bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 8997: TRPM7 Mediates Hypomagnesemia-Induced Mitochondrial Dysfunction, Diastolic Heart Failure, and Death
Authors: Liu Man , Liu Hong , Kang Gyeoung-Jin , Feng Feng , O-uchi Jin , Dudley Samuel C
Published: April 2022

Introduction:
Hypomagnesemia (HypoMg) induces mitochondrial dysfunction accompanied by disturbed Mg homeostasis in mouse hearts. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. Its upregulation has been observed in HypoMg. We investigated the role of TRPM7 in mitochondrial dysfunction mediated by HypoMg.

Methods:
Wild type (WT) C57BL/6J mice and transgenic mice with a K1646R mutation in the TRPM7 kinase domain (TRPM7
K1646R
, with no kinase function) were fed with a low-Mg diet (HypoMg mice, 15-30 mg/kg Mg) or a normal Mg diet (control mice, 600 mg/kg Mg) for 6 weeks. Human cardiac RL-14 cells were cultured in a normal (with 0.81 mM MgSO
4
) or a low-Mg medium (customized medium with 0.04 mM MgSO
4
) for 48 h. TRPM7 knockdown was achieved by siRNA in RL-14 cells.

Results:
WT HypoMg mice showed significantly decreased serum Mg, diastolic dysfunction, increased mitochondrial ROS in isolated cardiomyocytes, increased TRPM7 mRNA and protein level, decreased ATP production and decreased total mitochondrial Mg content in heart tissues. TRPM7
K1646R
mice on the low-Mg diet showed normal diastolic function, normal mitochondrial ROS levels in cardiomyocytes, and recovered ATP production and mitochondrial Mg content in hearts. Furthermore, TRPM7
K1646R
prevent HypoMg-induced seizures and death (64.8% death in WT HypoMg mice). Hypomagnesemia in RL-14 cells resulted in increased mitochondrial ROS (1.77±0.08-fold of control, P<0.0001), which was suppressed to 0.86±0.04-fold of control by TRPM7 siRNA (25-30% TRPM7 reduction confirmed by RT-PCR and Western blot).

Conclusions:
HypoMg induces elevation of TRPM7 protein expression, and TRPM7 is involved in mitochondrial dysfunction, diastolic dysfunction, and death associated with HypoMg.
Abstract 9404: Detecting Sars-cov-2 Orf3a and E Ion Channel Activity in Covid-19 Blood Samples
Authors: Yu Hangang , Sizemore Gina , Smoot Katy , Perrotta Peter
Published: April 2022

Introduction:
SARS-CoV-2 has been found in the heart of COVID-19 patients. It is unclear how the virus passes from the upper respiratory tract to the myocardium.

Hypothesis:
SARS-CoV-2 is present in the blood of COVID-19 infected patients.

Methods:
We targeted two viropotins, Orf3a and E, in SARS-CoV-2. Orf3a and E form non-voltage-gated ion channels. A combined fluorescence potassium ion assay with three channel modulators (4-aminopyridine, emodin-Orf3a channel blocker, gliclazide-E channel blocker) was developed to detect SARS-CoV-2 Orf3a/E channel activity. In blood samples, we subtracted the fluorescence signals in the absence and presence of emodin/gliclazide to detect Orf3a and E channel activity.

Results:
In lentivirus spiked samples, we detected significant channel activity of Orf3a/E based on increase in fluorescence induced by 4-aminopyridine, and this increase in fluorescence was inhibited by emodin and gliclazide. In 18 antigen/PCR positive samples, our test results found 15 are positive, demonstrating 83.3% concordance. In 24 antigen/PCR negative samples, our test results found 21 are negative, showing 87.5% concordance.

Conclusions:
We developed a cell-free, rapid, and high-throughput test that can detect Orf3a/E channel activity of SARS-CoV-2 in blood samples from COVID-19 infected individuals, which provides a likely explanation that the virus spreads to the heart via blood circulation.
Abstract 9433: The Combination of the Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as a Novel Predictor of Cardiac Death in Acute Decompensated Heart Failure Patients With Preserved Left Ventricular Ejection Fraction: A Multicenter Study
Authors: Tamaki Shunsuke , Nagai Yoshiyuki , Shutta Ryu , Masuda Daisaku , Murai Ryosuke , Yoshima Shohei , Abe Makoto , Sako Koji , Yamashita Shizuya , Seo Masahiro , Yamada Takahisa , Nakagawa Akito , Yasumura Yoshio , Nakagawa Yusuke , Yano Masamichi , Hayashi Takaharu , Hikoso Shungo , Sotomi Yohei , Sakata Yasushi ,   the OCVC-Heart Failure Investigator
Published: April 2022

Background:
Inflammation plays a central role in the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammatory markers which have been shown to predict post-discharge outcome in patients with HF. However, there is no information available on the combined usefulness of NLR and PLR in patients with HFpEF who are admitted with acute decompensated heart failure (ADHF).

Methods:
Patients' data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT-HFpEF), which is a prospective multicenter observational registry for ADHF patients with LVEF ≥50% in Osaka area. We studied 1011 patients who survived to discharge. NLR and PLR were measured at the time of admission. The NLR was calculated as the ratio of the neutrophil count to the lymphocyte count, and the PLR was calculated as the ratio of the platelet count to the lymphocyte count. The endpoint was cardiac death (CD).

Results:
During a follow-up period of 539±423 days, 81 patients had CD. Both NLR and PLR were significantly higher in the patients with than without CD. The optimal cut-off values of NLR and PLR were 4.5 and 193 on receiver operating characteristic curve analysis, respectively. At multivariate Cox analysis, higher NLR (hazard ratio [HR] 2.51, 95% confidence interval [CI] 1.49-4.22, p=0.0006) or higher PLR (HR 1.91, 95% CI 1.15-3.19, p=0.0130) were independently associated with CD. Moreover, the combination of higher NLR and higher PNR was the strongest predictor of CD (HR 2.84, 95% CI 1.56-5.17, p=0.0007). There was significant difference in the rate of CD among the three groups stratified by NLR and PLR values.

Conclusions:
In this multicenter study, the combination of NLR and PLR was shown to be a useful marker for the prediction of post-discharge outcome in patients with HFpEF admitted for ADHF.
Abstract 9440: Incidence, Charge, and Outcomes of Emergency Department Visits for Children with Single Ventricle Congenital Heart Disease from 2006-2018
Authors: Edelson Jonathan B , Gardner Monique , Kilaru Austin , Rossano Joseph , Griffis Heather M , Zhang Xuemei , Faerber Jennifer , Dodds Katie , O'Connor Matthew J , Ravishankar Chitra , Rychik Jack , Goldberg David , Mercer-rosa Laura M , Glatz Andrew C , Lin Kimberly
Published: April 2022

Introduction:
Children with single ventricle (SV) congenital heart disease have high morbidity, mortality and resource utilization when admitted to the hospital but few data exist on emergency department (ED) visits. Understanding patterns in ED encounters among children with SV may target interventions to improve outcomes. We described a national sample of SV ED visits and evaluated patient characteristics, encounters, and trends in admissions, charge, and mortality.

Methods:
This retrospective cohort study evaluates ED encounter level data from the 2006-2018 Nationwide Emergency Department Sample. Patients
<
18y with SV were identified using ICD-9/10 codes.

Results:
From 2006-2018, 52,512 SV ED visits were identified. Most SV ED encounters were male (61%) and
<
4y (65%). Patients with
>
1 complex chronic condition (CCC) comprised nearly 1/3 encounters (32%). Half of encounters (49%) resulted in admission or transfer, and the median inflation-adjusted charge per ED encounter was $1,939 (IQR $1,098-3,217). Nearly 1 in 50 SV ED visits resulted in death, in the ED or during the associated admission. Independent predictors of admission included age <1y [OR 2.60 (2.12, 3.19)], presenting to a metropolitan teaching hospital [OR 6.31 (4.53, 8.80)], presenting with HF [OR 7.70 (5.33, 11.12)], arrythmia [OR 2.81 (1.89, 4.18)], respiratory disease [OR 5.13 (4.13, 6.43)], or sepsis [OR 8.64 (4.09, 18.26)], and the presence of 1 [OR 2.15 (1.90, 2.42)] or
>
2 CCC’s [OR 6.89 (5.56, 8.53)]. Independent predictors of mortality included age <1y [OR 8.55 (3.28, 22.32)], presenting with HF [OR 4.97 (2.99, 8.27)], and
>
2 CCC’s [OR 2.19 (1.43, 3.36)]. Annual SV visits increased from 3,082 to 5,483 (
p for trend=0.003)
and the inflation-adjusted charge per ED encounter increased by 50%, from $1,760 to $2,612 (
p for trend=0.002).
There was no identified change in mortality (
p for trend=0.08).

Conclusions:
Half of ED visits of children with SV result in admission/transfer and 2% result in death. While the incidence and charges of SV ED visits increased over the years studied, there was no identified change in mortality. The high admission/transfer rate for children with SV presenting to the ED reflect a high-risk population; further attention must be given to improving their outcomes.
Abstract 9456: Changes in Cardiovascular Health During Young Adulthood and Subclinical Atherosclerosis in Middle Age
Authors: ye xiaomin , xiong zhenyu , Zhuang Xiaodong , Liao Xinxue
Published: April 2022

Introduction:
The benefits of reaching ideal cardiovascular health (CVH) is well known, but it is unclear whether positive CVH changes form young adulthood to middle age reduces subclinical atherosclerosis risk.

Hypothesis:
This study examined whether changes in CVH form young adulthood to middle age was associated with subclinical atherosclerosis.

Methods:
Data was analyzed from the Coronary Artery Risk Development in Young Adults (CARDIA) study. CVH was examined at Year 0 and 20 using 7 metrics (smoking, body mass index, diet, physical activity, blood pressure, fasting glucose, total cholesterol), each categorized as high (12 to 14 points), moderate (8 to 11) and low (0 to 7). Coronary artery calcium (CAC) was identified at Year 20 and 25. Carotid intima-media thickness (IMT) was identified at Year 20.

Results:
Among 2935 participants (56.2% women, 46.7% black), change of CVH metrics was -1.26 (2.13). For per 1-unit increase in CVH changes, the adjusted odds ratio of presence of CAC is 0.86 (95% CI 0.82, 0.90) and of IMT is 0.81 (95% CI 0.73, 0.90). Compared with stable moderate CVH, improvement from moderate to high CVH was associated with a lower risk of CAC (OR, 0.64 [95% CI 0.43, 0.96]), while retrogression from moderate to low CVH was associated with a higher risk of CAC (OR, 1.45 [95% CI 1.19, 1.76]).

Conclusions:
Positive changes of CVH during young adulthood is associated with negative subclinical atherosclerosis risk in middle age, indicating the importance of reaching an ideal cardiovascular health status through young adulthood.
Abstract 9467: Prevalence of Chest Pain in Diabetics with Inflammatory Heart Disease
Authors: Drenic Deni , Thodeti Sathwika , Raghavendran Rohith , Yim Michael , Mikolich J Ronald
Published: April 2022

Introduction:
The deleterious effects of chronic or poorly controlled diabetes mellitus (DM) on the cardiovascular system are well documented, but the prevalence of chest pain associated with inflammatory heart disease (IHD) has not been determined. This study was designed to assess and compare the prevalence of chest pain associated with IHD in diabetic (DM) and non-diabetic (ND) populations.

Hypothesis:
Diabetic patients may have decreased prevalence of chest pain due to IHD.

Methods:
A pooled cohort cardiac MRI (CMR) database was queried for all patients who had complete records pertaining to diabetes mellitus, inflammation on CMR, and concurrent chest pain. IHD was defined as myocarditis and/or pericarditis on CMR using using the Modified Lake Louise Criteria published in 2018 using not only T2 STIR and delayed gadolinium imaging, but also T1 and T2 relaxation mapping. Two of these 4 pulse sequences had to be abnormal for a IHD diagnosis. Patients were divided into disease (DM) and control (ND) groups, which were then stratified by IHD-associated chest pain. A two-tailed, two proportion Z-test with a significance value cutoff of p ≤ 0.05 was used for statistical analysis of populations.

Results:
A total of 951 DM patients and 3134 ND patients were identified. The DM group had 157 patients with CMR-confirmed IHD, of which 94 reported chest pain at 59.87% prevalence. The ND group had 699 patients with IHD, with 495 reporting chest pain at 70.81% prevalence. There was a statistically significant differences between groups related to prevalence of chest pain in cases of confirmed IHD (p<0.0001). There was also a statistically significant difference (p=0.0354) between groups in population prevalence of IHD-associated chest pain in DM (9.88%, 94/951) and ND (14.79%, 494/3134).

Conclusions:
The ND group demonstrated a 10.94% higher prevalence of chest pain among CMR-confirmed cases of IHD, and a 5.91% higher population prevalence of chest pain associated with IHD. This data suggests that diabetes confers a greater risk of asymptomatic IHD that may go undetected. The lower prevalence of chest pain in DM patients may possibly be explained by diabetic neuropathy induced attenuation of cardiac nociceptive pain response.
Abstract 9474: Clinical and Epidemiologic Characterization of Infective Endocarditis in a Predominant Hispanic Community of the United States - Mexico Border
Authors: Panneerselvam Ezhil , Cruz Rodriguez Jose , Montanez Ruben , Nepal Shristi , DESAI ROHAN , Okajima Kazue
Published: April 2022

Introduction:
We aimed to characterize the clinical, epidemiological and echocardiographic features of infective endocarditis (IE) in the United States (US)-Mexico border population.

Methods:
A retrospective cohort design of all patients with diagnosis of IE in a tertiary university health system in El Paso, Texas. The primary outcome was a composite of death, stroke, other embolic events or heart failure. Patients were risk-stratified using the Simplified Risk Score Calculation (scores >=5 were considered high risk). Kaplan-Meier method was used to evaluate time to outcome which was subsequently compared between groups by Wilcoxon log-rank test and a priori multivariable proportional hazard model.

Results:
Final analytic sample was 155 patients with a median follow-up of 2.21 years. Prosthetic valve IE composed 10.3% of our patients. The most prevalent organism was S. aureus (35.5%), followed by streptococcus species (20.0%). Echocardiographic features of severe endocarditis (indication of surgery) were present in 123 patients (79.5%). Surgical treatment occurred in 23.2% of patients, and the median time to surgery was 12 days. A total of 53% of patients were in the high-risk score category and these patients were more likely to have a conservative, medical treatment compared to those with a low to intermediate risk score (62.2% vs 37.8%, p<0.01). The composite outcome was met by 47.5% of our cohort. Median time to event was 69 days. In multivariable analysis, factors associated with increased risk of the composite outcome were high-risk score category (HR 2.6, 95%CI 1.6-4.3, p<0.01), Medicaid (HR 3.2, 95%CI 1.6-6.2, p<0.01) and uninsured status (HR 2.3, 95%CI 1.3-4.3, p<0.01).

Conclusion:
In a predominant Hispanic community of the US-Mexico border, high-risk IE patients were more likely to experience the composite outcome, and less likely to get surgical treatment. In multivariable analysis, uninsured patients had a significant higher risk of readmission, embolic events, heart failure or death.
Abstract 9476: Global Representation of Leaders, Collaborators, and Enrolled Participants in Heart Failure Clinical Trials: A Systematic Bibliometric Review
Authors: Zhu Jie Wei , Le NhatChinh , Wei Sunny , Zuhlke Liesl , Lopes Renato D , Zannad Faiez , Van Spall Harriette G
Published: April 2022

Introduction:
The geographic representation of investigators and participants in heart failure (HF) randomized clinical trials (RCTs) may not reflect the global burden of disease.

Objectives:
We assessed the geographic diversity of RCT leaders and explored associations with the geographic representation of enrolled participants among impactful HF RCTs.

Methods:
We searched MEDLINE, EMBASE, and CINAHL for HF RCTs published in journals with impact factor ≥ 10 between January 2000 and June 2020. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression models to explore associations between predictors and outcomes.

Results:
There were 414 eligible RCTs. Only 80 of 828 trial leaders (9.7%; 95% CI: 7.8% to 11.8%), and 453 of 4656 collaborators (9.7%; 95% CI: 8.8% to 10.6%) were from outside Europe and North America, with no change in temporal trends. The adjusted odds of trial leadership outside Europe and North America were lower with industry funding (aOR: 0.33; 95% CI: 0.15 to 0.75; P = 0.008). Among 157,416 participants in whom geography was reported, only 14.5% (95% CI: 14.3% to 14.7%) were enrolled outside Europe and North America, but odds of enrolment were ten-fold greater with trial leadership outside Europe and North America (aOR: 10.0; 95% CI 5.6-19.0; P < 0.001).

Conclusions:
Regions disproportionately burdened with HF are under-represented in HF trial leadership, collaboration, and enrolment. RCT leadership outside Europe and North America is independently associated with participant enrolment in under-represented regions. Increasing research capacity outside Europe and North America could enhance trial diversity and generalizability.
Abstract 9481: Inhibition of Apoptosis and Ferroptosis Signaling Pathways Alleviates Myocardial Ischemia-Reperfusion Injury in Rats Through Modulation of Mitochondrial Function
Authors: Luo Ying , Liao Suchan , Wu Jun , Maneechote Chayodom , Arunsak Busarin , Apaijai Nattayaporn , Benjanuwattra Juthipong , Chattipakorn Siriporn , Chattipakorn Nipon
Published: April 2022

Introduction:
Apoptosis and ferroptosis have been implicated in cardiac ischemia/reperfusion (I/R) injury. Inhibitors of apoptosis (Z-VAD) and ferroptosis (FER-1) have been shown to protect the heart in several cardiovascular disorders. However, the impacts of Z-VAD, FER-1, and combined therapy during cardiac I/R injury have not been elucidated.

Hypothesis:
Z-VAD and FER-1 provide cardioprotection by reducing myocardial cell injury and improving cardiac function. The combined treatment exerts better benefits than either single regimen.

Methods:
Male rats (n=25) were equally divided into 5 groups: sham, vehicle, Z-VAD at 3.3 mg/kg, FER-1 at 2 mg/kg, and combined FER-1 and Z-VAD. All treatments were intravenously injected to the rats 15 min before ischemia. Left anterior descending coronary was ligated for 30 min, followed by 120-min reperfusion in all animals except the sham group. Left ventricular ejection fraction (LVEF), infarct size, mitochondrial reactive oxygen species (ROS) production, and protein expressions of apoptosis and ferroptosis were determined.

Results:
Cardiac I/R injury led to cardiac mitochondrial dysfunction and cell death, contributed to infarct size expansion and LV dysfunction (Fig 1A-D). Z-VAD, FER-1 and combined treatments markedly increased %LVEF, reduced ROS levels and infarct size (the %reduction is 42.9%, 41.4%, and 47.7%, respectively, compared with vehicle). Cleaved caspase 3 (apoptosis) and ACSL4 (ferroptosis) expression levels were also reduced in those rats. The combined treatment did not show a significant advantage, compared with either single regimen (Fig 1A-D).

Conclusions:
Inhibitors of either apoptosis or ferroptosis similarly reduced cardiac mitochondrial dysfunction, apoptosis and ferroptosis, resulting in decreased infarct size, and finally leading to improved LV function. These findings indicate that ferroptosis could be a novel therapeutic target for cardioprotection in cardiac I/R injury.
Abstract 9483: Detection of Lipids by Near-infrared Spectroscopy in Calcified Coronary Plaques Containing Nodular Calcification: Insights from Multimodality Imaging and Histopathologic Assessment
Authors: Murai Kota , Otsuka Fumiyuki , Kataoka Yu , Kitahara Satoshi , Iwai Takamasa , Sawada Kenichiro , Matama Hideo , Honda Satoshi , FUJINO Masashi , Yoneda Shuichi , Takagi Kensuke , Asaumi Yasuhide , Tsujita Kenichi , Noguchi Teruo
Published: April 2022

Introduction:
Detection of lipids in coronary plaques by near-infrared spectroscopy (NIRS) is based on the absorbance of NIR light and can predict future coronary events. It remains unclear whether the ability of NIRS can be applied to calcified lesions containing nodular calcification (Ca), which potentially scatters NIR light.

Hypothesis:
We hypothesized that detection of lipids by NIRS is overestimated in calcified coronary plaques containing nodular Ca compared with those with conventional sheet Ca.

Methods:
We investigated a total of 322 culprit lesions from 283 patients with CAD who underwent both NIRS-IVUS and OCT. After identifying nodular and sheet Ca on cross-sectional images in both IVUS and OCT, the presence of NIRS signals behind Ca was determined and quantified as lipid arc divided by Ca arc. In addition, consecutive 30 autopsy cases with CAD were pathologically assessed for the prevalence of lipids within nodular and sheet Ca.

Results:
Among 8850 cross-sections in vivo, 382 nodular and 1190 sheet Ca were identified. Generalized estimating equation modeling showed the presence of NIRS signals was more frequent in nodular Ca (79% vs. 64%, p=0.001) and the extent of NIRS signals was greater in nodular than sheet Ca (70% vs. 23%, p<0.001, Figure). Multivariate analysis identified nodular Ca as an independent determinant of positive NIRS signals (Table). Among 2467 histologic coronary sections evaluated, 55 nodular and 456 sheet Ca were identified. In contrast to imaging assessment, pathology showed that the prevalence of lipids within nodular Ca was extremely low; only 4%, and less than that in sheet Ca (20%, p=0.015).

Conclusions:
Majority of nodular Ca exhibited positive NIRS signals, whereas lipids within nodular Ca was extremely rare in pathologic assessment. The discrepancy suggests that NIR light-based detection of lipids is overestimated in nodular Ca, which needs to be considered when interpreting co-localized lipids in calcified coronary plaques.
Abstract 9496: 30-days Mortality Risk in the Patients Following Atrial Fibrillation Ablation in the Entire Nation of Poland: An 8-Year Analysis from National Health Fund of Poland
Authors: Orczykowski Michal , Kowalski Marcin , Parikh Valay K. , Urbanek Piotr , Robert Bodalski , Derejko Pawel , Warminski Grzegorz , Hasiec Andrzej , Dubowski Krzysztof , Glowniak Andrzej , Sierpinski Radoslaw , Urbanski Filip , Bilinska Maria , Szumowski Lukasz
Published: April 2022

Introduction:
Atrial fibrillation (AF) is the most common sustained arrhythmia. Catheter Ablation (CA) is considered as a first-line therapy for AF. The risk of 30-days all-cause mortality associated with CA for AF may be underestimated in clinical trials and selected-cohort studies due to selection bias.

Hypothesis:
We evaluated 30-days all-cause mortality associated with CA for AF in the entire country of Poland

Methods:
The data was collected from the Polish national healthcare service (the National Health Fund of Poland). In the Polish health system covers >99% of CA for AF for the entire country. All consecutive CA in patients >18 years of age, between Jan 2012 and Dec 2019 were included in the study. CA for AF was identified by unique codes assigned to pulmonary vein isolation and CA for AF. The mortality rate was calculated for each age group.

Results:
During 8-year follow-up period, 31,214 CA of AF were performed in 26,767 patients. 9315 (34.8%) patients were female. 13758 (51.4%) patients had Cryoballoon ablation. Thirty-two deaths (0.1%) within 30-days of the CA were identified. The mortality rate was low and similar in each age group except in the oldest age group (age>80). The oldest age group had significantly higher 30-days mortality than any other age group. (Figure).

Conclusions:
In the large, consecutive patient population in the entire country of Poland, 30- days mortality following AF ablation for past 8-years remains low. In real-world clinical practice patients over the age of 80 have higher risk of 30-day all-cause mortality than any other age group found over last seven years. Systematic review is needed to further risk-stratify these findings.
Abstract 9512: Involvement of Orai1 Ca
2+
Channel in the Pathogenesis of Pulmonary Arterial Hypertension. Orai1 as a New Potential Therapeutic Target?
Authors: Masson Bastien , Le Ribeuz Helene , Sabourin Jessica , Woodhouse Emily , Foster Richard , Ruchon Yann , Dutheil Mary , Boet Angele , Ghigna Maria-Rosa , Mercier Olaf , Beech David J , Benitah Jean-Pierre , bailey marc , Humbert Marc , Montani David , capuano veronique , Antigny Fabrice
Published: April 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by a progressive obstruction of distal pulmonary artery (PA) leading to right ventricular hypertrophy and failure. Exacerbated intracellular Ca
2+
signalling contributes to functional abnormalities in pulmonary arterial smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration and pulmonary artery contractility. The role of archetypal Store-Operated Ca
2+
entry (SOCE) Orai1 Ca
2+
channel in PAH pathogenesis is unclear.

Methods:
Using a combination of Ca
2+
imaging, molecular biology,
in vitro
,
ex vivo
and
in vivo
approaches, we decipher the role of Orai1 Ca
2+
channel in pulmonary artery remodelling in PAH. We also analyzed the consequence of
in vivo
pharmacological inhibition of Orai1 in experimental models of PH.

Results:
We demonstrated that SOCE is increased in human PASMCs (hPASMCs) from patients with idiopathic PAH (iPAH) associated with an increased expression of Orai1 at mRNA and protein levels. Moreover,
in vitro
in iPAH-hPASMCs the pharmacological inhibition of Orai1 (by two different inhibitors) or the knockdown of Orai1 by siRNA reduced the SOCE as well as aberrant proliferation, apoptosis resistance phenotype and exacerbated cell migration. In addition, Orai1 knockdown reduced the exacerbated calcineurin activity in iPAH-hPASMCs. Using myograph experiments on isolated human and rat PAs we showed that pharmacological inhibition of Orai1 channels reduced the capacity of PAs to constrict. In rat experimental PH induced by Monocrotaline (MCT)-exposure or by Chronic-Hypoxia (CH) we found an overexpression of Orai1. Finally,
in vivo
pharmacological inhibition of Orai1 by three different blockers (BTP2, JPIII and 5J4) reduced experimental-PH in these experimental PH-models.

Conclusion:
In human PAH and experimental PH, the expression of Orai1 is increased compared to controls.
In vitro
and
in vivo
inhibition of Orai1 normalize the PAH phenotype of cultured iPAH-hPASMCs and reduce experimental-PH (MCT and CH). These results provide proof of concept that Orai1 contributes to PAH pathogenesis and that pharmacological inhibition of Orai1 should be considered as a new therapeutic target in PAH.
Abstract 9531: Septin4 Deletion Prevents Hypertrophy to Heart Failure Transition After Transverse Aortic Constriction
Authors: Yucel Dogacan , Parthiban Preethy , Xie An , Van Berlo Jop H
Published: April 2022

Introduction:
In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initially, these changes are compensatory, although ultimately, they lead to cardiomyocyte death and progression to heart failure. As one of the aspects of ventricular remodeling, cardiac fibrosis significantly reduces cardiac function. To identify potential new therapeutic targets, it is essential to understand the underlying mechanisms that regulate cardiac fibrosis. Previous research highlighted a possible interplay between TGF-β and Sept4. However, it is unknown if Sept4 is involved in TGF-β mediated cardiac fibrosis.

Hypothesis:
We hypothesized that Sept4 deletion prevents cardiac fibrosis and heart failure after transverse aortic constriction (TAC).

Methods:
10-week old Sept4 knockout (S4KO) and wild type (WT) mice were subjected to TAC or Sham surgery. Cardiac function was assessed 1- and 4-week post-injury. At both timepoints, hearts were harvested and used for transcriptomic and proteomic analyses. For cell culture experiments, primary cells were isolated from healthy 10-week old S4KO and WT mice and treated with TGF-β (10 ng/ml) or vehicle.

Results:
S4KO mice demonstrated improved cardiac function compared to WT mice at 1- and 4-weeks after TAC. Importantly, both groups displayed comparable levels of cardiomyocyte contractility
ex vivo
, highlighting that the beneficial effects of Sept4 deletion is through the non-cardiomyocyte population. Moreover, S4KO hearts demonstrated decreased levels of fibrosis compared to WTs at baseline and after injury. Lastly, by using primary cardiac fibroblasts, we discovered that Sept4 deletion prevents fibroblast activation and collagen secretion primarily by inhibiting Smad2 phosphorylation.

Conclusions:
Our results identify Sept4 as a potent mediator of cardiac fibrosis through regulation of Smad2 activity.
Abstract 9546: Cancer Therapeutics-Related Cardiac Dysfunction is Associated With High Risk of Cancer-Related Mortality in Patients Treated With Anthracycline-Containing Chemotherapy
Authors: Oikawa Masayoshi , Yaegashi Daiki , Yokokawa Sayoko , Yokokawa Tetsuro , Misaka Tomofumi , Sato Takamasa , Kaneshiro Takashi , KOBAYASHI ATSUSHI , Yoshihisa Akiomi , Nakazato Kazuhiko , Ishida Takafumi , Takeishi Yasuchika
Published: April 2022

Background:
Cancer therapeutics-related cardiac dysfunction (CTRCD) is a concerning problem in anthracycline-containing chemotherapy. However, the impact of CTRCD on cancer-related mortality is remained to be elucidated.

Methods:
Consecutive 174 patients planned for anthracycline-containing chemotherapy were enrolled. Echocardiography and blood test were performed at baseline, 3 months, 6 months, 12 months after starting chemotherapy, and after that every 3 months until cardiotoxic chemotherapy was completed.

Results:
Of 174 patients, CTRCD was developed in 16 patients (CTRCD group, median onset was 8 months), and the other patients (no-CTRCD group) showed normal left ventricular ejection fraction (LVEF). CTRCD group showed higher levels of peak troponin I (0.05 [0.04-0.16] ng/ml vs. 0.02 [0.02-0.04] ng/ml, P<0.001), peak B-type natriuretic peptide (59 [26-161] pg/ml vs. 25 [15-41] pg/ml, P=0.001), and lower LVEF at 12-month (54.1±7.5% vs. 64.6±4.8%, P<0.001) compared to no-CTRCD group. When we set the cut-off value of troponin I at 0.03 ng/ml, sensitivity, specificity, and area under the curve to predict CTRCD were 88%, 72%, and 0.792, respectively. In CTRCD group, 4 patients (25%) discontinued cardiotoxic chemotherapy due to CTRCD, and 12 patients (75%) showed recovered LVEF to more than 53%. In total study subjects, no patients presented cardiac death in follow up period (median 1056 days), but 22 patients (13%) died due to cancer progression. Kaplan-Meier analysis revealed that CTRCD group showed higher cancer-related mortality compared to no-CTRCD group (figure, P<0.001). Multivariate Cox-proportional hazard analysis showed that CTRCD was an independent risk factor for cancer death (HR 4.639, 95%CI [1.691-12.730], P=0.003).

Conclusion:
The development of CTRCD was associated with high risk of cancer death, but not with cardiac death. Cardioprotective treatment and careful cancer monitoring are required to the patients with CTRCD.
Abstract 9548: De Novo Atypical Atrial Flutters: Locations, Mechanisms, and Long Term Outcomes Post Ablation
Authors: Zaidi Alyssa , Kirzner Jared , Liu Christopher F , Cheung Jim W , Thomas George , Ip James E , Lerman Bruce B , Markowitz Steven
Published: April 2022

Introduction:
Atypical atrial flutter (aAFL) has been described in the absence of prior atrial interventions, but prognosis for these patients after catheter ablation is poorly defined. This study was designed to define characteristics and ablation outcomes in patients with de novo aAFL.

Methods:
Patients with non-CTI flutter, without prior ablation or cardiac surgery, were identified from an institutional database. Clinical, mapping, ablation, and follow up data were compared to an equally sized group of randomly selected patients with typical flutter (tAFL).

Results:
The 35 patients with aAFL had 45 mapped non-CTI flutters. aAFL patients had similar age, gender, cardiovascular comorbidities, and LA size compared to tAFL, except aAFL patients had higher LVEF (54 ± 12 vs 46 ± 19%, p=0.04). Cycle length of aAFL was longer (268 [IQR 231, 310] vs 230 [220, 250] msec, p=0.0006). aAFL localized to the RA in 16, LA in 28, and biatrial in 1. Mechanisms were macroreentry in 23 (8 RA, 15 LA) and localized reentry in 22 (8 RA, 14 LA). Areas of scar predominated in the lateral/posterior RA (N=9), anterior LA (N=14), and posterior LA (N=6). Most common LA circuits were perimitral reentry (N=8) and roof dependent (N=8), including dual loop reentry. Localized reentry occurred most commonly in the anterior LA (N=7) or involved the pulmonary veins (N=4). Ablation was acutely successful for 41/45 aAFLs (91%) and for all tAFL. After median follow-up of 33 [6.6, 55] mo, atrial arrhythmias recurred in 23/34 aAFL patients (68%) and 24/35 tAFL patients (69%); those with aAFL had earlier recurrences (1.9 [0.43, 11] vs 19 [2.3, 36] mo, p=0.01). First recurrences after aAFL ablation were more likely to be AFL rather than AF (83% vs 17%) whereas tAFL patients were more likely to recur with AF (24% AFL vs 76% AF, p<0.0001).

Conclusions:
Patients with de novo aAFL tend to have spontaneous scar, commonly in the lateral/posterior RA and anterior LA, consistent with an atrial myopathy. Ablation can be accomplished with high acute success, but recurrent atrial arrhythmias are common, most re-presenting with atrial tachycardias. Future studies should clarify if a substrate-based approach or adjunctive antiarrhythmic drugs would result in better long term outcomes.
Abstract 9588: Higher Survival With the Use of Extracorporeal Cardiopulmonary Resuscitation Compared With Conventional Cardiopulmonary Resuscitation in Children Undergoing Cardiac Surgery: Analysis of the Get With the Guidelines Registry©
Authors: Kobayashi Ryan L , Gauvreau Kimberlee , Alexander Peta , Teele Sarah A , Bembea Melania , Thiagarajan Ravi R
Published: April 2022

Introduction:
Extracorporeal cardiopulmonary resuscitation (E-CPR) has been increasingly utilized during in-hospital arrest in postoperative pediatric cardiac surgical patients. Despite this and the significant associated mortality, few pediatric multicenter analyses have evaluated if E-CPR increases survival for in-hospital cardiac arrest compared with conventional cardiopulmonary resuscitation (C-CPR).

Methods:
Children <18 years in the Get with the Guidelines-Resuscitation Registry© suffering in-hospital cardiac arrest following cardiac surgery who received ≥10 minutes of CPR between January 2008 and December 2020 were included. We compared patient factors, pre-arrest comorbid conditions, and survival to hospital discharge for E-CPR and C-CPR groups.

Results:
Among 1219 patients from 56 institutions, 483 patients (39.6%) received E-CPR. Nearly 75% (910/1219) of patients were <1 year of age with 39% (477/1219) under 1 month. Older patients were more likely to receive E-CPR (p=0.004). E-CPR utilization increased over the study period (p<0.001). Non-Hispanic White patients accounted for almost half of the population (575/1219) and were also more likely to receive E-CPR (p=0.044) compared to other races/ethnicities. Patients with cyanotic cardiac malformations (p=0.005), congestive heart failure prior to admission (p=0.007), and hypotension prior to arrest (p=0.014) were also more likely to receive E-CPR. Unadjusted survival of the index CPR event (98% vs. 63%, p<0.001) and to hospital discharge (47% vs 39%, p=0.007) were both higher in the E-CPR compared to C-CPR group.

Conclusions:
In a large, multicenter study of pediatric cardiac surgical patients suffering in-hospital arrest, we found that E-CPR is commonly used and had significantly higher survival to hospital discharge compared with C-CPR. E-CPR is an important rescue strategy for children with heart disease and centers performing cardiac surgery should develop E-CPR programs.
Abstract 9599: Rechommend: An Ecg-Based Machine-Learning Approach for Identifying Patients at High-Risk of Undiagnosed Structural Heart Disease Detectable by Echocardiography
Authors: Ulloa Cerna Alvaro , Jing Linyuan , Pfeifer John , Raghunath Sushravya , Ruhl Jeffrey , Rocha Daniel , Leader Joseph , Zimmerman Noah , Steinhubl Steven R , Lee Greg , Good Christopher , Haggerty Christopher M , Fornwalt Brandon , Chen Ruijun
Published: April 2022

Introduction:
Timely diagnosis of structural heart disease improves patient outcomes, yet millions remain undiagnosed. ECG-based prediction models can help identify high-risk patients for targeted screening, but existing individual disease models often have low positive predictive values (PPV) and limited clinical utility.

Hypothesis:
An ECG-based composite model can predict one of multiple, actionable structural heart conditions and yield higher prevalence and PPVs than individual models.

Methods:
Using 2,141,366 ECGs linked to echocardiography and EHR records from 461,466 adults from 1984-2021, we trained machine learning models to predict any of 7 echocardiography-confirmed diseases within 1 year. This composite label included: moderate or severe valvular disease (aortic stenosis or regurgitation, mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction of <50%, or interventricular septal thickness >15mm. We tested various combinations of inputs and evaluated model performance with 1) cross-validation and 2) a simulated retrospective deployment. We measured area under the receiver operating characteristic curve (AUROC) and precision-recall curve (AUPRC), and PPV at 90% sensitivity.

Results:
Our composite "rECHOmmend" model using age, sex and ECG traces had an AUROC of 0.91, AUPRC of 0.78, and PPV of 52% at 90% sensitivity and 23% disease prevalence. Individual disease models had similar AUROCs (0.88-0.93), but lower AUPRCs (0.07-0.71) and PPVs (2%-41%; Figure). Across inputs, model AUROCs ranged from 0.85 to 0.93. Our simulated deployment model classified 22% of at-risk patients in 2010 as high-risk, of whom 40% developed true, echo-confirmed disease within 1 year.

Conclusions:
An ECG-based machine learning model using a composite endpoint can predict undiagnosed structural heart disease, outperforming single disease models with higher PPVs to facilitate targeted screening with echocardiography.
Abstract 9609: Pioneering Cardiac Radioablation With the Use of an MRI Linear Accelerator. Can We Use a Gamma Knife

®

to the Heart as We Do in the Brain?
Authors: Biederman Robert W , Liu Emerson , Lee Danny , Oh Seungjong , Pavord Daniel , Trombetta Mark , Fast Martin , Colonias Tom , Verhoeff Joost , Doyle Mark , Shaw George , Thosani Amit , Parda David , Sohn Jason
Published: April 2022

Introduction:
VT is often refractory to medical therapy and on rare but critical cases, even EP ablation. Despite investigation into endocardial, mesocardial and occasionally even epicardial ablation for these recalcitrant and deadly arrhythmias, there remains an inability to more effectively, non-invasively, treat VT.

Hypothesis:
We propose that, paralleling a Gamma Knife

®

approach, the use of a novel MRI linear accelerator (MR Linac), the Unity
®
(Elekta AB, Stockholm, Sweden), a
proof of concept
could be applied to highly selected pts with obstinate VT.

Methods:
A multi-center team with EP, Radiation Oncology and CMR (GE 1.5T) in joint development with Pittsburgh, PA and Utrecht, The Netherlands, developed a completely EP-CMR-guided method for non-invasive VT ablation utilizing
S
tereo
T
actic
A
rrhythmia
R
adioablation (STAR) with 25 Gy in a single fraction via MR Linac.

Results:
To evaluate deliverability and applicability of MR Linac plans, four IMRT per clinical scan were developed with varying delivery parameters (7A: 7-beams: 52
o
in 70 segments (seg), 7B: 7-beams: 52
o
in 100 seg, 15A: 15-beams: 24
o
in 70 seg, and 15B: 15-beams: 24
o
in 100 seg). We used a 0.2 cm dose grid and a 1% uncertainty via Monte Carlo
®
dose calculation. Pt specific QA/QC used ArcCHECK
®
(Sun Nuclear, FL) to evaluate individual IMRT plans. 3D CMR with LGE scar fusion for lesion integration guided non-invasive MR LinAc ablation. Accordingly, all IMRT plans were clinically acceptable (>97% of 7-beams and ≥98.0% of 15-beams in 3%/3mm gamma) for MR LinAc VT-ablation successfully with pt target effective arrhythmogenic myocardial ROI volume as ascertained via CMR of 63-99cm
3
. All 4 pts tolerated the 25±5min procedure without esophageal, pericardial or pro-arrhythmic complications and were alive at 30d FU with marked attenuation of VT burden. At 30d FU, no SAE's occurred to include pro-arrhythmias, pericardial effusions or esophageal fistulas.

Conclusions:
Refractory, complex and anatomically endocardially-remote VT has the potential to be curative, incorporating an analogous Gamma Knife

®

approach via MR Linac radioablation heralding a migration to the Unity

®

platform. This nearly first-in-man
p
r
oof of concept
approach may shepherd a new methodologic era into heretofore intractable VT.
Abstract 9669: Association of Pathogenic DNA Variants for Cardiomyopathy With Cardiovascular Disease Outcomes and All-Cause Mortality
Authors: Patel Aniruddh P , Wang Minxian , Pirruccello James , Dron Jacqueline S , Ng Kenney , Natarajan Pradeep , Lebo Matthew , Ellinor Patrick T , Aragam Krishna , Khera Amit V
Published: April 2022

Introduction:
Pathogenic DNA variants associated with inherited cardiomyopathies are recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. The prevalence and clinical importance of such variants within the context of contemporary clinical care warrant further study.

Methods:
Using whole exome sequencing data from participants in Atherosclerosis Risk in Communities (ARIC) and the UK Biobank (UKBB), observed DNA sequence variants in any of 12 genes (
ACTC1, GLA, LMNA, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1,
and
TTN
) known to be causative of inherited cardiomyopathies with accepted preventative or therapeutic interventions were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status per recommendations from the American College of Medical Genetics. The relationship of carrier status to risk of death or cardiovascular disease was assessed.

Results:
Among 9,667 ARIC participants (mean [SD] age 54 [5.7] years; 43.8% female) and 49,744 UKBB participants (mean [SD] age 57.1 [8.0] years; 54.6% female), 68 (0.70%) and 362 (0.73%) harbored an actionable pathogenic or likely pathogenic variant associated with cardiomyopathy, respectively. Carriers of these variants were not reliably identifiable by imaging or electrocardiography signatures. Presence of these variants was associated with 1.7- to 1.8-fold increased risk of heart failure, 2.1- to 2.9-fold increased risk of atrial fibrillation, and 1.6- to 1.8-fold increased risk of all-cause mortality across studies.

Conclusions:
The findings suggest that approximately 0.7% of middle-aged adult population in ARIC and the UKBB harbored a pathogenic variant associated with cardiomyopathy. Carriers of these variants would be difficult to identify within routine clinical practice but suffer from increased risk of cardiovascular disease and all-cause mortality.
Abstract 9681: Guideline Directed Lipid Therapy Prescribing Patterns Contrasted by Achievement in Optimal Lipid Levels in Patients Following Acute Coronary Syndrome
Authors: Ambrosino Maxwell , Emerson Sydney , Hernandez Patricia , Jacoby Douglas
Published: April 2022

Introduction:
Initiation of guideline directed lipid therapy (GDLT) for patients following acute coronary syndrome (ACS) is a well-established secondary prevention. Despite this, variable prescriber adherence to GDLT has been observed and it is not well understood how this impacts achievement of optimal LDL across gender and racial groups.

Hypothesis:
Gender and racial disparities in GDLT and subsequent achievement of LDL <70 mg/dL exist.

Methods:
A cross-sectional study was employed across University of Pennsylvania Health System from 2018 to 2019. Electronic medical records were queried for all admitted patients diagnosed with ACS. Data was collected for age, gender, race, and prescribed lipid medication at both discharge and up to 1-year post-discharge.

Results:
We identified 3386 patients of which 66.8% were male and 33.1% were female. The majority was white (63.5%), followed by 21.2% Black, <4% Asian, <3%, <2% East Indian, and <1% American Indian. Discharge compared to post-discharge percentages of prescribed GDLT are as follows: 78.0% to 62.9% all patients; 75.2% to 60.8% White, 82.6% to 72.4% Black, 78.1% to 49.1% Asian, 85.8% to 64.7% Hispanic, 77.1% to 58.3% East Indian, 85.7% to 57.1% American Indian. At post-discharge, patients with LDL <70 mg/dL are as follows: 50.7% all patients, 55.5% male, 41.2% female, 53.9% White, 41.1% Black, 54.0% Asian, 44.4% Hispanic, 37.9% East Indian, and 80% American Indian. Non-statin therapy was only prescribed to 13.3% of all patients.

Conclusions:
Disparities were observed among gender and racial groups in both prescribed GDLT and sustained LDL levels < 70 mg/dL. The first step in overcoming disparities is through recognition. An improved holistic understanding of the existing disparities through further investigation will allow for targeted improvements in care and outcomes.
Abstract 9682: The Cardiac Protective Effects of Novel Synthetic Pan-Estrogen Related Receptor Agonists Slu-pp-332 and Slu-pp-915
Authors: Xu Weiyi , Billon Cyrielle , Li Hui , Nasiotis Eleni , Fu Chen , Pei Liming , Wynshaw-Boris Anthony , Burris Thomas P , Zhang Lilei
Published: April 2022

Introduction:
Estrogen receptor-related orphan receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Mice lacking ERRα and ERRγ develops lethal cardiomyopathy and heart failure. Therefore, activation of ERR is a potential therapeutic intervention for HF treatment. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effect
in vivo
.

Hypothesis:
ERR agonist can provide cardioprotection against heart failure.

Methods:
Two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915) were chemically synthesized. Transaortic constriction (TAC) was performed to induce heart failure in adult male mice. Cardiac function was assessed by echocardiography. Wheat germ agglutinin (WGA) staining was perform on cardiac muscle sections.
In vitro
study was performed in neonatal rat ventricular myocytes (NRVMs).

Results:
332 treatment significantly improved ejection fraction and mitochondrial ultrastructure, and reduced the expression of Nppa/Nppb and cardiac fibrosis in mice after 6-week TAC. Consistently, 915 treatment also greatly improved cardiac function
in vivo
. However, echocardiography and WGA staining showed that 332/915 failed to prevent cardiac hypertrophy in mouse after 6-week TAC. Moreover, 332/915 did not prevent the cardiomyocyte hypertrophy as well as activation of ERK1/2 and NFAT signaling pathways in NRVMs treated with phenylephrine. Further analysis using transcriptomics and metabolomics approaches revealed that 332/915 upregulated oxidative phosphorylation and fatty acid metabolism pathway
in vitro
. In addition, 332/915 induced downregulation of cell cycle genes
in vitro
, which was partially mediated by E2F1. Finally, interrogation of ERR dependency showed that siRNA knockdown of ERRγ, but not ERRα or ERRβ, abolished most of the 332/915-induced transcriptions of metabolic genes
in vitro
.

Conclusions:
332/915, mainly through ERRγ, elevate mitochondrial function and fatty acid metabolism leading to improved cardiac function in TAC-induced heart failure, suggesting ERR agonist holds potential as a heart failure therapeutic agent.