David , Yarabe Paul , Schwartz Jonathan , Patel Kinnari , Shah Guarav , Trevejo Jose
Published: March 2022

Background:
Danon disease (DD) is an X-linked disorder caused by mutations in the
LAMP2
gene that is essential for autophagy. DD is characterized by severe cardiomyopathy for which treatment options are limited. Median survival for male patients (pts) is approximately 19 years (y). DD natural history is notable for modest cardiac abnormalities in early phases detectable by measurement of left ventricular global longitudinal strain (GLS) or natriuretic peptides (NPs) followed by rapid progression, particularly in males during the second and third decade.

Methods:
This open-label Phase 1 study evaluates the safety of a single IV infusion of RP-A501 (AAV9.
LAMP2B
) at dose levels of 6.7 x 10
13
GC/kg (low dose) and 1.1 x 10
14
GC/kg (high dose) in male DD pts in two age groups: ≥15 y and 8-14 y. Eligibility criteria include a DD diagnosis with
LAMP2
mutation and cardiac involvement.

Results:
In Cohort 1 (N=3 pts, ≥15 y, 6.7 x 10
13
GC/kg), RP-A501 increased cardiac LAMP2B expression by Western blot (WB) and immunohistochemistry (IHC) in myocardial tissue. The two pts in Cohort 1 with observed immunosuppressive regimen compliance had high cardiac LAMP2B expression: 67.8% and 92.4% vs. normal control by IHC; up to 61% by WB. In both pts, NYHA Class improved from II to I. NPs were reduced by 59% and 42% at 9 and 12 months, respectively. All 3 pts had similar or mildly improved 6MWT, improved myocardial EM morphology with decreased autophagic vacuoles, improved/stabilized GLS and reported increases in physical activity. Adverse events were mostly manageable with transient immunosuppression. Reversible platelet decreases and transaminase elevations that returned to baseline within 2 months were seen. One patient treated with 1.1 x 10
14
GC/kg had complement-mediated thrombocytopenia and acute kidney injury requiring transient hemodialysis that fully recovered. An exacerbation of skeletal myopathy in 3 of the 5 patients resolved with steroid taper.

Conclusions:
This ongoing first-in-human trial demonstrates that the low dose of RP-A501 gene therapy for DD was generally well-tolerated, confers cardiac LAMP2B gene expression, and is associated with preliminary evidence of cardiac and clinical benefits.
Abstract 10730: Vascular Smooth Muscle Cell Phenotypic Switch and Replication Stress as a Key Contributors in CVD in HGPS
Authors: Coll-bonfill Nuria , Mahajan Urvashi , Gonzalo Susana
Published: March 2022

Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Patients show severe aging phenotypes, including alopecia, reduced fat and bone density, and cardiovascular disease (CVD), which ultimately causes their death as teenagers. HGPS has no cure and clinical trials obtained only minor benefits. It is urgent to identify mechanisms of progerin toxicity to target therapeutically. Progerin accumulates preferentially in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening and aortic atherosclerosis are accompanied by VSMCs depletion in the media, increased extracellular matrix (ECM), and adventitia thickening. Mechanisms whereby progerin causes massive VSMC loss and ECM accumulation are unknown. We previously demonstrated that progerin expression in fibroblasts hinders DNA replication, causes genomic instability, and triggers a phenotypic switch towards activated fibroblasts/myofibroblasts. These cells are known to promote tissue fibrosis by ECM deposition and release of inflammatory cytokines. VSMCs can also undergo phenotypic modulation or de-differentiation, a process whereby contractile cells revert to a synthetic/proliferative phenotype, leading to pathological accumulation of ECM and CVD. Here we show that progerin expression in VSMCs causes a switch towards the synthetic/proliferative phenotype. Similarly to fibroblasts, progerin represents a challenge for DNA replication in VSMC, triggering replication stress, genomic instability and ultimately VSMC death. Importantly, we found that calcitriol -hormonal active form of vitamin D- prevents VSMC switch and replication stress. Our data suggest that replication stress might be an underlying cause of VSMC loss in progeria and that preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might prevent the massive loss of VSMC and the vascular stiffness in HGPS patients.
Abstract 10732: Systemic Administration of Telomerase RNA Reverses Vascular Senescence and Extends Lifespan in Progeria Mice
Authors: Boada Christian , Walther Brandon , Holgate Rhonda , Morales Elisa , Qiu Xu , Cooke John P , Mojiri Anahita
Published: March 2022

Introduction:
Hutchinson-Gilford Progeria Syndrome (HGPS) is an accelerated aging syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS, a mutation in lamin A (progerin) alters nuclear morphology and gene expression. iPSCs derived endothelium from progeria patients show impairment in their morphology and function including replication arrest, DNA damage, increased expression of inflammatory markers, and telomere erosion, compared to iPSCs derived endothelial cells from their unaffected parents. We have shown that hTERT mRNA therapy rescues their senescent phenotypes and restores normal function and gene expression in-vitro. To validate our finding in-vivo, we have used lentivirus harboring mouse telomerase to treat mice model of progeria and investigated the beneficial effects on mice vasculature in different organs.

Hypothesis:
Gene therapy with mRNA encoding mice telomerase improves survival and reversing cell senescence in a mice model of HGPS.

Methods:
HGPS mice were injected twice with a lentivirus construct encoding mice telomerase via tail vein. Mice were monitored for survival; endothelial cells were isolated at the time of euthanasia and concentrations of cytokines, chemokines, and growth factors were analyzed using Elisa, PCR and immunofluorescence staining. For clinical translation we developed a lipid nanoparticle formulation to deliver mRNA encoding mTERT to mice, validating its function using mRNA encoding Luciferase to demonstrate biodistribution and safety profile.

Results:
Two treatments with lentiviral mTERT increased the lifespan of HGPS mice by 20% and reduced mediators of inflammation and thrombosis in HGPS such as thrombomodulin. HGPS mice treated with mTERT had lower DNA damage markers and increased SIRT1 in their vasculature and other organs. A Lipid nanoparticle encapsulating mTERT RNA and shows a favorable safety profile and the capacity to systemically and safely deliver luciferase mRNA, generating active luciferase, documenting a predominantly hepatic biodistribution.

Conclusions:
Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases. Further development in systemic delivery is thus underway
Abstract 10736: Gut Dysbiosis and Altered Circulating Microbial Metabolites in Patients with Pulmonary Arterial Hypertension
Authors: Moutsoglou Daphne , Weir Kenneth K , Khoruts Alexander , Tatah Jasmine , Prisco Sasha Z , Prins Kurt W , Pritzker Marc R , Thenappan Thenappan
Published: March 2022

Introduction:
Inflammation plays a mechanistic role in pulmonary arterial hypertension (PAH); however, what triggers inflammation remains unclear.

Hypothesis:
PAH is characterized by gut dysbiosis and barrier dysfunction, leading to an altered burden of circulating microbial metabolic products, promoting disease. We aimed to characterize the gut microbiome and circulating microbial metabolic products in healthy controls and PAH patients.

Methods:
The V4 hypervariable region of the 16S rRNA gene was analyzed from fecal samples of 40 healthy controls and 57 PAH patients. Plasma was analyzed for interleukin (IL)-6, claudin-3, trimethylamine N-oxide (TMAO), short chain fatty acids, and secondary bile acids.

Results:
PAH patients had elevated plasma IL-6 (Fig 1A,
P
=.02), claudin-3, a measure of intestinal permeability (Fig 1B,
P
=.04), and TMAO (Fig 1C,
P
=.04), and reduced taurolithocholic acid (Fig 1D,
P
=.02). Short chain fatty acid levels were not significantly different (data not shown). Principal component analysis (PCOA) of pairwise Bray-Curtis dissimilarity showed distinct microbiome compositions (Fig 1E,
P
<.001). The Shannon diversity index (Fig 1F,
P
<.001) and species richness (Fig 1G,
P
=0.005) were lower in PAH patients. Linear discriminant analysis (LDA) of effect size revealed that PAH patients had increased relative abundances of
Bacteroidetes
and
Proteobacteria
and decreased relative abundances of
Ruminococcaceae
and
Lachnospiraceae
(Fig 1H). There was no difference in gut microbiome richness and Shannon diversity between patients with low, intermediate, and high-risk REVEAL scores (data not shown).

Conclusions:
PAH patients have distinct gut dysbiosis, increased intestinal permeability (claudin-3), and circulating microbial metabolic products. These findings support our hypothesis that microbiome-driven, pro-inflammatory signals may contribute to PAH pathogenesis.
Abstract 10743: Overexpression of GLUT4 Induces Pulmonary Hypertension
Authors: James Joel , Valuparampil Varghes Mathews , Rafikova Olga , Rafikov Ruslan
Published: March 2022

Introduction:
Pulmonary arterial hypertension (PAH) induces significantly elevated glucose uptake in the patient lungs and right ventricles (RV), which correlates with the severity of the disease. However, the mechanisms responsible for the increased glucose uptake and its contribution to the PAH pathobiology remain unclear. We discovered that Sugen/hypoxia-induced PAH is associated with a marked overexpression of glucose transporter, GLUT4, starting from the early stage of the disease.

Hypothesis:
We investigated the role of GLUT4 overexpression in triggering PAH and evaluated the downstream mechanisms responsible for the PAH phenotype.

Methods:
In this study, we used the mouse model overexpressing human GLUT4 (hGLUT4). RV hemodynamics and function were assessed in hGLUT4 mice treated or not with IMPA1 inhibitor (L690,330, i.p., 22 mg/kg BW, daily for 6 weeks). Isolated pulmonary artery smooth muscle cells (PASMC) were used to perform glucose uptake assays and bioenergetics measurements.

Results:
hGLUT4 mice showed significantly increased RV systolic pressure (RVSP, 28.98±0.72, p<0.001, N=7-9) and RV hypertrophy (0.319±0.006, p<0.0001, N=7-9) compared to WTs and non-transgenic controls. GLUT4 overexpression significantly increased the glucose uptake in PASMC (~30% increase to control, p<0.01) and induced severe mitochondrial dysfunction in unstimulated and insulin-stimulated cells. Previously, we discovered that an increase in glucose uptake elevates the levels of glucose 6-phosphate (G6P) and activates the G6P metabolizing enzyme, myo-inositol monophosphatase 1 (IMPA1). We confirmed the increased expression of IMPA1, a critical activator of the inositol synthesis and inositol-dependent proliferative pathways in hGLUT4 mice. Notably, treatment with the IMPA1 inhibitor completely reversed PAH by reducing RVSP and RV hypertrophy.

Conclusions:
We conclude that increased GLUT4 expression is sufficient to induce spontaneous PAH through increased glucose uptake, initiation of mitochondrial dysfunction, and upregulation of IMPA1. This discovery introduces a novel potential target, IMPA1, that connects dysregulated glucose metabolism with activation of the proliferative signaling.