bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9685: Long-Term Efficacy and Safety of Mavacamten in Patients with Non-Obstructive Hypertrophic Cardiomyopathy: Interim Results from the MAVERICK-LTE Cohort of the MAVA-LTE Study
Authors: Owens Anjali , Sherrid Mark V , Wong Timothy C , Bach Richard G , Wever-Pinzon Omar , Rigolli Marzia , Balaratnam Ganesh , Ma Grace , Mealiffe Matthew E , Edelberg Jay M , Lakdawala Neal K , Masri Ahmad , Wang Andrew
Published: April 2022

Introduction:
In the phase 2 MAVERICK-HCM study in patients (pts) with non-obstructive hypertrophic cardiomyopathy (nHCM), mavacamten, a cardiac myosin inhibitor, was well tolerated and associated with significant reduction in biomarkers of myocardial wall stress and injury over 16 weeks (wks). Long-term efficacy and safety of mavacamten are being evaluated in MAVA-LTE.

Methods:
Pts who completed MAVERICK-HCM were eligible to enroll in the MAVERICK-LTE cohort of MAVA-LTE. Pts who received mavacamten in MAVERICK-HCM continued on the same dose; pts on placebo were randomized (1:1) to 1 of 2 target mavacamten plasma concentration groups (~200 or ~500 ng/mL) and started on 5 mg, with dose titration at Wk 6 (dosing not based on clinical response). Pts were evaluated at Wks 8, 12, 16, 24, and every 12 wks thereafter. An interim analysis was performed (longest follow-up at data cutoff, 96 wks; efficacy data presented through Wk 48).

Results:
At the data cutoff, 43 pts were enrolled in MAVERICK-LTE (mean age, 54 yrs; 65% female; mean dose, 7.6 mg/day). Median NT-proBNP significantly decreased by 58% at Wk 24 and by 67% at Wk 48 (Table). Significant reductions were also observed in tissue Doppler E/e’ at Wks 24 and 48 and in left atrial volume index (LAVI) at Wk 48. There was a modest reduction in left ventricular ejection fraction (LVEF) of 5.4% at Wk 48 without significant changes in LV stroke volume (Wk 48 mean ± SD change, 0.0 ± 8.5 mL). Most treatment-emergent adverse events were considered mild or moderate and unrelated to treatment. Nine pts temporarily discontinued treatment due to LVEF <50% (range, 36%-49%); 7 were asymptomatic, 8 resumed treatment at a lower dose after recovery of LVEF ≥50%, and 1 permanently discontinued.

Conclusions:
Consistent with the parent study, longer-term mavacamten was well tolerated and demonstrated sustained reduction in NT-proBNP in pts with nHCM. Improvements in LV relaxation and diastolic function by mavacamten were evidenced by lower E/e’ and LAVI.
Abstract 9690: Perceived Control, but Not Health Literacy or Self-Care Link Income Inequity and Health-Related Quality of Life in Patients With Heart Failure
Authors: Wu Jiarong R , Moser Debra K
Published: April 2022

Background:
Income, one of the social determinants of health, has a major impact on health outcomes, especially health-related quality of life (HRQOL) in patients with heart failure (HF). Yet, the mechanisms for the association between income inequity and HRQOL are not clear.

Objective:
To explore the effect of income inequity on HRQOL, as well as factors that mediate this relationship in patients with HF.

Method:
We included 540 patients with HF (age 65±13, female 41%, NYHA class III/IV 35%) in this study. Household income was collected by patient interview. HRQOL was measured using the Minnesota Living with Heart Failure. We collected demographic (age, ethnicity, education, marital status), clinical (NYHA, LVEF, ACE inhibitor use, beta-blocker use), and cognitive/behavioral data (health literacy, self-care behaviors, perceived control) as potential factors that might link income inequity and HRQOL. Chi-square, t-tests, and linear regression were used for data analyses.

Results:
About three quarters (74%) of patients had low household income (≤ $40K). Patients in the low household income group were more likely to be female, minority, not married, and to have less than a high school education, low health literacy, and lower levels of perceived control than those in the high household income group. There were no difference in age, LVEF, ACE inhibitor use, beta-blocker use, or self-care behaviors between low and high income groups. Income was associated with HRQOL. Patients in the low income group had poorer HRQOL. With and without adjustment for all covariates (age, gender, ethnicity, education, marital status, left ventricular ejection fraction, Angiotensin Converting Enzyme inhibitor use, beta-blocker use), income was not a significant predictor of HRQOL (
p =
.29) after entering perceived control (
p
< .001) in the model, demonstrating mediation. Health literacy and self-care behaviors did not mediate the relationship between income and HRQOL.

Conclusion:
HF patients with low household income were more likely to have poorer HRQOL. Perceived control was a mediator between income inequity and HRQOL. This suggests intervention to enhance patients’ perceived control may reduce the impact of income inequity on HRQOL.
Abstract 9701: Hemodynamic Parameters Deteriorate Over Time, and Relate to Adverse Clinical Outcomes, in Children and Adults with Fontan Circulation
Authors: Halickman Ryan , Erdmann Alexandra , Trucco Sara , Kreutzer Jacqueline , Seckeler Michael D , Alsaied Tarek , Goldstein Bryan H
Published: April 2022

Introduction:
In patients with univentricular heart disease, Fontan palliation allows for improved survival. However, Fontan circulatory function deteriorates over time, marked by the onset of functional limitations, morbidities, and mortality. Invasive surveillance offers insights into hemodynamic conditions and may facilitate identification of at-risk patients.

Objective:
To characterize longitudinal changes in invasive Fontan hemodynamics and evaluate for associations with adverse clinical outcomes.

Methods:
Single-center retrospective study of serial invasive hemodynamics (≥2 catheterizations) in Fontan patients from 2006-2020. The first and last procedures per patient were analyzed for Fontan pressure, ventricular end diastolic pressure (EDP), cardiac output (CO), systemic (SVR), pulmonary (PVR) and total vascular resistance (TVR). The composite clinical endpoint included death, heart transplant or listing, Fontan takedown, protein losing enteropathy, plastic bronchitis, admission for arrhythmia or congestive heart failure and Fontan revision.

Results:
Serial hemodynamic evaluations were analyzed in 71 Fontan patients, with first catheterization occurring at median age of 7.1 years (IQR 4.1, 14) and 8.4 years (4.7, 12.3) between assessments. The most common diagnosis was hypoplastic left heart syndrome (45%). Fontan pressure, CO and PVR did not significantly change between assessments, whereas EDP increased by 1.9±3.6 mmHg (
p
<0.001). The annualized rate of change in EDP was 0.2±0.14 mmHg/year. SVR (2.0±7.5 U x m
2
,
p
=0.012) and TVR (2.16 ±7.8 U x m
2
,
p
=0.031) also increased significantly between assessments. The clinical endpoint was met in 43 (61%) patients and was associated with a greater change in transpulmonary gradient (0.13±1.9 vs -0.87±2.0 mmHg,
p
=0.046) and Fontan pressure (1.1±5.4 vs -0.7±2.7 mmHg,
p
=0.066) but not EDP, CO, SVR, PVR or TVR.

Conclusion:
Over a relatively brief time period, this single-center cohort of Fontan patients demonstrated clinically significant longitudinal increases in EDP, SVR and TVR. Adverse clinical outcomes were common and associated with greater hemodynamic deterioration between assessments. Serial interrogation of Fontan hemodynamics is likely to prove clinically useful.
Abstract 9722: P53-phlda3 Signaling Induced by Carbon-Ion Irradiation is a Novel Therapeutic Target to Suppress Cardiac Hypertrophy in Mice
Authors: Furukawa Nozomi , Okano Naoko , Yoshida Yukari , Shimokawa Takashi , Kanai Akinori , Ohno Tatsuya , Koitabashi Norimichi
Published: April 2022

Background:
Irradiation to the heart increases the risk of several cardiac disease including coronary artery disease, heart failure, pericardial disease and cardiac arrythmia, therefore, the heart has been considered one of the organs at risk in thoracic irradiation. On the other hand, recent experimental studies suggested irradiation may ameliorate cardiac injury and arrhythmia after myocardial infarction. To test irradiation effects on pathological cardiac remodeling, we examine the effects from irradiation in a mouse model of heart failure.

Methods and Results:
We used cardiac hypertrophy and heart failure mice model induced by transverse aortic constriction (TAC), irradiated by X-ray (20, 30 Gy) or carbon-ion beam (10, 30 Gy) at 2 weeks after pressure overload, and examined the changes in cardiac function by echocardiography. Concerning to the X-ray, 1 week after irradiation, ventricular systolic dysfunction induced by TAC was attenuated compared with control group. Among the X-irradiated groups, the higher dose improved cardiac function better. However, at 2 weeks post-irradiation, the cardiac function decreased again. On the other hand, carbon-ion irradiation improved left ventricular function and cardiac hypertrophy even at 2 weeks post-irradiation. The BNP expression was increased in TAC-treated mice and markedly decreased in irradiated mice, suggesting improvement of cardiac hypertrophy and cardiac remodeling. Cardiac p53 phosphorylation is markedly induced by cardiac irradiation. RNA sequencing using irradiated heart revealed pleckstrin homology-like domain family A, member 3 (PHILDA3), a downstream of p53 was significantly upregulated after X-ray or carbon-ion irradiation. PHLDA3 was decreased by TAC treatment, but improved especially in 30 Gy carbon-ion irradiation group. Akt phosphorylation, a hypertrophic signal and downstream target of PHLDA3, was suppressed by irradiation after TAC.

Conclusion:
Irradiation, especially with carbon-ion beam, brought a beneficial effect on pathological cardiac remodeling. Irradiation induced p53-PHLDA3-Akt signaling might be novel therapeutic target in the pathogenesis of heart failure.
Abstract 9731: Improved Risk Stratification with Vendor Independent Coronary Calcium Scores: Data from the Multi-Ethnic Study of Atherosclerosis (mesa)
Authors: Dobrolinska Magdalena M , van der Werf Niels , Greuter Marcel J , Willemink Martin J , Fleischmann Dominik , Slart Riemer , Budoff Matthew , Leiner Tim
Published: April 2022

Introduction:
Coronary calcium score (CCS) plays a role in cardiovascular disease (CVD) risk calculators, but also reclassifies patients when considering statin therapy. However, CCS is still calculated following the Agatston methodology as developed on electron beam tomography (EBT) in the early 1990s. EBT has been replaced by multidetector computed tomography (MDCT). It is known that CCS differs substantially between MDCT-systems from different manufacturers, which can lead to risk reclassifications for 6.5% of examined individuals

Aims:
Our first aim was to identify CT system specific conversion factors to calculate a vendor-neutral Agatston score (rCCS). Second, we aimed to validate rCCS risk stratification for participants of the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods:
As a first step, we calculated conversion factors between six state-of the-art CT systems and the reference EBT system used in the MESA study. For this purpose, we scanned two calcium-containing inserts, which were placed in a small and large anthropomorphic thorax phantom. Linear regression was used to find a model which converts vendor-specific CCS to vendor-independent rCCS. As a second step, we recalculated the non-zero Agatston scores of 550 MESA participants. Following the Youden method, we calculated an optimal cut-off point for rCCS.

Results:
The linear model for each CT system allowed for prediction of Agatston scores as measured on the EBT system (p=0.001). rCCS for GE LightSpeed, used in MESA, was calculated as rCCS=0.049+1.97xMESA Agatston score and rCCS=1.903+1.37xMESA Agatston score for small and large size, respectively. The median MESA Agatston score was 100.5 (26.3-379.5), and the median rCCS was 135.8 (35.6-508.6). Participants were assigned to a high Agatston category with Agatston scores exceeding 100 (50.2%) and 187 (43.1%) for CCS and rCCS, respectively. The hazard ratio for CVD of individuals with high Agatston scores increased from 1.88 (95%CI: 1.31-2.68, p=0.001) with MESA scores to 2.15 (95%CI: 1.52-3.05, p=0.001) with rCCS. rCCS reclassified 39 participants into the lower risk group, without statin therapy.

Conclusions:
In conclusion, based on these preliminary results, rCCS may improve patient classification for statin therapy.
Abstract 9749: High-Avidity Binding Drives Nucleation of Amyloidogenic Transthyretin Monomer in Cardiac Amyloidosis
Authors: Gao Li , Xie Xinfang , Liu Pan , Jin Jing
Published: April 2022

Amyloidosis involves stepwise growth of fibrils assembled from soluble precursor proteins. Mutations of plasma carrier protein transthyretin (TTR) are associated with hereditary transthyretin amyloidosis (ATTR). TTR naturally folds into a stable tetramer for its function, whereas conditions and mutations that foster aberrant monomer formation facilitate TTR oligomeric aggregation and subsequent fibril extension. We investigated the dynamics of early assembly of oligomers by wild-type TTR, in comparison to its
TTR
V30M and
TTR
V122I disease mutants. We selected buffer conditions for monitoring time-dependent redistribution among monomer, dimer, tetramer, and oligomer contents in the presence and absence of multimeric TTR seeds. The seeds were artificially constructed recombinant multimers that contained 20-40 TTR subunits via engineered biotin-streptavidin interactions. As expected, these multimer seeds rapidly nucleated TTR monomers and dimers into larger complexes, while having no effect on tetramers.
In vivo
, streptavidin-induced multimers formed ATTR-like deposits in the heart and the kidney following
i.v.
injection in mice. While all three variants prominently deposited in the kidney glomerulus, only
TTR
V30M resulted in extensive deposition in the heart. The cardiac TTR deposits varied in size and shape and were localized to the intermyofibrillar space along the capillaries. These results are consistent with the notion of monomeric TTR to engage high-avidity interactions with tissue amyloids. Our multimeric induction approach therefore provides a new model for studying the initiation of TTR deposition in the heart.
Abstract 9751: Combined Cardiomyopathy and Arrhythmia Genetic Testing Identifies Clinical Management Implications and Unexpected Results
Authors: Dellefave-Castillo Lisa , Cirino Allison , Callis Tom E , Esplin Ed , Hatchell Kathryn , Johnson Britt , Morales Ana , Regalado Ellen , Rojahn Susan , Vatta Matteo , Nussbaum Robert , McNally Elizabeth
Published: April 2022

Introduction:
Genetic testing for heritable cardiomyopathy and arrhythmia syndromes has evolved rapidly and is now recommended by cardiology professional societies to establish a genetic etiology, guide clinical management, and identify at-risk family members through cascade screening. However, the advantages of comprehensive, multi-condition gene panels versus condition-specific gene panels are debated.

Objective:
To assess the yield and clinical management implications of combined cardiomyopathy and arrhythmia genetic testing in a diverse cohort of patients referred for a suspected inherited cardiomyopathy or arrhythmia using a no-charge, sponsored genetic testing program.

Methods:
De-identified clinical histories and genetic test results were reviewed from a no-charge cardiomyopathy and arrhythmia genetic testing program. Up to 150 genes associated with cardiomyopathies and arrhythmias were evaluated, and positive findings were compared to provider diagnoses at the time of testing request.

Results:
In a cohort of 4,782 patients, a positive result (molecular diagnosis) was observed in 961 (20%). Of the positive results, 670/961 (70%) conferred clinical management implications, including genes associated with targeted therapy (6%; 57/961) or increased risk of ventricular arrhythmia (18%; 169/961). Positive results for 11% (75/691) of evaluable patients would have been missed by condition-specific panels based on clinician-provided diagnoses.

Conclusions:
Combined cardiomyopathy and arrhythmia genetic testing identified clinically-relevant variants for 1 in 5 patients suspected of a cardiomyopathy or arrhythmia. Over two-thirds of positive findings had clinical management implications. Combined disease testing captures >10% of patients who would be missed with condition-specific panels and this greater clinical utility may outweigh the burden of uncertain results.
Abstract 9758: Estimating Cardiovascular and Limb Benefits of Combined Contemporary Risk Reduction Therapies in Patients with Symptomatic Peripheral Artery Disease: An Analysis of Randomized Controlled Trials
Authors: Hussain Mohamad A , Dey Tanujit , Lipsitz Stuart R , Bhatt Deepak L , Verma Subodh , Eikelboom John W , Bonaca Marc P , Belkin Michael , Ozaki C Keith , Al-Omran Mohammed
Published: April 2022

Introduction:
Individual randomized controlled trials (RCTs) have shown beneficial effects of low dose rivaroxaban and PCSK9 inhibition (PCSK9i) in addition to background aspirin and statin in patients with peripheral artery disease (PAD). However, the combined effect of these pharmacotherapies is not known. In this analysis of RCT data, we sought to estimate the combined effect of contemporary risk reduction therapies in patients with PAD.

Methods:
We used data from the COMPASS (n=4,129) and FOURIER (n=3,642) trials to estimate the combined effect of contemporary (aspirin, statin, low dose rivaroxaban and PCSK9i) versus standard therapy (aspirin and statin) in symptomatic PAD patients. The primary outcome was a composite of major adverse cardiovascular (MACE) or limb (MALE) events. Using the hazard rates for low dose rivaroxaban versus control and PCSK9i versus control from the two trials, we estimated the hazard rate for combined therapy by assuming that the treatment effects are approximately additive on the log hazard rate (no interaction between the two treatments). We then used an exponential model to simulate event-free survival and cumulative incidence functions, and hazard ratios (HRs) for the combined versus the standard therapy group.

Results:
Compared with standard therapy, combined contemporary pharmacotherapy estimated a 50% reduction in MACE or MALE (HR, 0.50; 95% confidence interval [CI], 0.36-0.70; P<0.001). The 3-year cumulative incidence probability of MACE or MALE was 9.1% in the combined group and 15.4% in the standard therapy group (
Figure
). The hazards for MACE (HR, 0.52; 95% CI, 0.36-0.75; P=0.001) and MALE (HR, 0.35; 95% CI, 0.18-0.68; P=0.002) also favored combined contemporary therapy.

Conclusions:
Thoughtful incorporation of contemporary pharmacotherapies that include low dose rivaroxaban and PCSK9i in addition to aspirin and statin has the potential to substantially reduce cardiovascular and limb events in patients with PAD.
Abstract 9759: Race Moderates the Relationship Between Anxiety and Quality of Life in Implantable Cardioverter Defibrillator Recipients
Authors: Miller Jennifer L , Chung Misook L , Hammash Muna H , Latimer Abigail , Czarapata Melissa M , Hesselson Aaron , Moser Debra K
Published: April 2022

Introduction:
The implantable cardioverter defibrillator (ICD) has significantly decreased mortality for populations at high risk for sudden cardiac arrest. Despite its effectiveness, this treatment modality comes with a high potential for psychological distress. The prevalence rate of anxiety in ICD recipients is 50%, with the highest levels reported in Black ICD recipients, yet little is known about the role of race in the relationship between anxiety and quality of life (QOL). Understanding racial disparities in the experience of ICD recipients has been limited due to low numbers of Black participants in research studies. This is reflective of the clinical reality that fewer Black patients for whom an ICD is appropriate are offered or accept the treatment.

Methods:
In this cross-sectional study we used the Hayes SPSS Process macro for moderation analysis (model 1) with 5000 bootstrap samples to determine whether race moderated the relationship between anxiety (Brief Symptom Inventory) and QOL (EURO-QOL-5D3L).

Results:
Using data from 136 participants (18% Black, 27% women with mean age 63
+
12 and education 14
+
3), we entered anxiety, race, and the interaction term into a simultaneous regression model while controlling for gender, age, education, depression, history of shock, and ICD knowledge. The interaction between anxiety and race was significant (B = -.1330, SE = .1339,
p
< .015), suggesting that the effect of anxiety on QOL differed between Black and White ICD recipients. Together, the variables accounted for approximately 33% of the variance in QOL (R
2
= .33, F (1,126) = 6.08, p < .001). Simple slope tests revealed a significant negative association between anxiety and QOL for Black ICD recipients (B = -.3712, SE = .05,
p
= .005) but not for White ICD recipients (B = -.0412, SE = .0478,
p
= .390).

Conclusion:
Assessment, recognition, and referral for treatment of anxiety in ICD recipients, particularly Black ICD recipients, may improve QOL for this population.
Abstract 9769: Bicarbonate Treatment Before Reperfusion Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibition of Spleen-Mediated Inflammatory Response
Authors: Zhang Aimee , Marsh Katherine , Rastogi Radhika , Kron Irving L , Yang Zequan
Published: April 2022

Introduction:
The spleen plays an important role in mediating myocardial ischemia/reperfusion injury (IRI). Sodium bicarbonate (NaHCO
3
) administration is reported to inhibit spleen-mediated inflammatory responses via vagus nerve activation.

Hypothesis:
NaHCO
3
treatment attenuates myocardial IRI in a spleen dependent-manner.

Methods:
C57BL/6 mice underwent 40 minutes of LCA occlusion followed by 60 minutes of reperfusion. PBS (control), NaHCO
3
(1 mEq/ml), or 5.8% NaCl of equivalent osmolality were administered intravenously (IV) 10 minutes before reperfusion at a dose of 1 μl/g. Intraperitoneal (IP) NaHCO
3
was administered 10 minutes before reperfusion at low dose (0.25 mEq/ml, 20 μl/g), high dose (0.5 mEq/ml, 20 μl/g), or as a localized topical rinse of the spleen or liver (1 mEq/ml, 1μl/g). Infarct size (IF), denoted as percentage of risk region (RR, % of LV), was measured by TTC-Phthalo blue staining. Additional groups (n=4) without IRI received IV PBS, IV NaHCO
3
, or IP NaHCO
3
splenic rinse and underwent plasma and spleen harvest 10 minutes after treatment.

Results:
RR was comparable among all groups with IRI. Among IV-treated groups (Figure A), IF was similar with PBS and 5.8% NaCl (51±4% and 46±3%), while IV NaHCO
3
significantly reduced IF to 25±3% (p<0.05 vs. PBS & 5.8% NaCl). Among IP-treated groups (Figure B), low-dose NaCO3, high-dose NaHCO
3
, and topical NaHCO
3
spleen rinse equally attenuated IF compared to control (p<0.05), while topical NaHCO
3
liver rinse did not reduce IF (51±2%, p = NS vs. control). IV NaHCO
3
administration elevated base excess and HCO
3
-
without changing pH, pO
2
or pCO
2
. IV and topical splenic NaHCO
3
elevated plasma GLP-1 and enhanced splenic monocyte M2 polarization.

Conclusions:
Both IV and IP NaHCO
3
treatment attenuated IF via inhibiting spleen-mediated inflammatory responses. Sodium bicarbonate administered prior to reperfusion may a potential therapeutic adjunct for ischemia/reperfusion injury in acute coronary syndrome.
Abstract 9771: Novel Contribution of an Epigenetic Factor "g9a" in Pulmonary Arterial Hypertension
Authors: Awada Charifa , Grobs Yann , Breuils-bonnet Sandra , Krishna Vinod , JEYASEELAN Jey R , Potus Francois , Paulin Roxane , Provencher Steeve , Bonnet Sebastien , BOUCHERAT Olivier
Published: April 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a vascular disease characterized by an increased mean pulmonary artery (PA) pressure. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients exhibit a “cancer-like” hyperproliferative and apoptosis-resistant phenotype leading to pulmonary vascular remodeling. It is believed that these alterations are influenced by epigenetic processes. However, it is still not clear which gene are the drivers. “G9a”, a histone methyltransferase, is known to be overexpressed in different types of cancer, promoting cell survival and proliferation. Given the similarities between PAH and cancer, we hypothesized that G9a could be implicated in PAH progression and pathogenesis.

Methods and Results:
Using Western blot (WB) and immunofluorescence (IF), we showed that G9a is significantly upregulated in distal PAs and isolated PASMCs from PAH patients (n= 6-14, p<0.01). Similarly, G9a was increased (p<0.05) in three PAH animal models: monocrotaline (MCT), fawn-hooded rat (FHR) and mice exposed to chronic hypoxia.
In vitro,
pharmacological G9A inhibition using BIX01294 reduces PAH-PASMC proliferation (Ki67/ EdU assays, p<0.001) and survival (Annexin V assay, p<0.001). Through RNA sequencing analysis conducted in PAH-PASMCs treated or not with BIX01294, we found that upregulated genes were significantly enriched in “cholesterol biosynthesis” and “autophagy”. Consistently, G9a inhibition was accompanied by an increased lipid accumulation and an impaired autophagy flux as evidenced by the appearance of numerous cytoplasmic vacuoles positive for LC3-II (IF, WB), the accumulation of yellow puncta in PAH-PASMCs expressing the RFP-GFP-LC3 fusion protein, the unaffected LC3-II expression after adding chloroquine and the defect in cathepsin B and D maturation (WB). Same results were seen with UNC0642, another G9A inhibitor.
In vivo
, we showed that BIX01294 significantly improved established PAH in FHR (reduced RVSP and mPAP, increased SV and CO, by right heart catheterization, and attenuated pulmonary vascular remodeling, p<0,001).

Conclusion:
We showed that G9a upregulation contributes to the pro-proliferative phenotype of PAH-PASMCs; and its inhibition represents a novel avenue to improve PAH.
Abstract 9777: Acute Anemia and Outcomes in ACS Treated with Mechanical Circulatory Support
Authors: Harutyunyan Misak , Adhikari Anish , Hamza Mohammad , Belov Dmitri , Torosoff Mikhail
Published: April 2022

Introduction:
Anemia increases mortality in acute coronary syndromes (ACS). Mechanical circulatory devices (MCS) are known to cause anemia due to mechanical shearing, but there is limited data evaluating the prognostic significance of anemia in ACS patients treated with MCS.

Methods:
A single center retrospective cohort study included 210 consecutive ACS (56% STEMI) patients treated with MCS (IABP in 73%, 27% micro-axial pump Impella®) based on the clinical need. Clinical characteristics, hospital course details, and outcomes were obtained from the electronic health records.

Results:
The study cohort included 76% males, 66.9±10.9 years old, with atrial fibrillation (AF) in 9%, HTN in 43%, CHF in 37%, CAD in 42%, CABG in 40%, diabetes in 24%, COPD in 8%, and stroke in 6%. Average MCS duration was 4.0±2.8 days, with vascular complications in 17%, bleeding in 42%, transfusion in 40%, and kidney replacement therapy (KRT) in 15%. All-cause mortality was 16.2% with mean time to death of 11.2±1.2 days. There were no differences in pre-MCS Hgb between expired patients and survivors (12.3±2.6 vs. 12.8±2.2 g/dL, p=0.197). Post-MCS 24-hour Hgb was significantly lower in the expired patients (10.4+/-2.4 vs. 11.7+/-2.3, p=0.003) and in patients with prior CAD (11.1+/-2.1 vs. 11.8+/-2.5, p=0.037), while sex, AF, HTN, CABG, DM, COPD, or stroke did not affect Hgb. Admission shock (HR 4.7, 95%CI 2.087-10.783, p<0.001) and KRT (HR 5.4, 95%CI 2.331-12.667, p<0.001) decreased survival, while higher 24-hour Hgb (HR=0.74, 95% CI: 0.61-0.90, p=0.002) and higher presentation GFR (HR 0.968, 95%CI 0.948-0.989, p=0.003) improved survival. Transfusion did not affect mortality (18% vs. 15% in non-transfused patients, p=0.549). In a multivariate analysis, admission shock (HR 2.9, 95%CI 1.192-7.059) and KRT post MCS (HR 3.876, 95%CI 1.574-9.546, p=0.003) remained predictive of reduced survival, while Hgb and GFR were not important.

Conclusion:
Acute anemia in ACS patients treated with MCS is not prognostically significant. It remains unclear whether there is an optimal hemoglobin level which could alter the prognosis. Ongoing trials (MINT) are evaluating the optimal strategy of managing anemia in AMI.
Abstract 9779: The Utility of Endoscopic Screening in Mitigating the Risk of Gastrointestinal Bleeding After Left Ventricular Assist Device Placement. A Retrospective Chart Review Study
Authors: Mohamed Wael T , Azab Mohamed , Shatla Islam , Sammour Yasser , Everley Mark P , Heimes Jessica K , Sperry Brett W
Published: April 2022

Introduction:
Left ventricular assist device (LVAD) is a lifesaving bridge to transplantation or destination therapy for patients with end-stage heart failure. More than one-third of patients suffer from gastrointestinal (GI) bleeding within one year of placement. We investigated the yield and safety of endoscopic screening for potential sources of GI bleeding before LVAD insertion.

Hypothesis:
Endoscopic screening prior to LVAD placement does not necessarily reduce the risk of GI bleed post LVAD.

Methods:
We performed a retrospective chart review study of patients at Saint Luke’s Mid America Heart Institute who underwent continuous-flow LVAD implantation from 2010 to 2020. Study participants were categorized based on whether or not they underwent screening endoscopy prior to LVAD implantation. Patients were followed for one year after implantation, and outcomes were collected to determine the yield and safety of these procedures. A multivariable logistic regression analysis was performed using SPSS® controlling for the following confounding factors: age, gender, race, and history of GI bleeding.

Results:
Among 205 patients with an LVAD, 169 patients were included in the study after excluding those with lack of data or those lost to follow up. 68 (40.23%) patients who received pre-LVAD screening by either upper and/or lower endoscopies, and 42 (24.85%) patients who had post-LVAD GI bleed. Patients who underwent pre-LVAD screening had similar rates of GI bleeding after LVAD compared to those who were not screened (odds ratio 1.66, 95% CI 0.648-4.264, P=0.2). Moreover, in patients with post LVAD GI bleed, endoscopy findings were typically different than those pre LVAD. No complications to the endoscopic interventions were reported.

Conclusions:
While endoscopic screening appears to be safe in patients before LVAD implantation, it had no association with GI bleeding risk or etiology after LVAD.
Abstract 9782: Disruption of Notch1 and Gata5 in Mice Results in Clinically Relevant Aortic Valve Disease
Authors: Yasuhara Jun , Ueyama Yukie , Adamczak Sara , Cameron Emily , Garg Vidu
Published: April 2022

Congenital malformations of the aortic valve are the most common type of congenital heart defect, but the underlying mechanisms of congenital aortic valve disease (AVD) remain poorly understood.
NOTCH1
mutations are associated with AVD, and we previously reported that
Notch1;Nos3
mutant mice display AVD. However, this mouse model has limitations since ~65% mutant mice suffer neonatal lethality.
GATA5
is also implicated in human AVD, and
Gata5
-/-
mice display bicuspid aortic valve, with an associated reduction in Notch signaling. We hypothesized that interaction of Notch1 and Gata5 was critical for aortic valve morphogenesis, and generated novel murine models by intercrossing
Notch1
and
Gata5
heterozygote mice. We characterized the cardiac phenotype in mice that are heterozygous for
Notch1
and
Gata5
(

Notch1
+/-
;Gata5
+/-

) and also those that are heterozygous for
Notch1
and null for
Gata5
(

Notch1
+/-
;Gata5

-/-
). While normal Mendelian ratios were present at 6 weeks and 4 months of age, echocardiography demonstrated an increased incidence of aortic stenosis/regurgitation in

Notch1
+/-
;Gata5
+/-

mice (52%: 11/21) and

Notch1
+/-
;Gata5

-/-
mice (86%: 6/7). Histological examination revealed thickened, dysmorphic aortic valve cusps and left ventricular hypertrophy in

Notch1
+/-
;Gata5
+/-

and

Notch1
+/-
;Gata5

-/-
mice compared to wild-type,

Notch1
+/-
, Gata5
+/-

, and
Gata5
-/-
mice. In addition, 1 year old

Notch1
+/-
;Gata5
+/-

mice displayed 100% incidence of aortic valve stenosis/regurgitation with thickened valve cusps. At postnatal day 10, the aortic valve cusps of

Notch1
+/-
;Gata5
+/-

and

Notch1
+/-
;Gata5

-/-
mice were significantly larger than controls consistent with a neonatal phenotype. Interestingly,

Notch1
+/-
;Gata5

-/-
mice displayed significantly thickened aortic valve cusps compared to

Notch1
+/-
;Gata5
+/-

mice. Further examination at embryonic day 18.5 demonstrated thickened, malformed aortic valves in
Notch1;Gata5
mutant embryos. In conclusion, our findings demonstrate a novel genetic interaction of Notch1 and Gata5 necessary for the proper remodeling of aortic valves. Our new mouse models display highly penetrant congenital AVD without lethality, allowing for studying disease progression to identify novel therapeutic targets.
Abstract 9786: Myocardial Contractile Dysfunction and Anti-Troponin I Immunoreactivity in a Mouse Model of Combination Immune Checkpoint Inhibitors
Authors: Xu Shirley , Karthikeyan Badri , Pechenik Peninah , Kattel Sharma , Spernyak Joseph , Turowski Steven , Sonkawade Swati D , Nepali Sarmila , Sharma Umesh C , Pokharel Saraswati
Published: April 2022

Introduction:
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many incurable cancers. However, serious cardiotoxic side effects, such as fatal myocarditis, have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known.

Hypothesis:
Combination ICIs are more cardiotoxic than monotherapy alone and can induce both T- and B-cell mediated responses against cardiac proteins.

Methods:
We intraperitoneally administered either 200μg of programmed cell death-1 (PD-1) antibody (Ab), 100μg of cytotoxic T-lymphocyte associated protein-4 (CTLA-4) Ab, both treatment Abs, or IgG control every 3 days for a total of 17 doses in mice. Cardiac function was monitored by MRI and myocardial inflammatory cells were characterized by immunohistochemistry. After identifying specific cardiac troponin I (cTnI) antigenic sequences by bioinformatic analyses, biotinylated peptides were synthesized and immobilized to streptavidin-coated plates for enzyme-linked immunosorbent assays (ELISA) to detect self-reactive anti-troponin Abs.

Results:
PD-1 Ab, CTLA-4 Ab, and the combination significantly decreased cardiac contractile velocities compared to IgG (peak systolic velocity cm/s: IgG -1.27 ± 0.131, PD-1 Ab -1.14 ± 0.0531, p=0.02 vs. IgG, CTLA-4 Ab -1.07 ± 0.0359, p<0.01 vs. IgG, PD-1+CTLA-4 Ab -1.04 ± 0.0872, p<0.001 vs. IgG). However, ejection fraction (EF) was only reduced with combination treatment (EF%: IgG 60.1 ± 2.80, PD-1+CTLA-4 Ab 56.6 ± 3.17, p=0.03). There were also significantly more myocardial CD8
+
cells with combination treatment (cells/mm
2
: IgG 3.03 ± 1.34, PD-1+CTLA-4 Ab 7.93 ± 2.41, p=0.004). Serum ELISA showed cross-reactivity against cTnI, suggesting the formation of auto-antibodies and significantly high titers were detected with combination treatment (450 nm absorbance: IgG 0.162 ± 0.0859, PD-1+CTLA-4 Ab 0.397 ± 0.121, p=0.002).

Conclusions:
Our study showed that ICI-therapy induced myocardial inflammation (including CD8
+
T-cell infiltration), contractile dysfunction, and immune-reactive antibodies directed against immunogenic targets of cTnI. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.
Abstract 9794: Factors Associated with Enhanced Low-Density Lipoprotein Cholesterol Lowering with Bempedoic Acid Among Patients Enrolled in Phase 3 Studies
Authors: Ballantyne Christie M , Bays Harold E , Smart Jeremy , Zhang Yang , Ray Kausik K
Published: April 2022

Bempedoic acid (BA) inhibits ATP-citrate lyase in the cholesterol synthesis pathway. In phase 3 studies, 12 weeks of BA lowered low-density lipoprotein cholesterol (LDL-C) levels compared with placebo by a mean of 17.8% among patients primarily receiving moderate- to high-intensity statin and by 24.5% among statin intolerant patients who were receiving low-dose or no statin. Cholesterol guidelines (Grundy et al.
J Am Coll Cardiol
. 2019;73:e285) categorize statins according to percent LDL-C lowering: high-intensity (≥ 50%), moderate-intensity (30-49%), and low-intensity (< 30%). We examined LDL-C lowering with BA similarly using pooled data from 4 phase 3 studies in patients on background maximally tolerated statins; 3488 (2321 BA, 1167 PBO) patients were included in the analysis. From baseline to week 12, BA lowered LDL-C levels comparable to that of a moderate- or high-intensity statin (≥ 30%) in 28.9% of patients; this degree of LDL-C lowering was observed in 50.9% of the patients not receiving background statin therapy (Table). A multivariate analysis showed that the absence of baseline statin use was associated with increased rates of achieving at least a 30% reduction in LDL-C with BA treatment (odds ratio [95% CI], 2.49 [1.94, 3.19;
P
< .0001). Further, being female, a history of diabetes, baseline ezetimibe use, and a higher baseline hsCRP level were also associated with at least a 30% reduction in LDL-C levels (
P
< .01 for each). These findings suggest that 1) a significant proportion of patients initiating BA treatment may achieve LDL-C lowering comparable to moderate- or high-intensity statin therapy, especially among patients who cannot tolerate a statin, and 2) patients with hypercholesterolemia who are at higher risk for a cardiovascular event, including women and patients with a history of statin intolerance, diabetes, or higher baseline hsCRP levels, may also achieve enhanced LDL-C lowering with bempedoic acid.
Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension
Authors: Rhodes Christopher J. , Sweatt Andrew J. , Maron Bradley A.
Published: April 2022

Pulmonary hypertension is a complex disease with multiple causes, corresponding to phenotypic heterogeneity and variable therapeutic responses. Advancing understanding of pulmonary hypertension pathogenesis is likely to hinge on integrated methods that leverage data from health records, imaging, novel molecular -omics profiling, and other modalities. In this review, we summarize key data sets generated thus far in the field and describe analytical methods that hold promise for deciphering the molecular mechanisms that underpin pulmonary vascular remodeling, including machine learning, network medicine, and functional genetics. We also detail how genetic and subphenotyping approaches enable earlier diagnosis, refined prognostication, and optimized treatment prediction. We propose strategies that identify functionally important molecular pathways, bolstered by findings across multi-omics platforms, which are well-positioned to individualize drug therapy selection and advance precision medicine in this highly morbid disease.
The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure
Authors: Boucherat Olivier , Agrawal Vineet , Lawrie Allan , Bonnet Sebastien
Published: April 2022

Pulmonary hypertension (PH) describes heterogeneous population of patients with a mean pulmonary arterial pressure >20 mm Hg. Rarely, PH presents as a primary disorder but is more commonly part of a complex phenotype associated with comorbidities. Regardless of the cause, PH reduces life expectancy and impacts quality of life. The current clinical classification divides PH into 1 of 5 diagnostic groups to assign treatment. There are currently no pharmacological cures for any form of PH. Animal models are essential to help decipher the molecular mechanisms underlying the disease, to assign genotype-phenotype relationships to help identify new therapeutic targets, and for clinical translation to assess the mechanism of action and putative efficacy of new therapies. However, limitations inherent of all animal models of disease limit the ability of any single model to fully recapitulate complex human disease. Within the PH community, we are often critical of animal models due to the perceived low success upon clinical translation of new drugs. In this review, we describe the characteristics, advantages, and disadvantages of existing animal models developed to gain insight into the molecular and pathological mechanisms and test new therapeutics, focusing on adult forms of PH from groups 1 to 3. We also discuss areas of improvement for animal models with approaches combining several hits to better reflect the clinical situation and elevate their translational value.
Novel Approaches to Imaging the Pulmonary Vasculature and Right Heart
Authors: Alenezi Fawaz , Covington Taylor A. , Mukherjee Monica , Mathai Stephen C. , Yu Paul B. , Rajagopal Sudarshan
Published: April 2022

There is an increased appreciation for the importance of the right heart and pulmonary circulation in several disease states across the spectrum of pulmonary hypertension and left heart failure. However, assessment of the structure and function of the right heart and pulmonary circulation can be challenging, due to the complex geometry of the right ventricle, comorbid pulmonary airways and parenchymal disease, and the overlap of hemodynamic abnormalities with left heart failure. Several new and evolving imaging modalities interrogate the right heart and pulmonary circulation with greater diagnostic precision. Echocardiographic approaches such as speckle-tracking and 3-dimensional imaging provide detailed assessments of regional systolic and diastolic function and volumetric assessments. Magnetic resonance approaches can provide high-resolution views of cardiac structure/function, tissue characterization, and perfusion through the pulmonary vasculature. Molecular imaging with positron emission tomography allows an assessment of specific pathobiologically relevant targets in the right heart and pulmonary circulation. Machine learning analysis of high-resolution computed tomographic lung scans permits quantitative morphometry of the lung circulation without intravenous contrast. Inhaled magnetic resonance imaging probes, such as hyperpolarized 129Xe magnetic resonance imaging, report on pulmonary gas exchange and pulmonary capillary hemodynamics. These approaches provide important information on right ventricular structure and function along with perfusion through the pulmonary circulation. At this time, the majority of these developing technologies have yet to be clinically validated, with few studies demonstrating the utility of these imaging biomarkers for diagnosis or monitoring disease. These technologies hold promise for earlier diagnosis and noninvasive monitoring of right heart failure and pulmonary hypertension that will aid in preclinical studies, enhance patient selection and provide surrogate end points in clinical trials, and ultimately improve bedside care.
A new fossil representative of the scorpionfly subfamily Panorpinae (Mecoptera, Panorpidae) from the Miocene of France
Authors: JOUAULT CORENTIN , NEL ANDRÉ
Published: April 2022

The extant representatives of the order Mecoptera (except Siphonaptera now considered to belong to the Mecoptera: Tihelka et al., 2020) are famous among insects because of their long beaklike rostrum but also, because the males of the family Panorpidae have enlarged genitals raised over the body, and are called scorpionflies. The order Mecoptera is thought to have arisen during the Carboniferous period (Misof et al., 2014), a dating corroborated by their abundant fossil record during the Permian period (https://paleobiodb.org), and the presence of the antliophoran sister group Amphiesmenoptera during the late Carboniferous (Nel et al., 2007). The origin of the main family of Mecoptera i.e., the Panorpidae, was estimated to date to the Early Cretaceous (ca. 122.5 Ma) (Miao et al., 2019). The phylogenetic relationships within the family Panorpidae were recently investigated and revised using morphological data (Wang & Hua, 2021) and new hypotheses were proposed for their past dispersal events. Wang & Hua (2021: fig. 17) assumed that the Panorpidae originated from Asia and that at least two dispersal events have shaped the west European fauna. Here we describe a new specimen of scorpionfly from the Miocene of Murat (Cantal, France).
On the Clubiona reclusa species-group in China, with the description of Clubiona qianlei sp. nov. (Araneae, Clubionidae)
Authors: ZHANG JIANSHUANG , CHEN LULU , DING YANMEI , ZHANG FENG , YU HAO
Published: April 2022

The representation of the Clubiona reclusa species-group in China is here established in two species: Clubiona qianlei sp. nov. from Central China and C. interjecta L. Koch, 1879, which is mainly distributed in northern China. Detailed description, diagnosis, photographs of the new species are given. DNA barcodes (a partial fragment of the mitochondrial cytochrome oxidase subunit I gene, COI) of the new species were obtained to confirm matching of the sexes and for future use in molecular studies. Supplementary micrographs of C. interjecta are provided for the first time, alongside an emended diagnosis, to demonstrate the validity of C. qianlei sp. nov.. A distribution map of the reclusa group species in China is given.
Three new species in the genus Chanohirata (Hemiptera: Cicadellidae: Deltocephalinae: Penthimiini) from China
Authors: WANG DONGMING , ZHANG YALIN
Published: April 2022

Two morphologically similar genera of Penthimiini, Chanohirata Hayashi & Machida, 1996 and Reticuluma Cheng & Li, 2005 are reviewed. Three new species, Chanohirata yunnana, C. minima and C. plania spp. nov., are described and illustrated and a new synonymy is proposed: C. theae (Matsumura, 1912) equals Reticuluma testacea (Kuoh, 1991) syn. nov. The following new combinations are also proposed for species previously included in Reticuluma: C. bipennata (Xu, Yu, Dai & Yang) comb. nov., C. dactyla (Fu & Zhang) comb. nov., C. eurya (Fu & Zhang) comb. nov., C. hamata (Wang & Zhang) comb. nov., C. lini (Cheng & Li) comb. nov., C. lageniformia (Wang & Zhang) comb. nov. and C. spinata (Cheng & Li) comb. nov. As a result, the definition of Reticuluma is restricted to include only the type species, R. citrina Cheng & Li, which differs from Chanohirata in having an apical process on the male pygofer. A species checklist and a key to all known species of Chanohirata are presented along with a distribution map for China.