bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 24021: Sacubitril/Valsartan Attenuates Fibrosis and Improves Left Ventricular Function in a Rabbit Model of HFrEF
Authors: Torrado Juan , Cain Chad , Mauro Adolfo G , Ockaili Ramzi A , Romeo Francisco , Nestler John , Devarakonda Teja , Das Anindita , Salloum Fadi N
Published: March 2022

Background:
Sacubitril/Valsartan (SAC/VAL), a drug combining a neprilysin inhibitor and an angiotensin receptor blocker, was shown to reduce myocardial infarct size and left ventricular (LV) dysfunction in preclinical models of myocardial infarction (MI). In the PARADIGM-HF trial, SAC/VAL prevented the clinical progression of patients with heart failure (HF) more effectively than enalapril. Whether SAC/VAL attenuates cardiac fibrosis and improves LV function in a rabbit model of MI-induced HF with reduced ejection fraction (rEF) is unknown.

Methods:
Anesthetized adult male NZW rabbits (~2.5kg) underwent left thoracotomy and the left anterior descending (LAD) coronary artery was identified and occluded for 45 min followed by reperfusion. Weekly echocardiography was performed to confirm reduced EF (~40%), which was uniformly achieved at 5 weeks post MI. Subsequently, rabbits were randomized to orally receive placebo (volume-matched water, BID), SAC/VAL (10 mg/kg, BID) or VAL (9.1mg/kg/day) starting on week 6. At 10 weeks post MI, rabbits were sacrificed and hearts were harvested, fixed with 10% formalin and embedded in paraffin to assess myocardial fibrosis (Picrosirius red staining). Operators performing echocardiography, Picrosirius red staining and analysis were blinded to treatment allocation.

Results:
Two weeks after treatment initiation, a significant improvement in LVEF was observed in the SAC/VAL group compared to both placebo and VAL, a benefit that lasted throughout the entire study (Fig. A). The functional improvement observed was associated with a significant reduction in LV scar size compared to placebo at week 10 (Fig. B). However, when compared to VAL, the decrease in scar size did not reach statistical significance despite a clear trend.

Conclusion:
Our results suggest that SAC/VAL may offer superior benefits compared to equivalent dose of stand-alone VAL in attenuating LV scar size and improving LVEF in a rabbit model of ischemic HFrEF.
Abstract 24024: Utilizing Telemedicine to Construct Population-Based STEMI Systems of care in Developing Countries
Authors: Mehta Sameer , Botelho Roberto , Fernandez Francisco , Agarwal Sunil , Perin Marco , Cardoso Rodolfo , Dusilek Cesar , Gamba Marco A , Perez-Alva Juan C , Torres Mario , Rodriguez Daniel
Published: March 2022

Background:
Major disparities exist between developed and developing countries in the outcomes of patients presenting with Acute Myocardial Infarction (AMI). Telemedicine has emerged as a powerful, cost-efficient, and scalable tool. Whether telemedicine can improve AMI results remains unclear.

Methods:
We incorporated a hub and spoke strategy for Latin America Telemedicine Infarct Network (LATIN) to expand access to care in regions in Brazil, Colombia, and Mexico that lacked AMI care. Small clinics and primary care health centers in remote areas (spokes) were strategically connected to hubs that could perform 24/7 primary PCI. Experts at 3 central sites in Uberlandia, Sao Paulo, and Bogota, provided urgent EKG diagnosis and tele-consultation for the entire LATIN network by triggering ambulance dispatch and implementing standardized AMI protocols.

Results:
A total of 257 LATIN centers (Brazil 95, Colombia 113, Mexico 49) were networked using similar telemedicine protocols. In Colombia, LATIN coverage was established to cover 31% of the nation’s 48 million population. With this expanded geographic reach, 4.694 (1.2%) of the 401,095 screened patients were diagnosed as having STEMI. A total of 2,041 (43.5%) STEMI were urgently reperfused. Primary PCI was performed in the majority of patients - 1,578 (77.3%) that were referred for urgent perfusion. The major reasons for non-treatment included insurance denials, lack of ICU beds and chest pain >12 hours. Time to Telemedicine Diagnosis (TTD) was 5.1 minutes, and tele-ECG accuracy was 98%. D2B time for the cohort was 53 minutes, but chest pain to treatment time was >6 hours. Overall, in-hospital mortality was 5.8%.

Conclusions:
LATIN demonstrates the feasibility of creating a population based and telemedicine-guided AMI management strategy that can hugely expand access to reperfusion strategies. Telemedicine has important public health implications as a global approach to urgent AMI care in developing countries.
Abstract 24037: ZMYND8 Regulates the Hypoxic Response in Cardiomyocytes
Authors: Schunke Kathryn J , Walton Chad B , Shohet Ralph V
Published: March 2022

Introduction:
The Zmynd8 gene contains a variety of recognized motifs including a bromodomain and PHD finger, which are implicated in cooperative binding to acetylated nucleosomes. It was recently identified as a key regulator of cancer progression and transcriptional repression by directing modification of histone methylation in the enhancer regions of genes. Mutations and dysregulation of Zmynd8 have been found in multiple cancer types, however its role in the cardiac myocardium is unexplored. Hypoxia-inducible factor 1α (HIF-1α) upregulation and stabilization is a common feature of both cancer and myocardial ischemia, promoting cellular functions such as proliferation, glucose metabolism and angiogenesis. Therefore, we investigated the role of Zmynd8 in the pathophysiology of cardiac ischemia in a model of HIF-1 activation.

Hypothesis:
Zmynd8 modulates the HIF-1 response in ischemic heart disease by inhibiting enhancer activity of HIF-1 target genes.

Methods & Results:
We expressed an inducible cardiac-specific, oxygen-stable form of HIF-1α in a mixed strain of mice that genetically express increased Zmynd8 (Z+). Compared to HIF-induced wild-type (WT) mice, these mice did not exhibit the expected HIF-1 phenotype of increased heart weight to body weight (6.4±0.3 vs. 4.8±0.2 vs. 5.1±0.3 mg/g, WT vs. Z+ vs. uninduced; p<0.05) with reduced ventricular function and associated chamber dilation. Semi-quantitative qPCR analysis of HL-1 and H9C2 cardiac cell lines transfected with CMV-expression plasmids for Zmynd8 and oxygen-stable HIF-1α resulted in striking reduction of multiple HIF-1 target genes such as PDK1 (45% reduction) compared to the HIF-1α plasmid alone. RNAi mediated knockdown of Zmynd8 alleviated this negative regulation (65% increase). Bioinformatic analysis of human Zmynd8 and HIF-1α ChIP-seq data indicates that Zmynd8 binds to the enhancer of 78% of HIF-1 regulated genes. This further supports our observation that Zmynd8 modulates HIF-1 activity in the heart.

Conclusion:
We have discovered a new regulator of HIF-1 action that modifies the hypoxic response, likely through chromatin remodeling. We suggest that this new form of regulation can modify the pathophysiology of ischemia and potentially provide new targets for therapy.
Abstract 24044: Therapeutic Effects of human Pluripotent Stem Cell-derived Lymphatic Endothelial Cells encapsulated with Nanomatrix Gel on Experimental Lymphedema
Authors: Lee Shin-Jeong , Sohn Young-Doug , Sohn Dongchan , Yoon Young-sup
Published: March 2022

Background:
Current systems generating lymphatic endothelial cell (LEC) from human induced pluripotent stem cells (hPSCs) have limited value due to low purity, the use of undefined components for differentiation, and poor cell survival in vivo. Here, we developed a fully defined system to differentiate hPSCs into LECs and evaluated their therapeutic and engraftment potential when encapsulated in a nanomatrix gel (PA-RGDS). Methods and

Results:
hPSCs were cultured with GSK3β inhibitor on collagen-coated plates for 2-3 days to induce differentiation into the mesodermal lineage. The mesodermally differentiated cells were then cultured with VEGFC, VEGFA, EGF, and bFGF for another 6 days and double-sorted by PDPN and FLT4. These hPSC-PDPN+FLT4+ cells (hPSC-derived lymphatic endothelial cells, hPSC-LECs) showed highly purified and fully functional LEC characteristics in vitro. These hPSC-LECs express LEC markers such as PDPN, LYVE1, PROX1, and FLT4 at the mRNA level and the protein level, and formed tube-like structures in Matrigel. We next determined the lymphatic vascular reparative effects of engineered hPSC-LECs. After inducing lymphedema in the tail of mouse, hPSC-LECs, hPSC-LECs encapsulated with PA-RGDS, human dermal lymphatic endothelial cells (hdLEC), PA-RGDS, or PBS were injected into the tail of mouse. Tail thickness significantly decreased in the groups injected with hPSC-LECs with or without PA-RGDS compared to the other groups at day 28. At day 45, mice injected with PA-RGDS encapsulated hPSC-LECs showed significant decrease in the tail diameter compared to all other groups including those injected with hPSC-LECs. Histological examination demonstrated that the skin thickness was significantly reduced and the density of lymphatic vessels was markedly increased when the hPSC-LECs were encapsulated with PA-RGDS compared to others.

Conclusion:
This study demonstrated for the first time that hPSC can be differentiated into LECs in a clinically compatible manner with a high yield. Furthermore, nanomatrix encapsulated hPSC-LECs can substantially improve lymphedema in mouse tail through enhancement of cell survival and lymphatic neovascularization. This engineered hPSC-LEC therapy represents a novel option for treating lymphedema.
Abstract 24047: G Protein-coupled Receptor Kinase 2 Negatively Regulates Fatty Acid Utilization and Mitochondrial Bioenergetics
Authors: Pfleger Jessica M , Koch Walter J
Published: March 2022

During cardiac injury or stress, G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression levels and activity are increased, leading to a desensitization of myocardial β-adrenergic receptors (βARs) and contributing to the loss of contractile reserve. Up-regulated GRK2 has been shown to be pathogenic in the post-injured heart and is involved in the promotion of heart failure (HF). There is evidence that GRK2 has other, non-GPCR dependent pathological functions within cardiomyocytes. For example, GRK2 localizes to the mitochondria following oxidative stress, where it acts as a pro-death kinase and decreases fatty acid utilization. As metabolic substrate utilization and bioenergetics are key parameters in the maintenance of cardiomyocyte contractility, our objective is to examine the role of GRK2 on metabolism and bioenergetics in the adult heart. We hypothesize that desensitization of βARs via an increase in GRK2 will result in decreased fatty acid-fueled respiration and will compromise cardiomyocyte function. Conversely, ablation of GRK2 will result in increased respiration and function, under these conditions. Our results show that basal respiration, maximal respiration, and reserve respiratory capacity (RRC) are highest in the presence of palmitate versus glucose (1.6, 3, and 7.2-fold, respectively), accompanied by increased (1.3-fold) ATP levels. Moreover, basal and maximal respiration was decreased (1.6 and 1.2-fold, respectively) cardiomyocytes isolated from cardiac-specific GRK2 transgenic mice. This correlates with a decrease in ATP levels and
in vivo
cardiac fatty acid uptake (1-fold and 1.6-fold, respectively). Conversely, cardiomyocytes isolated from βARKct, a peptide inhibitor of GRK2, transgenic mice or GRK2 knockout mice, show increased maximal respiration (1.5 and 1.4-fold, respectively) and RRC (2.7 and 2.2-fold, respectively) with fatty acids. This correlates with an increase in ATP levels (1.2-1.9-fold). Thus, we propose that increased GRK2, as seen during heart failure, compromises fatty acid-driven mitochondrial respiration, while GRK2 inhibition under these conditions enhances RRC, which is known to improve cellular survival during stress.
Abstract 24055: Naturally Occurring Hypertension is Related to Cardiac Diastolic Dysfunction in Rhesus Monkeys
Authors: Liang Yinan , Yang Zunyuan , Yao Zunwei , Gong Li , Liang Zhigang , Shen Yubo , Chen Yuanhai , Zeng Wen , Hansen Barbara C
Published: March 2022

Introduction:
The lack of effective treatment for Diastolic Dysfunction (DD) is partially due to the differences between widely used preclinical rodent models and humans in the physiology and function of the heart. In previous studies, we have demonstrated that rhesus monkeys with naturally occurring adult onset Type 2 Diabetes (T2DM) frequently have DD that is similar in characteristics to DD in diabetic patients. To further characterize DD in rhesus monkeys, we studied the relationship between hypertension and DD, and evaluated the response of rhesus monkeys with DD to Entresto (sacubitril/valsartan).

Methods:
Blood pressure, fasting plasma glucose and cardiac function were measured in 322 adult rhesus monkeys (
Macaca mulatta
, 7-22 yrs) under light anesthesia with ketamine. Monkeys with LV hypertrophy, e'<8 cm/s and E/e'>10 were defined as DD. Ten monkeys with DD were enrolled in the validation study and divided into the Entresto group (n=5) and the vehicle group (n=5). Cardiac function and blood pressure were measured before and at the end of 13 weeks of treatment.

Results:
Among the 322 adult rhesus monkeys studied, 53 monkeys (16.46%) had SBP>140 mm Hg or DBP>90 mm Hg. Among the 174 monkeys with fasting glucose >80 mg/dL, 67 monkeys had isolated DD, and 8 had DD+ SD (systolic dysfunction). The incidence of isolated DD was 31% in monkeys with SBP<140 mm Hg and 74% in monkeys with SBP>140 mm Hg. Following Entresto administration (1.66 to 13.33 mg/kg) for 13 weeks, DD and BP evaluation showed an increase of e’ (5.27±0.51 to 6.43±1.27 cm/s), a decrease of E/e’ (12.74±2.23 to 10.53±2.09) and a decrease of SBP (128±5 to 113±16 mm Hg). These parameters remained stable and unchanged in the vehicle group.

Conclusions:
The incidence of naturally occurring hypertension in adult rhesus monkeys was similar to that in adult humans. Entresto reduced blood pressure, but led to no significant improvement of DD in monkeys. The extent of change in rhesus monkeys was similar to that observed in clinical trials. In rhesus monkeys, as in patients, hypertension is significantly related to cardiac diastolic dysfunction. These monkeys, therefore, provide important new opportunities to understand the pathogenesis of DD, as well as to predict the human response to new therapeutic agents.
Abstract 24057: Induced Pacemaker Spheroids As A Model To Reverse-Engineer The Native Sinoatrial Node
Authors: Grijalva Sandra I , Sung Jung H , Furman Benjamin W , Han Pengcheng , Li Jun , Cho Hee C
Published: March 2022

Background:
The sinoatrial node (SAN) has intricate architecture, which facilitates the spontaneous action potentials generated from the SAN to pace and drive the neighboring myocardium. We sought to create an engineered SAN that recapitulates the native SAN’s ability to overcome source-sink mismatch. We hypothesized spheroids consisting of induced pacemaker cells (iPM) can pace and drive surrounding quiescent myocardium.

Methods:
The iPMs were created by singular expression of a transcription factor, TBX18, to neonatal rat ventricular myocytes as we have previously demonstrated. The iPM or GFP-spheroids (control) were created by subjecting the NRVMs to the AggreWell™ plate at 1000 cells/well, and cultured for three days in suspension. Spheroids consisted of 90% NRVM and 10% cardiac fibroblast.

Results:
iPM-spheroids demonstrated spontaneous pacing at 145±26 bpm compared to 66±1 bpm (p=6.5770E-9) of control, GFP-spheroids. When one iPM-spheroid was surrounded by a monolayer of quiescent NRVMs (iPM:NRVM=1:100), the iPM-spheroids were able to pace and drive the quiescent ventricular myocardium at a capture rate of 48±7%. In contrast, the random activity of control spheroids captured the myocardium at 7±4% (p=0.0078). A monolayer of TBX18 cells (1:4=TBX18:NRVM) failed to pace and drive the neighboring sheet of ventricular myocytes. iPM-spheroids had a 17-fold increase in SAN-specific gap junction, Cx45, transcripts (p=0.0001) and a 2-fold decrease in myocardial gap junction, Cx43 (p=0.0030), compared to GFP-spheroids. The iPM-spheroids have superior viability compared to control GFP-spheroids, 87±1% and 72±5% respectively (p= 0.0463). TUNEL staining confirmed apoptotic fibroblast in the periphery. When cultured for >2 weeks, iPM-spheroids demonstrated small α-sarcomeric actinin positive cells organized as a mesh in the core, similar to the pacemaker cells in the native SAN.

Conclusion:
iPM-spheroids can pace and drive surrounding quiescent myocardium, overcoming the source-sink mismatch. The iPM-spheroids are viable in long-term and exhibit native SAN-like pacemaker cell organization. These data provide an in vitro platform on which the design principles of native SAN could be tested.
Abstract 24059: Optogenetic-induced Mitochondrial Membrane Potential Depolarization and Targeting Cell Death
Authors: Ernst Patrick , Xu Ningning , Goh KahYong , O'Rourke Brian , Zhang Jianyi J , Liu Margaret X , Zhou Lufang
Published: March 2022

Introduction:
There is growing evidence that mitochondrial dysfunction is closely associated with the development of cardiovascular diseases, although the precise mechanism is not well defined. Normal functioning of mitochondria relies on maintaining the inner membrane potential (
a.k.a.
ΔΨ
m
) to drive oxidative phosphorylation and redox balance. Thus, developing a tool to induce controlled mitochondrial depolarization and examine the effects on downstream intracellular processes will lead to critical information that helps to reveal the mechanisms underlying mitochondria-induced cellular dysfunction.

Methods and Results:
In this study, we developed a new generation optogenetic-based technique for targeting mitochondrial depolarization with light. Particularly, a heterologous light-gated channelrhodopsin protein, named ChR2, was targeted to and expressed on the inner mitochondrial membrane (IMM). We showed that ChR2 formed functional cationic channels on IMM with properties similar to that on the plasma membrane, allowing light-induced targeting ΔΨ
m
depolarization. We also showed that sustained moderate light illumination caused significant cell death in mitochondrial ChR2-expressing cells but not in the mock transfected or mitochondrial YFP-expressing cells. Finally, we provided evidence that the mitochondrial optogenetic-induced cell death is via apoptosis and is independent of the opening of the permeability transition pore.

Conclusion:
This new generation optogenetic tool can be used to study the mechanisms how a change of mitochondrial membrane permeability influences cell and organ functions.
Abstract 24060: Alpha Calcitonin Gene-Related Peptide (CGRP) Protects Against Pressure-induced Heart Failure
Authors: Kumar Ambrish , Supowit Scott , Potts Jay D , DiPette Donald J
Published: March 2022

Introduction:
Calcitonin gene-related peptide (CGRP), a 37 amino acid neuropeptide, is a potent vasodilator, and plays a critical role in the efferent functions of the sensory nervous system. A protective role for CGRP in cardiovascular diseases (hypertension, cardiac ischemia, and failure) has been well established by our laboratory and others. In the present study we determined whether long-term exogenous administration of α-CGRP protects against pressure-induced heart failure.

Method:
Three groups of nine-week-old C57/BL6 mice were studied: one group received a sham procedure (n= 4) and two groups underwent transverse aortic constriction (TAC). Two days after TAC, one group had CGRP-filled osmotic pumps (4 mg/kg bwt/day) implanted subcutaneously (n= 7) while the second group was TAC-only (n=6). At day 28, all groups had echocardiography performed and were sacrificed and heart tissue collected.

Results:
Echocardiographic and histological data showed that TAC markedly decreased fractional shortening (FS) and ejection fraction and increased heart and lung weight, cardiac hypertrophy, and fibrosis compared to sham. However, the TAC-CGRP mice had preserved cardiac function and less cardiac fibrosis (FS ±SEM: sham 46.2±1.8%
vs
TAC 25.4±1.1%,
p
< 0.001; and TAC 25.4±1.1%
vs
TAC-CGRP 36.6±1.2%,
p
< 0.001). CGRP significantly reduced apoptotic cell death and lipid peroxidation (an oxidative stress marker measured by malondialdehyde and 4-HNE staining) in the TAC hearts [malondialdehyde (nmol/mg protein) ±SEM: sham 3.5±0.19
vs
TAC 14.3±0.57,
p
< 0.05; and TAC 14.3±0.57
vs
TAC-CGRP 5.5±0.12,
p
< 0.05]. TAC alone decreased the level of p-ERK1/2 and increased p-JNK compared to sham. CGRP-TAC hearts had higher p-ERK1/2 levels but equal p-JNK levels compared to the TAC hearts. HIF1α and nrf2 protein levels were not different between experimental groups. Compared to TAC hearts, TAC-CGRP hearts had lower p-AMPK and nuclear Sirt1 level, regulatory proteins of energy metabolism.

Conclusion:
Our results suggest that CGRP, mediated through energy metabolic, and oxidative stress pathways, decreases myocyte apoptosis and is protective in pressure-induced heart failure. Thus, CGRP is a potential therapeutic agent in preventing the progression of heart failure.
Abstract 24077: Differential, Sex Related, Response To High-fat Diet In Mice Impairs Cardiac Autophagy And Mitophagy
Authors: Thomas Amandine , Marek Stefanie , Tucker Kyle C , Andres Allen M , Gottlieb Roberta A
Published: March 2022

Introduction:
Premenopausal women, as well as females in animal studies, have a reduced risk of cardiovascular diseases and a reduced myocardial susceptibility to ischemia/reperfusion (I/R) injury. However, with constantly increasing prevalence of obesity, the impact of diet-induced obesity on females remains unclear. Mechanisms of autophagy and mitophagy, differentially regulated between males and females, have been shown to be cardioprotective and impacted under nutritional overload.

Hypothesis:
Autophagy and mitophagy pathways can be involved in both female cardio protection and deleterious effect of obesity.

Methods:
Male and female C57Bl/6J mice (n =20 per group) of 8 weeks old were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 60% fat) diet for 12 weeks. At 12 weeks, hearts from mice were studied under basal conditions and after global no-flow ischemia and reperfusion on a Langendorff perfusion system.

Results:
In both males and females, HFD significantly increases body weight (31.4g vs 48.3g and 22.1g vs 39.9g respectively), fat mass (+200% in males and +300% in females) and blood glucose (+79mg/dl and + 54mg/dl, respectively) (all p<0.01). HFD tends to decrease flow reperfusion after global no-flow ischemia and to increase infarct size (p=0.08 in female and p=0.1 in male, n=5) in both sexes. In males and females, HFD increases pSer757-Ulk1 and decreases Parkin levels under basal conditions (all p<0.006). Moreover, HFD tends to decrease pThr172-AMPK only in females. After I/R, Parkin levels remain lower in HFD groups without sex-difference (p<0.004) but a drastic increase of LC3-II occurs only in females under HFD (p=0.047).

Conclusion:
All together, these results suggest an impairment of autophagy and mitophagy pathways under HFD. A more drastic change occurs in female mice and may imply a more important response of female mice to HFD, although further studies are needed. However, this result suggests that cardiovascular disease may be more deleterious in women despite their lower cardiovascular risk; additional studies examining sex differences in the response to metabolic syndrome and ischemic heart disease are warranted.
Abstract 24082: A Combined Basic Science and PopulationScience Approach Demonstrating the Potential for Simvastatin to MitigateCardiovascular Disease after Lower Hemi Body Radiotherapy
Authors: Olson Jessica , Taylor Reiauna , Sparapani Rodney , Lenarczyk Marek , Baker John
Published: March 2022

Radiation is a cornerstone of successful cancer treatment, with one-half to two-thirds of all patients receiving radiotherapy. Survivors of cancer treated with radiation are at increased risk for cardiovascular disease (CVD). Understanding how radiation causes CVD will allow development of novel therapies. Irradiation of the lower hemi body, but not the upper hemi body, with 10 Gy in rats increases risk factors for CVD and results in cardiac fibrosis quantitatively similar to total body irradiation, suggesting radiation injury to the heart can be indirect. Simvastatin, an inhibitor of liver cholesterol synthesis administered continuously to rats (10 mg/kg/day) after 10 Gy lower hemi body irradiation mitigated against increased blood cholesterol and cardiac fibrosis. These findings indicate simvastatin limits transmission of a signal from the lower hemi body that decreases risk for and occurrence of CVD independent of any direct exposure of the heart to radiation. Bivariate examination of 3,607 patients following therapeutic lower hemi body irradiation using Chi-square, Wilcoxon rank-sum and t-tests was used to examine risk factors for CVD in patients diagnosed with congestive heart failure, myocardial infarction, atrial fibrillation, and cardiomyopathy before 80 years of age. We found that 47.4% of patients age 70-80 developed CVD compared to 29.7% who received simvastatin (p= < 0.001, n = 293 and 361, respectively). Patients who were male, overweight, smokers, and had a diagnosis of chronic kidney disease and diabetes also had significantly higher risk of CVD. Race and hypertension were not indicative of increased risk for CVD. These clinical findings, taken together with the results from our animal studies, support a new research paradigm where radiation-induced heart disease can be indirect, with abdominal organs exporting factors that cause CVD. Simvastatin can be developed to mitigate and treat CVD after therapeutic radiation.
Abstract 10004: Novel Coronavirus Disease 2019 Infection in a Cohort of Patients with Phenotypic Hypertrophic Cardiomyopathy
Authors: Gasimli-Gamache Leyla , Le Marjolein , Cabrera Felicia , Shirani Jamshid
Published: March 2022

Background:
Cardiovascular diseases have been identified as major risk factors for adverse outcomes in patients with novel coronavirus 2019 disease (COVID-19). Patients with genetic diseases of the heart, including those with hypertrophic cardiomyopathy (HCM), have been warned regarding higher risk of adverse outcomes following COVID-19. No specific data, however, has been reported regarding the actual risk of COVID-19 in adults with HCM. We aimed to evaluate incidence and outcomes of COVID-19 in a cohort of adults with HCM followed at one center.

Methods:
Adults with phenotypic HCM [n=199, age 57±17 years, 55% men, 22% New York Heart Association class >1, 57% obstructive, 9% septal reduction therapy, 22 % positive family history, 41% selectively genotyped (40% positive for pathogenic mutations in MYBPC3, MYH7, and TNNI3 genes), 24% cardioverter-defibrillator implants, 24% paroxysmal or permanent atrial fibrillation (AF), 7% AF ablation] were retrospectively evaluated.

Results:
Overall, 14 (7%) were diagnosed with COVID-19 [50% men, age 56±16 years, 57% obstructive HCM, 21 % positive family history, 7% genotype positive]. There was no statistically significant demographic or clinical differences between 14 with and 185 without [56% men, age 58±17 years, 57% obstructive, 22 % positive family history, 17% genotype positive] COVID-19. Among those with COVID-19, 4 (27%) were hospitalized and 1 (7%) died of COVID-19. Compared to those with mild disease, hospitalized patients with COVID-19 were older (age 63±13 vs. 53±16 years), more often men (75% vs. 40%) and more often had a positive family history of HCM (50% vs. 10%) without significant differences in other demographic or clinical features. Only 1 patient (7%) was fully vaccinated prior to COVID-19 and had mild symptoms. Currently, 104 (52%) have received at least one dose of a COVID-19 vaccine and 83 (42%) are fully vaccinated.

Conclusions:
Although COVID-19 infection rate (7%) in this cohort of patients with HCM was below the rate in the general US population (~10%), hospitalization rate (27%) and death rate (7%) were above those noted in the nation (6.7% and 1.8%, respectively). The data confirms the notion that patients with HCM may have higher risk for developing COVID-19 related adverse outcomes.
Abstract 10005: Sodium Intake and Risk of Cardiovascular Disease: A Pooled Analysis of Individual Data from Six Cohort Studies with Multiple 24-Hour Urine Collections
Authors: Ma Yuan , He F J , Sun Qi , Yuan Changzheng , Kieneker Lyanne M , Curhan Gary C , MacGregor Graham A , Bakker Stephan J , Campbell Norman , Wang Molin , Rimm Eric B , Manson Joann , Willett Walter , Hofman Albert , Gansevoort Ron T , Cook Nancy R , Hu Frank B
Published: March 2022

Background:
The relationship between sodium intake and cardiovascular disease (CVD) remains controversial, in part, due to inaccurate assessment of sodium intake. 24-hour urinary excretion over multiple days is considered the optimal method.

Methods:
We included individual participant data from 6 prospective cohorts among generally healthy adults with sodium and potassium excretion assessed by at least two 24-hour urine collections. Out of 10,709 participants (54% women; mean [SD] age, 51.5 [12.6] years), 571 incident CVD events (including myocardial infarction, coronary revascularization, and stroke) were ascertained during a median follow-up of 8.8 years. We analyzed each cohort using consistent methods and combined the results using random-effects meta-analysis.

Results:
Median 24-hour urinary sodium excretion (10
th
-90
th
percentile) was 3,270 (2,099-4,899) mg. Higher sodium excretion, lower potassium excretion and higher sodium-to-potassium ratio were all associated with higher risk of CVD events after controlling for confounding factors (all
P
values for trend≤0.02); there was no evidence of nonlinearity. The hazard ratio [HR] comparing top with bottom quartiles was 1.67 [95% confidence interval [CI]: 1.21-2.30] for sodium, 0.77 [0.57-1.02] for potassium and 1.72 [1.27-2.32] for sodium-to-potassium ratio. Each 1,000 mg/d increment in sodium excretion was associated with an 18% increase in CVD risk (95%CI: 5%-32%) and each 1,000 mg/d increment in potassium excretion was associated with 18% lower risk (95%CI: 6%-28%).

Conclusions:
Higher sodium and lower potassium intakes, measured in multiple 24-hour urine samples, were associated with higher risk of CVD in a dose-response manner. These findings support current recommendations to reduce sodium and increase potassium intakes.
Abstract 10007: AMP Deaminase in Mitochondria-Associated ER Membranes Contributes to Reduction of the Threshold for Mitochondrial Permeability Transition in Type 2 Diabetic Hearts
Authors: Osanami Arata , Tanno Masaya , Kuno Atsushi , Kouzu Hidemichi , Yano Toshiyuki , Sato Tatsuya , Miura Tetsuji , Ogawa Toshifumi
Published: March 2022

Introduction:
Despite the growing clinical burden of diabetic cardiomyopathy, there is no specific treatment for the disorder. We previously demonstrated that increased activity of AMP deaminase (AMPD) contributes to diastolic dysfunction in diabetic myocardium through ATP depletion and augmentation of xanthine oxidase-mediated ROS production. Additionally, the threshold for mitochondrial permeability transition (mPT), a major mechanism of cell necrosis, was found to be reduced by diabetes.

Hypothesis:
Increased localization of AMPD in mitochondria-associated ER membranes (MAMs) lowers the threshold for mPT, via accelerated Ca
2+
transport from the ER, by interaction with IP3 receptor (IP3R), VDAC and/or mitochondrial Ca
2+
uniporter (MCU).

Methods and Results:
The 90-kDa full-length and 70-kDa N-terminus-truncated form of AMPD3, a main isoform in rat hearts, were detected in the myocardium. The 90-kDa full-length AMPD3 was exclusively observed in outer mitochondrial membranes (OMMs), and both 90-kDa AMPD3 and 70-kDa AMPD3 were observed in MAMs. The 90-kDa AMPD3 levels in OMMs and MAMs were significantly higher in OLETF, type 2 diabetic rats, than in LETO, non-diabetic control rats, while 70-kDa AMPD3 levels were comparable in OLETF and LETO. The area of the MAM quantified by using electron micrographs was 57% larger in OLETF than in LETO (p<0.05). Immunoprecipitation experiments showed that 90-kDa AMPD3 was associated with VDAC, whereas 70-kDa AMPD3 did not interact with IP3R, VDAC or MCU. Ca
2+
retention capacity (CRC), an index of the threshold for mPT, analyzed in MAM-containing crude mitochondria was 21% lower in OLETF than in LETO (p<0.05). Although an inhibitor of AMPD (cpd3) had no effect on CRC, knockdown of 90-kDa AMPD3 significantly ameliorated H
2
O
2
-induced loss of mitochondrial membrane potential that was determined by TMRE in cultured isolated cardiomyocytes.

Conclusions:
The results suggest that 90-kDa AMPD3 in MAMs plays a role in regulation of the mPT threshold in a deaminase activity-independent manner and that increased AMPD3 in MAMs contributes to mitochondrial respiratory dysfunction in diabetic myocardium.
Abstract 10020: Worse Outcomes of Out-of-Hospital Cardiac Arrest in COVID-19 versus Non-COVID-19: A Systematic Review and Meta Analysis
Authors: Dyutima Dr , Singh Sandeep , Castillo Zaymis D , Igbenabor Christiana A , Sanchez Lorannys Y , Rueda Maria J , Valdez Confesora , Galan Mirian , Spasova Violeta , Desai Rupak
Published: March 2022

Introduction:
A surge in incidence of out-of-hospital cardiac arrest (OHCA) has been reported during COVID-19 outbreak in certain countries. However, limited data exists on a comparison of outcomes among COVID-19 positive OHCA patients vs. non- COVID-19 OHCA patients. Therefore, we aimed to perform a meta-analysis comparing characteristics and outcome of COVID-19 OHCA vs COVID-19 negative OHCA patients.

Methods:
We reviewed PubMed/Medline, SCOPUS, and EMBASE until April 2021 using relevant keywords COVID-19, SARS-CoV-2, “out of hospital cardiac arrest” or OHCA to identify studies that included outcomes data on OHCA with COVID-19 positive and negative status. Random-effects models were obtained to perform a meta-analysis. I
2
statistics was used for heterogeneity.

Results:
Of 5789 OHCA patients included from 6 studies, patients who were COVID-19 positive comprised of 61.46% males while COVID-19 negative patients included 63.37% of males (p=0.2). COVID-19 OHCA patients were younger (Mean±SD, 68.94±17.93 vs 70.23±17.93, p=0.03) compared to COVID-19 negative patients. Incidence of OHCA at home/private address was higher (OR=1.92, 95%CI:1.52-2.43), while shockable rhythm (OR=0.34, 95%-CI:0.24-0.46) and use of AED (OR=0.77, 95%CI 0.61-0.97) were less frequently noted in COVID-19 patients (p<0.0001). As shown in
Fig. 1
, return of spontaneous circulation did not differ significantly (OR=1.01, 95%CI:0.85-1.20, p<0.92); however, survival to admission (OR=0.64, 95%CI:0.48-0.86, p<0.01), and survival to discharge (OR=0.28, 95%CI:0.13-0.59, p<0.01) were significantly lower in COVID-19 OHCA admissions compared to non-COVID-19 OHCA admissions.

Conclusions:
This meta-analysis demonstrated that the SARS-CoV-2 infection in OHCA patients was associated with poorer outcomes as compared to COVID-19 negative OHCA admissions. Future studies are warranted to assess long-term residual effects of COVID-19 on OHCA risk and outcomes.
Abstract 10023: Association of Systolic and Diastolic Blood Pressure with Age in Rural Indians
Authors: Inamdar Aniket
Published: March 2022

Introduction:
It is known from various studies that rising blood pressure is associated with increased cardiovascular risk. The increase in blood pressure with age is mostly associated with structural changes in the arteries. Studies from today’s industrialized world have shown change towards an increase in Blood Pressure (BP), possibly due to change in diet, reduction in exercise and increase in stress. Daily salt intake in Indians is very high compared to western population. A high salt diet may induce changes in the vascular smooth muscle cells resulting in collagen accumulation in the large artery walls and consequent increased arterial stiffness.

Hypothesis:
The main objective was to determine the association of systolic and diastolic blood pressure with age in rural Indians.

Methods:
310 patients from age 30 to 85 years who visited our hospital in rural India from January 01,2021 to February 28,2021 were included in this study. Data were collected directly by measuring the systolic and diastolic blood pressure manually in comfortable sitting position. One way ANOVA, post hoc Tukey test and Pearson’s correlation test were used to analyze the data.

Results:
Statistical analysis showed that there was statistically significant positive correlation between age and systolic blood pressure (

p
= 0.045

, r = 0.114). This study showed negative correlation between age and diastolic blood pressure (
p
=0.124, r = - 0.087) but it was not statistically significant. This study shows that as age increases systolic BP increases.

Conclusions:
This study shows elevation of systolic blood pressure with increasing age in rural Indians. Data obtained during the Framingham Heart Study, which followed patients for 30 years, showed that systolic blood pressure (SBP) shows a continuous increase between the ages of 30 and 84 years or over. Diastolic blood pressure (DBP), however, has a varying pattern with ageing, increasing until the fifth decade and slowly decreasing from the age of 60 to at least 84 years of age. In the elderly, the most powerful predictor of risk is increased pulse pressure due to decreased diastolic and increased systolic blood pressure. To reduce the risk of cardiovascular events, adequate efforts are necessary to screen our population regularly for hypertension.
Abstract 10027: Pulsatile Load, Rather Than Cardiac Power Output, for the Right Ventricle Determines the Prognosis in Heart Failure Patients
Authors: Chiba Yasuyuki , Iwano Hiroyuki , Motoi Ko , Ishizaka Suguru , Tsujinaga Shingo , Tanemura Asuka , Murayama Michito , Yokoyama Shinobu , Nakabachi Masahiro , nishino hisao , Okada Kazunori , Kaga Sanae , Kamiya Kiwamu , Nagai Toshiyuki , Anzai Toshihisa
Published: March 2022

Background:
Although cardiac power output (CPO), a parameter of cardiac performance, for the left ventricle (LV) is reported to be a powerful prognostic indicator in heart failure (HF), significance of the right ventricular (RV) CPO in HF has not been elucidated. On the other hand, RV pulsatile load stands for one of the prognostic markers in HF. We thus investigated the relationship of the RV CPO and pulsatile load to the outcome in HF.

Methods:
Right heart catheterization and echocardiography were performed in 231 HF patients (62±16 years, LV ejection fraction 42±18%). Invasive and noninvasive CPOs were calculated from mean systemic or pulmonary arterial pressures and cardiac output for the LV and RV. LV CPO was then corrected by LV mass (LV CPO/M). Pulmonary artery compliance (PAC) and the ratio of acceleration time to ejection time (AcT/ET) of the RV outflow velocity were used as parameters of RV pulsatile load. Cardiac death, HF hospitalization, ventricular arrhythmia and LVAD implantation after the examination were recorded.

Results:
Noninvasive CPOs were moderately correlated with invasive ones (LV: R=0.73, RV: R=0.58, P <0.001 for both). During a median follow-up period of 441 days, cardiac events occurred in 57 patients. Using the cut-off of median values, lower LV CPO/M was associated with higher event rates, however, RV CPO did not discriminate the risk of future cardiac events. In contrast, higher RV pulsatile load was associated with higher event rates regardless of the level of LV CPO/M (
Figure
). In multivariable Cox proportional hazard analyses, echocardiographic LV CPO/M and AcT/ET both determined cardiac events independently of age, NYHA classification, LV ejection fraction and plasma brain natriuretic peptide levels.

Conclusion:
Pulsatile load, rather than CPO, for the RV was associated with cardiac events in HF. Furthermore, combination of echocardiographic LV CPO/M and AcT/ET could become a novel noninvasive prognostic indicator in HF patients.
Abstract 10039: Rise in Incidence of Takotsubo Syndrome, Associated Comorbidities and Major Adverse Cardiac and Cerebrovascular Events Among Cancer Survivors: A Nationwide Analysis of Two Cohorts a Decade Apart (2007 & 2017)
Authors: Modi Malak , Bhatt Nilay R , Jabar Ali Jamila Begum , Binkam Mounika , Isufi Mimoza , yar khan Nibras , Asfeen Ummul , Gandhi Zainab J , Kalolia Bansari , Desai Rupak
Published: March 2022

Introduction:
Studies in the last decade have shown an increased prevalence of Takotsubo syndrome (TTS); however, there is limited data on the prevalence and impact of TTS on hospitalizations among cancer survivors.

Methods:
We identified adult hospitalizations with prior cancer and TTS using National inpatient samples from 2007 & 2017. We then compared the demographics, comorbidities, and in-hospital outcomes between two cohorts 10-years apart. In addition, we also performed multivariable analysis to evaluate the composite outcomes of MACCE (all-cause mortality, cardiac arrest, arrhythmia and stroke) after adjusting for sociodemographic, type of admission, hospital characteristics, comorbidities, current cancer, and prior chemo/radiotherapy.

Results:
Prevalence of TTS per 100,000 hospitalizations among cancer survivors increased about 8-fold from 23 to 163 (p<0.001) between 2007 and 2017
(Fig. 1a)
. There was high prevalence of TTS among Caucasian, elderly and females in both cohorts, female (38 to 261/100,000 hospitalizations) and geriatric cancer survivors (24 to 174/100,000 hospitalizations) showed nearly 7-fold increase in TTS in 2017 vs. 2007 (p<0.001). Traditional cardiovascular risk factors, heart failure, chronic pulmonary disease, depression, renal failure and other neurological disorders also increased in the 2017 cohort vs. 2007 cohort. Along with higher rates of atrial tachyarrhythmias
(Fig. 1b)
, There was nearly 40% (OR 1.39, 95%CI: 1.06-1.82, p=0.016) higher risk of composite MACCE in the 2017 TTS cohort compared to 2007 cohort among cancer survivors

Conclusions:
Prevalence of TTS among hospitalized cancer survivors increased 8-fold in 2017 compared to 2007. Despite increased awareness about etiopathogenesis and access to improved diagnostic measures, this analysis of TTS cohorts among cancer survivors showed increasing comorbidities with nearly 40% higher risk of composite MACCE across two cohorts selected a decade apart.
Abstract 10041: Long Term Durability of Transcatheter Bioprosthetic Aortic Valves
Authors: Shishido Koki , Yamanaka Futoshi , Moriyama Noriaki , Saito Shigeru
Published: March 2022

Introduction:
Transcatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement in patients with severe aortic stenosis. However, data on long-term durability of bioprosthetic valve dysfunction (BVD) remain not enough. Therefore, we investigated the durability of transcatheter heart valve (THV) using new standardized criteria in patients at 5-year after TAVI.

Hypothesis and Methods:
From January 2012 to September 2015, among 114 patients with severe aortic stenosis, 28 and 86 patients underwent TAVI with self-expandable Medtronic CoreValve and balloon-expandable Edwards SAPIEN-XT, respectively.BVD was defined as Valve Academic Research Consortium 3 (VARC-3) criteria. Moderate/ severe hemodynamic valve deterioration (HVD) was defined as increase in mean transvalvular gradient > 10 mmHg/ > 20 mmHg resulting in mean gradient > 20 mmHg/ > 30 mmHg with concomitant decrease in effective orifice area (EOA) < 0.3 cm
2
/ < 0.6 cm
2
or new occurrence or increase of > 1 grade/ > 2 grade of intra-prosthetic aortic regurgitation (AR) resulting in moderate/ severe AR. Bioprosthetic valve failure (BVF) was defined as valve related death, aortic valve reintervention, any bioprosthetic valve dysfunction associated with clinically expressive criteria or severe hemodynamic HVD.

Results:
During 5-year follow-up period, all-cause mortality was 43.8% (50 patients). There was 1 patient with severe BVD due to severe aortic regurgitation after CoreValve implantation. Four patients (3.5%) showed moderate BVD, which resulted in increased mean THV gradient, and all of whom received SAPIEN-XT implantation. BVF occurred in 2 patients (1.8%) during 5 years after CoreValve and SAPIEN-XT implantation. Follow-up echocardiography at 5 year were conducted in 48 patients (42.1%). The mean pressure gradient was 7.7 ± 3.8 mmHg and 11.9 ± 4.9 mmHg in patients with CoreValve and SAPIEN-XT, respectively (p=0.012).

Conclusions:
This study was evaluated THV durability using the VARC-3 definition. The incidence of BVD were uncommon during long-term follow-up period. Furthermore, the 5-years’ THV performance of early generation balloon-expandable and self-expandable device were maintained after TAVI.
Abstract 10043: Disparities in Femoropopliteal Endovascular Intervention and Subsequent Outcomes by Race and Socioeconomic Status
Authors: Krawisz Anna K , Wadhera Rishi , Natesan Sahana , Chen Siyan , Song Yang , Yeh Robert W , Jaff Michael R , Secemsky Eric A
Published: March 2022

Introduction:
Disparities in the diagnosis, treatment, and outcomes of patients with peripheral artery disease are well-established. It is not known whether race or wealth-based disparities exist in the use of or outcomes following femoropopliteal endovascular intervention (PVI).

Hypothesis:
Black and lower socioeconomic status (SES) patients are treated with PVI more frequently and have worse outcomes following PVI.

Methods:
All fee-for-service Medicare beneficiaries ≥66 years of age from 2016 to 2018 were evaluated to determine the population-level use of PVI by race (Black/White/Other) and dual Medicaid enrollment (DE) status standardized by age and sex. Separately, age and sex standardized risks for the composite of death and amputation within 1 year after PVI were examined by race and DE status. Subgroup analyses were performed by indication for PVI (claudication/critical limb ischemia/other).

Results:
215,320 patients underwent PVI. Black beneficiaries underwent 928 PVIs per 100,000 Black beneficiaries compared with 530 PVIs per 100,000 White beneficiaries and 469 PVIs per 100,000 beneficiaries of Other races (risk ratio [RR] = 1.75 for Black vs. White, 95% CI 1.73-1.77, p<0.01; RR = 0.89 for Other vs. White, 95% CI 0.87-0.90, p<0.01). DE patients underwent 999 PVIs per 100,000 DE beneficiaries compared with 495 PVIs per 100,000 non-Medicaid beneficiaries (RR = 2.02, 95% CI 2.00-2.04 p<0.01). 17.6% of Black patients who underwent PVI suffered amputation or death by 1 year vs. 15.2% of White patients (RR = 1.16, 95% CI 1.12-1.20, p<0.01). This association persisted after adjustment by DE status. 19.3% of DE patients experienced amputation or death by 1 year vs. 14.4% of patients with Medicare alone (RR = 1.34, 95% CI 1.31-1.38, p<0.01). These findings persisted after adjustment by race. All analyses demonstrated consistent findings across indications for PVI.

Conclusions:
Among Medicare beneficiaries, Black patients underwent more PVIs than White patients and patients of other races and experienced greater rates of subsequent amputation and death. Patients with lower SES underwent more PVIs than patients with higher SES and had higher rates of subsequent amputation and death. Findings persisted after adjustment for age, sex, and race or SES.