bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14264: The Impact of Bariatric Surgery on Echocardiographic Features of Cardiac Remodeling and Diastolic Function
Authors: Dalsania Raj K , Ibrahim Kaitlyn , Soans Rohit , Haddad Abdullah , Eddy Vikram J , Tragesser Lauren , Zhang Liti , Whitman Isaac R , McComb Joseph J , Keane Martin G
Published: May 2021

Introduction:
Candidates for bariatric surgery are at increased risk for cardiovascular disease and often develop adverse cardiac remodeling as a result of obesity. Bariatric surgery can alter cardiac structure and function in these patients; however, this has not been fully investigated.

Hypothesis:
We hypothesized that patients undergoing bariatric surgery would demonstrate favorable cardiac remodeling and improvement in diastolic parameters according to the American Society of Echocardiography (ASE) guidelines.

Methods:
All patients undergoing bariatric surgery at our institution from 2014-2018 were reviewed. In patients with pre- and post-operative echocardiograms, the following were measured: left ventricular (LV) size, pulmonary artery systolic pressure (PASP), LV mass, mitral E/A, LV ejection fraction (EF), medial and lateral E/e’, medial e’ and a’, lateral e’ and a’, tricuspid regurgitation (TR) velocity, left atrial volume index (LAVI), degree of LV hypertrophy, and relative wall thickness (RWT). The grade of diastolic dysfunction (DD) was calculated according to ASE guidelines.

Results:
A total of 69 patients met criteria for inclusion, with 77% (n=53) female, 87% (n=60) non-white, and mean age 49±10.7. Mean decrease in BMI one year post-operatively was 14.6±5.7 kg/m
2
. Median time between bariatric surgery and post-operative echocardiogram was 21.8 months. Post-operatively, there was a mean 17.8 cm/s decrease in TR velocity (p=0.0064) and 4.2 mmHg decrease in PASP (p=0.02). LAVI increased by 3.4 mL/m
2
(p=0.048). There was no significant change in LV size, LV mass, LVEF, LV hypertrophy, or RWT. Out of the 29 patients with pre-existing DD (grade 1, n=20; grade 2, n=8; grade 3, n=1), 45% (n=13) demonstrated improvement in grade of DD. When compared to pre-operative DD, post-operatively, 5 of 20 patients with G1DD had no DD, 2 of 8 patients with G2DD had no DD, 5 of 8 patients with G2DD had G1DD, and 1 patient with G3DD had G1DD. This was driven by a decrease in TR velocity and medial E/e’.

Conclusions:
In patients undergoing bariatric surgery, TR velocity and PASP improved while LAVI paradoxically increased. Patients with pre-existing DD demonstrated improvement in diastology, driven by changes in TR velocity and medial E/e’.
Abstract 14265: Physical Activity Lowers Cardiovascular Mortality by Mediating Systemic Inflammation: The Strong Heart Study
Authors: Unlu Ozan , Almarzooq Zaid , Fretts Amanda M , Zhang Ying , Stoner Julie , Umans Jason G , Cole Shelley A , Roman Mary J , Devereux Richard B , SINGH Parmanand
Published: May 2021

Background:
Prior work has shown that fibrinogen, a well-known inflammatory marker, is associated with cardiovascular (CV) events. While it is known that physical activity (PA) imparts CV health benefits, there remains a knowledge gap on the interactions of PA with systemic inflammation on risk of CV death among American Indians.

Hypothesis:
To investigate the relationship between PA, inflammation, and CV death, we tested the hypotheses that: (i) PA is associated with lower risk of CV death, and (ii) the CV benefit of PA is mediated via an inflammatory pathway.

Methods:
We examined the association between PA (leisure-time plus occupational as METs[Metabolic Equivalent of Task]-hours per week via a validated questionnaire) and CV death among 3,135 adults (mean age 56 ± 8) without baseline CV disease in Strong Heart Study (1989-1991), a longitudinal study among American Indians. Preacher and Hayes bootstrap method was used for the model assessing mediation by fibrinogen.

Results:
During 26 years (mean 17.3 ± 8 years) of follow-up, there were 378 CV deaths. Compared to participants with minimal activity, subjects with higher levels of PA had a lower risk of CV death. Odds ratios were 0.91 (95% confidence interval [CI]: 0.65-1.21), 0.69 (95% CI: 0.51-0.92), and 0.56 (95% CI: 0.39-0.71) (p-trend=0.003), for increasing quartile of activity compared to the lowest, after adjustment for age, sex, study site, education, smoking, diabetes, hypertension, BMI, LDL cholesterol, and urine albumin-creatinine ratio. Mediation analysis showed the effect of PA on CV death was fully mediated via fibrinogen level (correlation coefficient: 0.998, 95% CI 0.995-0.999; Sobel test z= -3.11, p=0.03) (Figure).

Conclusion:
In a population-based study of American Indians, PA compared to inactivity, was associated with lower risk of CV death. This study highlights that PA is associated with improved CV outcomes and this effect is largely driven by inflammation.
Abstract 14266: Management of Spontaneous Coronary Artery Dissection: Trends Over Time
Authors: Fitzsimmons Elliot , Thompson Elizabeth , Wilensky Robert L , McCarthy Clare , Lewey Jennifer
Published: May 2021

Introduction:
Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of ACS that preferentially impacts young women. Increasing evidence suggests that patients with SCAD do well with a conservative approach, as intramural hematoma frequently resolves with medical management and complications from PCI are common. Our objective is to describe changes in management of SCAD over time at the University of Pennsylvania Health System (UPHS).

Methods:
We conducted a retrospective cohort study among patients treated within UPHS from 2005-2019. We identified all patients in the electronic health record with SCAD using ICD-9 (414.12) and ICD-10 (I25.42) codes. Charts were manually reviewed and indexed by date of SCAD event. Time categories were calculated by tertiles of patients. Since the first tertile spanned 21 years, this category was subdivided. The most recent time period represents practice after the AHA Scientific Statement on SCAD was published. Cochran-Armitage trend tests compared trends over time.

Results:
We identified 140 patients with SCAD. In this cohort, 43% of patients treated from 1993-2005 were managed conservatively, compared to 89% of patients treated in 2018-2019, while 57% of patients treated from 1993-2005 were managed invasively, compared to 11% of patients treated in 2018-2019, p<0.001 for trend over time (Figure). Between 1993-2005 and 2018-2019, the use of DAPT increased from 40% to 80% (p<0.001 for trend) and use of statins increased from 60% to 85% (p=0.021 for trend). Beta blocker use remained stable (80% vs. 89%, p=0.401) and ACEi/ARB use varied considerably without a clear trend over time (p=0.553).

Conclusions:
The proportion of patients with SCAD managed conservatively has steadily increased since 2015. This trend corresponds to the increased understanding of clinical outcomes of this patient population. Medical treatment has changed over time and most patients are treated with DAPT, statins, and beta blockers.
Abstract 14268: Responses to Exercise During Right Heart Catheterisation in Pulmonary Hypertension
Authors: Wiltshire Stephanie , Kearney Katherine , Brown Karen , Corrigan Carolyn , Pidoux Annette , Koppe Erik , Lau Edmund , Muthiah Kavitha , Hayward Christopher S , Kotlyar Eugene , Keogh Anne
Published: May 2021

Background:
Hemodynamic changes during exercise at right heart catheterisation (RHC) may be a diagnostic and prognostic tool in pulmonary arterial hypertension (PAH).

Method and Results:
We retrospectively assessed the hemodynamic response to exercise during RHC of 138 patients with PAH secondary to idiopathic PAH (IPAH), connective tissue disease (CTD) or congenital heart disease (CHD). RHCs were performed at a single centre between 2007 and 2018. A submaximal comfort-based protocol on a reclined bicycle or straight leg raise test (SLRT) was employed. IPAH demonstrated the highest mean pulmonary artery pressure (mPAP) at rest, rising 47% with exercise, but a 66% rise in CO allowed pulmonary vascular resistance (PVR) to fall. Those with CTD demonstrated a 56% rise in mPAP, 70% rise in CO and PVR remained unchanged. In CHD, there was a 46% rise in mPAP, 49% rise in CO and a rise in PVR. Notably, there was a rise in pulmonary artery wedge pressure (PAWP) in all groups, most marked in those with IPAH. Total peripheral resistance (TPR), pulmonary artery compliance (PAC) and pulmonary artery elastance (Ea) changes were variable. TPR marginally decreased in IPAH patients, remained unchanged in those with CTD and increased in CHD. PAC decreased in all groups, with the lowest values observed in those with IPAH. Ea increased in all groups but was most notably higher in those with IPAH. Right ventricular stroke work index (RVSWI) increased in all patients, the lowest values before and after exercise were observed in the CTD cohort. Mean pulmonary artery pulsatility index (PaPi) increased in all groups, although was subtle and didn’t meet statistical significance for those with CTD and CHD.

Conclusions:
The hemodynamic response to exercise in patients with PAH differs between aetiologies. A rise in PAWP occurred in all groups, with ventricular interdependence a possible explanation. Whether there is a relationship between exercise hemodynamic changes and prognosis remains undetermined.
Abstract 14270: The Effect of Evinacumab on Apheresis Eligibility in Patients With Homozygous Familial Hypercholesterolemia
Authors: Raal Frederick J , Rosenson Robert S , Reeskamp Laurens F , Hovingh G. Kees , Kastelein John J , Rubba Paolo , Ali Shazia , Banerjee Poulabi , Chan Kuo-Chen , Khilla Nagwa , McGinniss Jennifer , Pordy Robert , Zhang Yi , Gaudet Daniel
Published: May 2021

Background:
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Evinacumab, a fully human monoclonal antibody against angiopoietin-like protein 3, has demonstrated approximately 50% reductions in LDL-C in HoFH patients when added to maximally tolerated lipid-lowering therapies.

Objective:
In this post-hoc analysis, we assessed the effect of evinacumab on the eligibility for apheresis using predefined US and EU apheresis criteria.

Methods:
This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to evinacumab 15 mg/kg intravenously every 4 weeks (Q4W; n=43) or placebo (n=22). We assessed the proportion of patients who met per protocol US apheresis criteria (LDL-C ≥300 mg/dL), newer US criteria for FH (LDL-C ≥300 mg/dL or LDL-C ≥160 mg/dL with coronary heart disease or peripheral artery disease) and per protocol EU apheresis criteria (LDL-C >160 mg/dL [primary prevention] or >120 mg/dL [secondary prevention]) at baseline and week 24.

Results:
Under the newer US criteria (2018), 62.8% (n=27) of evinacumab-treated patients and 54.5% (n=12) placebo-treated patients qualified for apheresis at baseline (Table). Following 24 weeks of treatment, 48.8% of all evinacumab versus 9.1% of all placebo patients no longer qualified for apheresis. Similar results were observed using EU apheresis criteria, where 46.5% of evinacumab-treated patients shifted from qualifying for apheresis at baseline to not qualifying at week 24, compared with 4.5% of placebo-treated patients. The majority of evinacumab (65.1%) and placebo (68.2%) patients did not qualify for per protocol US apheresis at baseline, however a shift of 27.9% and 9.1% was observed, respectively.

Conclusions:
Evinacumab has the potential to reduce the need for apheresis in patients with HoFH.
Abstract 14290: Treadmill Exercise Training Reduces the Systolic Blood Pressure Response to Walk Exercise in Patients With Peripheral Artery Disease
Authors: Slysz Joshua , Tian Lu , Zhao Lihui , Zhang Dongxue , McDermott Mary M
Published: May 2021

Introduction:
Supervised exercise therapy (SET) improves functional capacity in people with peripheral artery disease (PAD). However, the effects of SET on improving cardiovascular health remain unclear. This study investigated the effects of a 6-month SET intervention on the blood pressure (BP) response to walking exercise in patients with PAD.

Methods:
Participants with PAD randomized to either SET or control group in the NHLBI sponsored PROPEL clinical trial were included. The SET intervention consisted of 3X weekly supervised treadmill exercise for 6 months. Participants in the control group attended weekly education sessions for 6 months. A Gardner-Skinner treadmill test (GSTT) and six-minute walk (6MW) test were completed at baseline and 6-month follow-up. BP was measured at the end of each 2-min stage of the GSTT. Mixed-effects regression models compared the 6-month change in systolic BP (SBP) & diastolic BP (DBP) between groups for each of the first 5 stages of the GSTT. Pearson correlation coefficients were used to relate the average 6-month change in DBP & SBP for the first 5 stages of the GSTT with the 6-month change in 6MW distance.

Results:
Ninety-seven participants with PAD (67 ± 9 years, 39 (40%) female, 65 (67%) black) completed a 6-month GSTT. Compared to the control group, SET significantly decreased SBP at stage 1, stage 2, stage 3, and stage 4 of the GSTT (Table 1). There were no effects of SET on DBP (Table 1). A greater reduction in SBP during the first 5 stages the GSTT test was associated with significantly greater improvement in 6MW distance at 6-month follow-up of SET (Pearson’s r = -0.37; 95%CI: -0.52, -0.19; p < 0.001). However, there were no associations of reduction in DBP with improvement in 6MW distance.

Conclusions:
These results show that SET improves cardiovascular health in people with PAD. Furthermore, results suggest that improved CV health in part explains the improved 6MW in response to SET in people with PAD.
Abstract 14297: Potential Role of the Tumor Suppressor WWOX in Mediating Skeletal Muscle-Lung Vasculature Crosstalk in PH-HFpEF
Authors: Halliday Gunner , Bai Yang , Gomes Marta T , Goncharov Dmitry , Goncharova Elena , Gladwin Mark T , MacHado Roberto F , Lai Yen Chun
Published: May 2021

Introduction:
Pulmonary hypertension due to left heart disease (PH-LHD; Group 2), particularly in the context of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide. At present, no specific effective therapy has been identified mainly due to the fact that major pathways involved in the regulation of PH-HFpEF are still not well understood.

Results:
We have recently reported on a role of skeletal muscle sirtuin-3 (SIRT3) in modulating PH-HFpEF. Using skeletal muscle-specific SIRT3 knockout mice (
Sirt3
skm-/-
), we showed that absence of SIRT3 in skeletal muscle drastically reduced the pulmonary vascular tree accompanied by vascular proliferative remodeling. Interestingly, we found that expression levels of the tumor suppressor WW domain-containing oxidoreductase (WWOX) were decreased in pulmonary arterial smooth muscle cells (PASMCs) obtained from
Sirt3
skm-/-
mice, while no changes in SIRT3 activation levels were detected. Reduced WWOX expression levels were also found in PASMCs isolated from SU5416/Obese ZSF1 (Ob-Su) rat model of PH-HFpEF, in which the levels of SIRT3 activation were found to be decreased in skeletal muscle, but not in the lungs and PASMCs. No changes of WWOX levels were observed in skeletal muscle of Ob-Su rats or in pulmonary artery endothelial cells (PAECs) treated with plasma obtained from Ob-Su rats.

Conclusions:
Since reduction of WWOX in PASMCs has been shown to promote cell proliferation, HIF1α stabilization and pulmonary arterial hypertension (PAH; Group 1), our data suggest a potential role of WWOX in mediating skeletal muscle SIRT3 deficiency-associated remote pulmonary vascular remodeling in PH-HFpEF.
Abstract 14306: Mural Cell SDF1 Signaling is Associated With the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Yuan Ke
Published: May 2021

Introduction:
Pericytes and pulmonary artery smooth muscle cells (PASMCs) are NG2+ mural cells that provide structural support to pulmonary vessels. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization, but whether distinct mechanisms that are responsible for their behavior is unclear.

Methods:
RNA-Seq was used to compare the gene profile of pericytes and PASMCs isolated from PAH and healthy lungs. NG2-CreER mice were used to generate tamoxifen-inducible NG2-selective reporter mice (NG2tdT
fl/+
) for cell lineage identification and for NG2-selective SDF1 knockout (SDF1
NG2-KO
).

Results:
Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is significantly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that tdT+ cells accumulate in muscularized arteries. RNAseq analysis performed on these hypoxic tdT+ cells demonstrated significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared to controls, SDF1
NG2-KO
mice in chronic hypoxia had reduced RVSP, fulton index, less muscularization and lower abundance of NG2+ cells around microvessels (Fig. 1). In addition, SDF1 stimulation in human healthy pericytes induced greater contractility, impaired their capacity to establish endothelial-pericyte tube formation and increased expression of SMC markers SMA, Calponin and SM22. In contrast, SDF1 knockdown reduced PAH pericyte proliferation, contractility and improved endothelial cell tube formation on matrigel.

Conclusions:
SDF1 is upregulated in NG2+ mural cells. High expression of SDF1 could drive pericyte detachment and gain an SMC-like phenotype that contributes to abnormal muscularization and vascular obstruction. Targeting SDF1 could help prevent and reverse muscularization in PAH.
Abstract 14312: Hexokinase 1 Cellular Localization Regulates the Metabolic Fate of Glucose
Authors: DEJESUS Adam
Published: May 2021

Introduction:
The product of hexokinase (HK) enzymes, glucose-6-phosphate (G6P), can be metabolized through glycolysis or directed to alternative pathways, such as the pentose-phosphate-pathway (PPP) for anabolism. However, it is not known what determines the fate of G6P. HK1 contains an N-terminal mitochondrial-binding domain, but its physiologic significance remains unclear. Inflammation is a tightly controlled process sensitive to dynamic changes in the tissue environment and the intrinsic state of immune cells, both contributing to the initiation and resolution of inflammation. The loss of HK1 attenuates glycolytic reprogramming and inflammatory cytokine production in LPS stimulated macrophages. Given the importance of HK1 in the innate immune response, we used myeloid cells as a model system to study the effect of HK1 subcellular localization on cellular metabolism and inflammation.

Results:
We overexpressed full-length and truncated HK1 in tissue culture and generated mice lacking the HK1 mitochondrial-binding domain (ΔE1HK1). Although ΔE1HK1 mice displayed no overt phenotype, HK1 dislocation from the mitochondria increased glucose flux through the PPP, decreased flux below the level of GAPDH, and induced a hyper-inflammatory response to lipopolysaccharide. The mechanism for the increased PPP flux is through a glycolytic block at GAPDH, which is mediated by binding of cytosolic HK1 with S100A8/A9 and increased GAPDH nitrosylation through iNOS. Human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed an increase in cytosolic HK1 and cytokine production, along with reduced GAPDH activity.

Conclusions:
Our data indicate that HK1 subcellular localization is a critical regulator of glucose metabolism and determines whether glucose is shuttled into PPP at the expense of glycolysis, and regulates the inflammatory response in macrophages (Figure).
Abstract 14314: Men Admitted With Takotsubo Syndrome (TTS) Have Increased In-Hospital Morbidity and Mortality: Perspectives From the National Inpatient Sample Database
Authors: Vincent Louis T , Grant Jelani , Ebner Bertrand , Maning Jennifer , Montana Paul , olarte neal , Olorunfemi Odunayo P , de Marchena Eduardo , Colombo Rosario A
Published: May 2021

Introduction:
Takotsubo Syndrome (TTS), also known as Stress Induced Cardiomyopathy, is characterized by reversible left ventricular dysfunction without obstructive coronary disease, and largely affects post-menopausal women. However, limited data suggest increased mortality risk in men. We sought to compare national in-hospital outcomes between men and women admitted with TTS.

Methods:
All patients above 18 years who were admitted with primary diagnosis of TTS between 2012-2017 were identified by International Classification of Diseases (ICD)-9 and ICD-10 diagnostic codes in the National Inpatient Sample (NIS) Database. The primary endpoint was in-hospital all-cause mortality. Secondary endpoints included in-hospital complications, total cost, and duration of hospitalization.

Results:
A total of 8732 patients (90.8% female) were admitted with primary diagnosis of TTS. Women with TTS were older compared to men (66.9±12.4 vs. 63.1±15.7 years, p<0.001). However, men had increased tobacco use (48.8% vs 37.2%), alcohol use (11.6% vs 3.1%), and coronary artery disease (47.0% vs 39.7%, p<0.001 for all). Prevalence of diabetes, hypertension, atrial fibrillation, anemia, and heart failure was similar between groups. Men more frequently developed cardiogenic shock (7.1% vs 4.4%, p<0.001) requiring mechanical circulatory support (2.9% vs 1.7%, p=0.01), and had greater all-cause mortality compared to women (2.5% vs 1.4%, p=0.01). Using a multivariate regression model to adjust for age, race, substance use, and comorbidities, male gender (OR 2.12, 95% CI [1.69-2.68], p<0.001) and cardiogenic shock (OR 15.1, 95% CI [12.6-18.0], p<0.001) were associated with increased all-cause mortality. Lastly, men experienced greater length and cost of stay (4.0±4.2 vs. 3.6±3.6 days, and $56,428 vs. $46,908), fewer routine discharges (74.3% vs. 77.6%), and greater need for skilled nursing facility (11.6% vs. 9.2%, p<0.001 for all).

Conclusion:
TTS occurs predominantly in women but carries increased risk of in-hospital mortality in men, especially when complicated by cardiogenic shock. Perhaps improved risk stratification and early identification of patients with signs of shock or hemodynamic instability may help to improve outcomes.
Abstract 14325: Pooled Analysis of Bleeding, Major Adverse Cardiovascular Events and Mortality in Clinical Trials of Time-constrained Dual-antiplatelet Therapy After Percutaneous Coronary Intervention
Authors: Ramsay Jennifer , McClure John , Berry Colin
Published: May 2021

Introduction:
The net clinical benefit of dual antiplatelet therapy (DAPT) reflects the paradoxical effects of an increased risk of bleeding and a reduced risk of major adverse cardiovascular events (MACE). A time-constrained approach to DAPT has been recently investigated in five multicenter trials including GLOBAL LEADERS, STOP-DAPT2, SMART-CHOICE, TWIGHLIGHT and TICO.

Methods:
We undertook a pooled analysis of these trials to assess the overall associations between time-constrained P2Y12 inhibitor monotherapy (“aspirin free regimen”) for bleeding events, MACE and all-cause mortality as compared to standard care with DAPT for at least 12 months post-PCI. We implemented a DerSimonian and Laird random effects meta-analysis using the metafor package in R.

Results:
32,361 randomized trial participants, including 16,898 (52.2%) with a history of ACS, underwent PCI and had outcome data available. P2Y12 inhibitor monotherapy from 1 - 3 months was associated with a reduced risk for bleeding (hazard ratio (HR) (95% confidence interval (CI)) 0.60 (0.45, 0.81); p=0.024), including in the ACS group in which the magnitude of risk reduction was greatest (HR (95% CI) 0.50 (0.41, 0.61). The estimates of the effect of P2Y12 inhibitor monotherapy on the hazard were also favorable for MACE (0.88 (0.77, 1.02)) and all-cause mortality (95% CI 0.85 (0.71, 1.03)).

Conclusions:
Compared with DAPT for 12 months post-PCI, P2Y12 inhibitor monotherapy from 1-3 months substantially reduces the risk of major and fatal bleeding and, in addition, potentially protective effects, for MACE and all-cause mortality. Considering patient safety, the results support a strategy of DAPT for 1-3 months followed by ‘aspirin free’ P2Y12 inhibitor monotherapy.
Abstract 14331: Patient Outcomes Enhanced by Partner Involvement in Social Cognitive Interventions After an Initial Implantable Cardioverter Defibrillator
Authors: AULD Jon , Thompson Frances Elaine , Dougherty Cynthia M
Published: May 2021

Background:
Research points to reciprocal influences that patients and partners may have on one another’s recovery in cardiac illness, yet interventions to enhance recovery after an implantable cardioverter defibrillator (ICD) are usually directed only toward the patient.

Purpose:
To compare 2 social cognitive (SC) intervention conditions (patient only or P-only, and patient + partner or P+P) from the Patient + Partner RCT. Patient physical symptoms and depression were compared
with
partner caregiver burden over 12 months post initial ICD.

Methods:
The study included 301 patient-partner dyads (151=P-only; 150=P+P) who participated in 1 of 2 nurse-led SC interventions delivered by telephone in the first 3 months after the patient received an ICD. Patient symptoms were measured with the PCA, depression with the PHQ-9, and partner caregiver burden with the OCBS, at baseline, 3, 6, and 12 months. Parallel process growth modeling and mixed effects models were used to compare intervention outcomes.

Results:
Patients were on average 64±12 years old, male (74%), white (91%), and most received an ICD for primary prevention (60%). Partners were on average 62±12 years, female (74%), and white (88%). In the first 3 months, decline in patient depression was significantly associated with decline in partner caregiver burden in P+P (β=0.93; p<0.001), but
not
in P-only (β= -0.14; p=0.54). Decline in physical symptoms was more strongly associated with decline in partner caregiver burden in P+P (β=0.93, p<0.001) than P-only (β=0.58, p=0.02). At 3 months, there were no significant differences in patient physical (p=0.59) and depressive symptoms (p=0.27) for P+P vs P-only. Partner caregiver burden was significantly lower in P+P vs P-only (p=0.01). At 12 months, patient physical and depressive symptoms and partner caregiver burden were significantly lower in P+P vs P-only (p=0.043, p=0.008, p=0.001, respectively).

Conclusion:
A SC intervention that included intimate partners (P+P) showed greater reductions in patient physical and depressive symptoms and partner caregiver burden and reflected greater reciprocal influence than the P-only intervention. Dyadic SC interventions can provide added support for patients after an ICD and may improve partner caregiver burden.
Abstract 14352: Staged Hybrid Atrial Fibrillation Ablation With Addition of Endoscopic Left Atrial Appendage Closure Reduces Arrhythmia Recurrence Between 3 and 12 Months Compared to Non-staged Hybrid Without Closure
Authors: Kress David C , Erickson Lynn , Perez Moreno Ana C , Niazi Imran , Mortada M. Eyman , Zilinski Jodi , Krum David , Sra Jasbir
Published: May 2021

Introduction:
The hybrid, or convergent procedure, uses a minimally invasive combined epicardial/endocardial ablation approach for patients in persistent AF. In the staged hybrid approach, the electrophysiologist performs the endocardial ablation a minimum of 30 days after the surgeon performs epicardial ablation. Placement of a left atrial appendage (LAA) closure device (AtriCure AtriClip) has been shown to electrically isolate the LAA. Added to the scar formation on the posterior wall via epicardial ablation, it eliminates additional substrate in persistent atrial fibrillation (AF).

Hypothesis:
Patients with persistent AF who underwent a staged hybrid approach with thoracoscopic placement of the AtriClip may have less likelihood of arrhythmia recurrence between 3 and 12 months compared with those who underwent nonstaged hybrid ablations without use of the AtriClip.

Methods:
Patients in persistent or long-standing paroxysmal AF underwent ablation using either a staged hybrid approach with AtriClip (n=23) or a nonstaged hybrid approach without AtriClip (n=136). Groups were compared by running a t-test (mean±SD) or Wilcoxon rank sum [median, interquartile range (IQR)]. Categorical data were compared with Pearson’s chi-squared test.

Results:
Significantly fewer patients who had undergone a staged hybrid with AtriClip recurred with arrhythmia (2, 8.7%) compared to those with a nonstaged, no AtriClip approach (40, 29.4%) (p=0.04) between 3 and 12 months. The staged hybrid approach also had significantly fewer patients requiring cardioversion to restore sinus rhythm during the procedure (p<0.001).

Conclusions:
A staged hybrid approach with AtriClip placement reduced recurrent arrhythmia between 3 and 12 months compared to a nonstaged hybrid procedure without AtriClip. A benefit was also seen in a steep reduction in the need for cardioversion during the subsequent endocardial ablation to restore sinus rhythm.
Abstract 14355: Mono- and Biallelic Structural Variants in Alpha-actinin 2 Cause Contractile Dysfunction and Cardiomyopathy in Humans
Authors: Lindholm Malene E , Zhu Han , Seo Kinya , Jimenez-Morales David , Zhao Chunli , Ashley Euan A , Wheeler Matthew T
Published: May 2021

Background and Aim:
Cardiomyopathy is a common cause of sudden cardiac death in children that often requires heart transplantation. Alpha-actinins are critical cytoskeletal proteins that anchor actin filaments within the cardiac sarcomere. Mutations in
ACTN2
have been associated with cardiomyopathy, but the mechanisms behind how those lead to cardiac dysfunction remain poorly understood. The aim of the present study was to investigate the effects of two novel structural
ACTN2
mutations in human cardiac tissue and patient-specific iPSC-derived cardiomyocytes.

Methods and Results:
We identified a patient homozygous for a stop-gain mutation (p.Q860X) and a family heterozygous for a large exon 8-10 deletion with a 41bp insertion (indel) in
ACTN2
, using a custom mutation pipeline optimized for rare variant discovery. In the explanted cardiac tissue of the homozygous patient, we observed mild hypertrophy and interstitial fibrosis. Patient-specific hiPSC-CMs from both families were hypertrophic, displayed sarcomeric structural disarray on transmission electron microscopy, and had slower contractile velocity compared to control hiPSC-CMs. The ACTN2indel protein was expressed, with subsequent incorporation into cardiac sarcomeres. In the homozygous stop-gain cells and normal controls, we used Co-IP followed by mass-spectrometry to identify C-terminal interacting proteins that are disrupted with C terminal loss. We found an intricate ACTN2 interactome with many sarcolemma-associated proteins and showed lack of interaction of the truncated ACTN2 with ACTN1 and GJA1 (Fig. 1). ACTN1 association was verified using colocalization and Co-IP followed by Western blot.

Conclusion:
We provide evidence that two loss of function genetic variants in
ACTN2
are associated with contractile dysfunction and lead to cardiac abnormalities through distinct mechanisms within cardiac sarcomeres and through lack of critical protein-protein interactions.
Abstract 14368: Artificial Intelligence-Electrocardiography to Predict Time to Atrial Fibrillation: An Analysis of Mayo Clinic Study of Aging
Authors: Christopoulos Georgios , Lopez Camden L , Yao Xiaoxi , Attia Zachi I , Graff-radford Jonathan , Rabinstein Alejandro A , Ronald Petersen C , Knopman David , Mielke Michelle M , Kremers Walter , Friedman Paul , Noseworthy Peter A
Published: May 2021

Introduction:
An artificial intelligence (AI) algorithm applied to electrocardiography (ECG) during normal sinus rhythm (NSR) has been shown to predict concomitant atrial fibrillation (AF). We sought to characterize the value of AI-ECG as a predictor of future AF and assess its performance compared to other clinical prediction scores in a population-based sample.

Methods:
We calculated the AI-ECG probability during NSR in patients who enrolled in the population-based Mayo Clinic Study of Aging with at least one ECG in NSR within two years prior and no history of AF at the time of the baseline study visit. The cumulative incidence of AF was estimated for strata defined by AI-ECG probability and CHARGE-AF score. Cox proportional hazards were fit to assess the independent prognostic value and interaction of AI-ECG probability and CHARGE-AF score. Concordance (c) statistics were calculated for AI-ECG probability, CHARGE-AF score and combined AI-ECG and CHARGE-AF score.

Results:
A total of 1,936 patients with a median age 75.8 (quartile range [QR] 70.4, 81.8) years, median CHARGE-AF score 14.0 (QR 13.2, 14.7) and median CHADS2VASC score 3 (QR 2, 4) were included in the analysis. The cumulative incidence of AF increased in a stepwise fashion across quartiles of AI-ECG probability and CHARGE-AF score (Figure 1). When compared in the same model, both AI-ECG probability (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.51-2.04) and CHARGE-AF score (HR 1.90, 95% CI 1.58-2.28) independently predicted AF without significant interaction (p=0.54). C statistics were 0.69 (95% CI 0.66-0.72) for AI-ECG probability, 0.69 (95% CI 0.66-0.71) for CHARGE-AF and 0.72 (95% CI 0.69-0.75) for combined AI-ECG and CHARGE-AF score.

Conclusions:
In the Mayo Clinic Study of Aging, both the AI-ECG probability and CHARGE-AF score independently predicted time to AF. The AI-ECG may offer a means to assess risk with a single test without requiring manual or automated clinical data abstraction.
Abstract 14374: Peripheral Artery Disease and Gait Speed in Women With and at Risk for HIV
Authors: Cedarbaum Emily R , Ma Yifei , Scherzer Rebecca , Adimora Adaora A , Bamman Marcas , Cohen Mardge , Fischl Margaret A , Gustafson Deborah R , Matsushita Kunihiro , Ofotokun Igho , Plankey Michael , Seaberg Eric C , Sharma Anjali , Tien Phyllis C
Published: May 2021

Introduction:
Peripheral artery disease (PAD) is associated with decreased physical function and increased mortality in the general population. PAD is common in women with and at risk for HIV infection, but its association with functional decline is unclear. We examined the contribution of PAD to gait speed in the Women’s Interagency HIV Study, controlling for traditional cardiovascular risk factors and HIV-related factors.

Methods:
1,839 participants (72% HIV+) with measured ankle-brachial index (ABI) and 4-meter gait speed were included in analysis. ABI scores were categorized as: <0.7, moderate-severe PAD; 0.7-<0.9, mild PAD; 0.9-<1.0, borderline PAD; 1.0-<1.1, low-normal; 1.1-1.4, normal. Longitudinal regression models with repeated measures were used to examine the association of PAD category with log-transformed gait speed after controlling for demographic, behavioral, and cardiovascular disease risk factors, and HIV and HCV status. Coefficients represented percentage differences.

Results:
Median age was 50 years, >70% were Black. Figure 1 shows median gait speed by PAD group. In univariate analysis, compared to normal ABI, each category of PAD severity was associated with slower gait speed: 6% slower for low-normal (95% confidence interval [CI]:4%, 9%), 10% for borderline (95% CI:6%, 13%), 14% for mild (95% CI:9%, 18%), and 16% for moderate-severe (95% CI:5%, 25%). In multivariate analysis, PAD severity remained associated with 6% (95% CI:4%, 9%), 10% (95%CI:7%, 14%), 12% (95%CI:8%, 17%), and 11% (95%CI: -1%, 22%) slower gait speed, respectively. HIV/HCV coinfection reduced gait speed by 9% (95%CI:4%, 14%). Among HIV+ women, neither CD4 count nor HIV viral load was associated with gait speed.

Conclusions:
In middle-aged women with and at risk for HIV, greater PAD severity is associated with progressively slower gait speed. ABI measurement may be a simple and clinically useful tool for early assessment of functional declines.
Abstract 14388: Aortic Pulsatility Index Strongly Predicts Clinical Outcomes in Heart Failure Patients: A Sub-analysis of the Escape Trial
Authors: Belkin Mark N , Alenghat Francis J , Besser Stephanie , Nguyen Ann , Chung Bow , Smith Bryan , Kalantari Sara , Sarswat Nitasha , Blair John , Kim Gene H , Grinstein Jonathan
Published: May 2021

Introduction:
Aortic pulsatility index (API), calculated as (systolic - diastolic blood pressure)/pulmonary capillary wedge pressure, is a novel hemodynamic measurement representing cardiac filling pressures and contractility.

Hypothesis:
API would better predict clinical outcomes than traditional hemodynamic metrics of cardiac function in decompensated heart failure patients.

Methods:
The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial individual-level data were used. API, cardiac power output (CPO), Fick cardiac index (CI), and pulmonary artery pulsatility index (PAPI) were calculated after final hemodynamic-monitored optimization. The primary outcome, assessed by univariable analysis, was combined death or need for heart transplant or left ventricular assist device at six months. Receiver operator characteristic (ROC) analyses were used to determine the cutoff value, from which Kaplan-Meier (KM) curves were constructed.

Results:
A total of 433 patients were enrolled in the ESCAPE trial, of which 155 had accurate final hemodynamic data. Of these, 45 (29%) experienced the primary outcome. Final API measurements predicted the primary outcome, OR 0.45 (95% CI 0.30-0.70, p<0.001), while CI, CPO, and PAPI did not. ROC analyses of final advanced hemodynamic measurements indicated API best predicted the primary outcome with a cutoff (sensitivity, specificity, correctly classified, AUC) of 2.9 (76.2%, 55.3%, 61.4%, 0.71), compared to CPO 0.69 (57.8%, 57.8%, 57.4%, 0.57), CI 2.2 (50.0%, 48.2%, 48.7%, 0.52), and PAPI 2.6 (60.5%, 64.5%, 63.3%, 0.64). KM analyses indicated API (83.5% vs 58.4%, p=0.001) and PAPI (78.3% vs 59.0%, p=0.03) were predictive of freedom from the primary outcome, but not CPO or CI.

Conclusions:
The novel hemodynamic measurement API better predicted clinical outcomes in the ESCAPE trial when compared to traditional invasive hemodynamic metrics of cardiac function.
Abstract 14391: Transient Cell Cycle Induction in Cardiomyocytes is a Promising Approach to Treat Ischemia Induced Heart Failure
Authors: Abouleisa Riham , Ou Qinghui , Tang Xian-liang , Solanki Mitesh , Guo Yiru , McNally Lindsey , Lorkiewicz Pawel , Choudhary Krishna , Thomas Reuben , Juhardeen Hamzah Ruxshan , Siddique Aisha , Ifthikar Zainab , Salama Abou Bakr , Huang Yu , Ivey Kathryn N , Hill Bradford , Srivastava Deepak , Bolli Roberto , Mohamed Tamer
Published: May 2021

Rationale:
The regenerative capacity of the heart to repair itself after myocardial infarction (MI)is limited. Our previous study showed that ectopic introduction of Cdk1/CyclinB1 andCdk4/CyclinD1 complexes (4F) promotes cardiomyocyte proliferation
in vitro
and
in vivo
andimproves cardiac function after MI. However, its clinical application is limited due to the concernsfor tumorigenic potential in other organs.

Objectives:
To first, identify on a single cell transcriptomic basis the necessary reprogrammingsteps that cardiomyocytes need to undertake to progress through the proliferation processfollowing 4F overexpression, and then, to determine the pre-clinical efficacy of transient andcardiomyocyte specific expression of 4F in improving cardiac function after MI in small and largeanimals.

Methods and Results:
Temporal bulk and single cell RNAseq of mature hiPS-CMs treated with4F or LacZ control for 24, 48, or 72 h revealed full cell cycle reprogramming in 15% of thecardiomyocyte population which was associated with sarcomere disassembly and metabolicreprogramming. Transient overexpression of 4F specifically in cardiomyocytes was achievedusing non-integrating lentivirus (NIL) driven by TNNT2 (TNNT2-4F-NIL). One week after inductionof ischemia-reperfusion injury in rats or pigs, TNNT2-4F-NIL or control virus was injectedintramyocardially. Compared with controls, rats or pigs treated with TNNT2-4F-NIL showed a 20-30% significant improvement in ejection fraction and scar size four weeks after treatment, asassessed by echocardiography and histological analysis. Quantification of cardiomyocyteproliferation in pigs using a novel cytokinesis reporter showed that ~10% of the cardiomyocyteswithin the injection site were labelled as daughter cells following injection with TNNT2-4F-NILcompared with ~0.5% background labelling in control groups.

Conclusions:
We provide the first understanding of the process of forced cardiomyocyteproliferation and advanced the clinical applicability of this approach through minimization ofoncogenic potential of the cell cycle factors using a novel transient and cardiomyocyte-specificviral construct.
Abstract 14416: Mechano-arrhythmogenicity is Enhanced in Late Repolarisation During Acute Ischemia by a Calcium- and TRPA1-dependent Mechanism
Authors: Cameron Breanne A , Quinn T Alexander
Published: May 2021

Introduction:
Altered tissue mechanics in acute regional ischemia contribute to arrhythmias by a mechano-sensitive, Ca
2+
-dependent mechanism. This is facilitated by uncoupling of voltage-Ca
2+
dynamics, creating a vulnerable period (VP) in late repolarisation for stretch-induced arrhythmias (‘mechano-arrhythmogenicity’). However, cellular mechanisms driving mechano-arrhythmogenicity in acute ischemia are unknown.

Objective:
Define cellular mechanisms of mechano-arrhythmogenicity in the VP during acute ischemia in rabbit ventricular myocytes.

Methods:
Rabbit (♀, NZW) LV myocytes were transiently stretched (8-16% change in sarcomere length, 100 ms) during diastole or the VP in normal Tyrode (NT) or simulated ischemia (SI) solution (hyperkalemia, acidosis, metabolic inhibition). Drugs were used to buffer Ca
2+
(BAPTA), stabilise RyR (dantrolene), block mechano-sensitive TRPA1 channels (HC-030031), or block (DPI) or increase (bi-product of di-4-ANBDQPQ excitation) ROS production. Voltage-Ca
2+
was simultaneously monitored with fluorescent dyes (di-4-ANBDQPQ, Fluo-5F) and a single camera-optical splitter system.

Results:
SI shortened AP duration (APD
NT
=384
vs
APD
SI
=219ms;
p
<0.0001) more than Ca
2+
transient duration (CaTD
NT
=424
vs
CaTD
SI
=357 ms;
p
<0.0001) and increased the length of the VP (=CaTD-APD; VP
NT
=54
vs
VP
SI
=146ms;
n
=50 cells for

N
NT

=6 and

N
SI

=14 rabbits
; p
<0.0001). Mechano-arrhythmogenicity (single ectopy and complex sustained activity) was increased in SI compared to NT, but only for stretch in the VP (7
vs
1% of stretches;
n
=50,
N
=6 each
; p
<0.005), and arrhythmias in the VP were proportionally more complex than those that occurred with stretch in diastole (100
vs
69%;
n
=50,
N
=6;
p
<0.05). Arrhythmia incidence in the VP during SI was reduced by BAPTA (2% of stretches;
p
<0.05), HC-030031 (1%;
p
<0.005), and DPI (2%;
p
<0.05), while dantrolene had no effect (
n
=50,
N
=6 each). Fluorescence imaging during SI further increased mechano-arrhythmogenicity in both the VP and diastole (29 and 14%;
n
=42,
N
=4;
p
<0.05).

Conclusions:
Acute ischemia enhances cellular mechano-arrhythmogenicity specifically in the VP through a mechanism involving Ca
2+
, ROS, and TRPA1, suggesting potential targets for anti-arrhythmic therapy.
Abstract 14418: Association Between 2018 Unos Heart Transplant Policy Changes and Likelihood of Transplant for Patients in Rural versus Urban Settings
Authors: Breathett Khadijah , Knapp Shannon , Addison Daniel , Mehta Nishaki , Sweitzer Nancy , Mazimba Sula
Published: May 2021

Introduction:
United Network for Organ Sharing (UNOS) recently extended the radius for which a heart transplant candidate can be matched with a donor in order to improve transplantation access for the most critically-ill patients. However, this means that smaller transplant centers serving rural populations may not retain the hearts that were donated within their geographic area. It is unknown whether the UNOS policy change of 2018 was associated with differences in likelihood of heart transplantation or death on the waiting list for patients from rural versus urban (metropolitan or micropolitan) settings.

Methods:
Using the Scientific Registry of Transplant Recipients, we analyzed U.S. adult patients who were listed for heart transplant from January 2017 through January 2020. Patients were stratified by home zipcodes to either metropolitan, micropolitan, or rural settings. Fine and Gray proportional hazard regression models were used to estimate the sub-distribution hazard ratio (SHR) of heart transplantation with death or removal from transplant list as a competing event according to geographic residence with date of UNOS policy change October 18 2018 as a time-varying covariate. Interaction (p-int) tests were performed between geographic setting and time of policy change.

Results:
Among 8756 patients, 82% were from metropolitan, 9% micropolitan, and 9% rural settings. The 2018 UNOS policy change was associated with increased receipt of heart transplantation within each geographic setting [metropolitan SHR 1.41 (95%CI: 1.33-1.50); micropolitan SHR 1.30 (95%CI: 1.08-1.56); rural SHR 1.33 (95%CI: 1.10-1.62); p-int=0.60]. Policy changes were not significantly associated with death on the transplant list for any geographic setting [metropolitan SHR 0.97 (95%CI: 0.82-1.14); micropolitan SHR 1.25 (95%CI: 0.80-1.96); rural SHR 0.89 (95%CI: 0.55-1.46); p-int=0.52].

Conclusions:
Independent of geographic location, the 2018 UNOS policy change for heart transplantation was associated with increased heart transplantation and no significant difference in hazard of death. Additional follow-up is needed to determine whether improvements are sustained.
Abstract 14437: Age-related Variations in Takotsubo Syndrome in the United States
Authors: NAZIR SALIK , Ahuja Keerat R , Patel Neha J , Soni Ronak G , Raheja Hitesh , Saleem Sameer , Hsiung Ingrid , Eltahawy Ehab , Madias John E
Published: May 2021

Introduction:
Several studies have described age-related variation in clinical outcomes for Takotsubo Syndrome (TTS) patients with conflicting results. The present study aimed at analyzing the influence of age on TTS outcomes from a large national database.

Methods:
The National Inpatient Sample (2009-2015) was used to identify patients with a primary admitting diagnosis of TTS. All patients were stratified according to age and categorized into 3 groups (younger: ≤ 50 years, middle age: 51-74 years, and older: ≥ 75 years). Data on patient demographics, comorbidities, hospital characteristics, and in-hospital complications were extracted.

Results:
Of 40,326 patients, 11.2% of the patients were ≤ 50 years of age, 59.95% were 51 to 74 years of age, and 29.0% were ≥75 years of age. Young patients were more likely to be male, and less likely to have hypertension, diabetes mellitus, atrial fibrillation, and heart failure (Table). Our analysis showed that in-hospital mortality was higher in the older age group compared to the middle and younger age group. However, younger patients were more likely to have cardiogenic shock, cardiac arrest, invasive ventilation, circulatory support, and ventricular arrhythmias (Table). On multivariate analysis, using middle age as a reference group, older age was independently associated with in-hospital mortality (OR, 1.68; 95% CI: 1.37-2.07), while young age was independently associated with cardiac arrest (OR, 2.92; 95% CI: 2.33-3.63), and ventricular arrhythmias (OR, 2.09; 95% CI: 1.81-2.43).

Conclusions:
Our study reveals that young patients with TTS are critically ill with higher rates of cardiogenic shock, cardiac arrest, circulatory support, invasive ventilation, and ventricular arrhythmias. However, in-hospital mortality was still higher in the older age group. Further studies are needed to better understand the pathophysiological mechanism of relatively poor outcomes in younger TTS patients.