bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15609: Risk of Aortic Valve Disease and Aortopathy in Patients With Bicuspid Aortic Valve Referred to a Central County Hospital in Denmark
Authors: Procida Kristina , Oksjoki Riina , Wulffeld Sandra , Guldbrand Nielsen Dorthe , Schmiegelow Soren , Ngo Anh T , Schmiegelow Michelle , Bruun Niels E
Published: May 2021

Introduction:
Patients with bicuspid aortic valve (BAV) are at increased risk of developing severe aortic valve disease and aortopathy at an early age. We therefore performed a retrospective study to describe all patients diagnosed with BAV in an entire region of Denmark.

Methods:
We included patients≥18 years old with BAV, who had a transthoracic echocardiography (TTE) at our hospital before May 2020, and through electronic health records and our echocardiography database, we achieved baseline data.

Results:
A total of 545 patients with BAV (74.1% men) were identified. At the time of BAV diagnosis the median age was 54 years (IQR 42-62), and the causes for referral to TTE were primarily chest discomfort (21.1%), dyspnea (17.6%), or a newly discovered murmur (40.0%). Upon diagnosis 19.3% of the patients had an aortic valve area (AVA)<1,0 cm
2
, 2.4% had severe aortic regurgitation and the majority (84.0%) had normal left ventricular ejection fraction. The ascending aorta was dilated in 51.9% of the patients while aortic coarctation was found in 5.1% of all patients. According to Sievers BAV classification 24.4% (N=133) had Type 0, 58.7% (N=320) had Type 1 left/right(L/R) fusion, 10.6% (N=58) had Type 1 right/noncoronary (R/N) fusion, 2.6% (N=14) had Type 1 left/noncoronary (L/N) fusion and 2.2% (N=12) had Type 2. Coexisting diabetes mellitus (10.1%), ischemic heart disease (13.2%) and chronic obstructive pulmonary disease (10.1%) was low, whereas hypertension was frequent (47.9%). The majority had sinus rhythm (75.6%) and normal eGFR (84.4%). Surgery was performed in 37.3% (N=203) of all patients and primarily due to aortic valve stenosis (N=172, 84.7%). Surgery was performed in a higher frequency of patients with Sievers Type 1 L/N fusion (N=9, 4.4%; 64.3% of all Type 1 L/N) and Type 2 (N=10, 4.9%, 83.3% of all Type 2) and lowest in patients with Sievers Type 0 (N=35, 17.2%; 26.3% of all Type 0). However, likelihood of surgery was only significantly different between patients with BAV Type 2 and Type 1 L/R (OR 14.21 (2.83-71.35).

Conclusion:
In this cohort of patients with BAV a higher fraction of patients with BAV type 1 L/N and BAV type 2 required valve replacement compared with particularly BAV type 0 suggesting important differences according to BAV subtype.
Abstract 15613: Evaluating the Heart Failure With Preserved Ejection Fraction (HFpEF) Phenotype Amongst Persons Living With HIV; a Miami Health System Analysis
Authors: Grant Jelani , Ebner Bertrand , Vincent Louis , Loyd Quentin , Powell Alexis , Boulanger Catherine , Hurwitz Barry E , Martinez claudia
Published: May 2021

Introduction:
Current evidence suggests a 1 to 2-fold increased risk of heart failure among persons living with HIV (PWH), with possible underlying mechanisms including increased vascular stiffness, chronic inflammation and myocardial toxicity. This study evaluated the prevalence of HFpEF and differences in cardiovascular complications in PWH with and without HFpEF.

Methods:
Participants included 257 of 965 PWH at our Special Immunology Clinic at the Jackson Memorial and University of Miami Hospitals from 2017-19. Demographic, clinical, and laboratory information, were obtained from retrospective review of the electronic health records. HFpEF was confirmed by clinical and echocardiography findings, from which H2FpEF score was derived. Patients with an EF <50% were excluded.

Results:
The prevalence of HFpEF was 0.7%, while the mean H2FpEF score was 3.3±1.4. Thus, on average the cohort had an intermediate probability of HFpEF. When comparing persons with compared with those without HFpEF, mean age (56.4 vs. 52.0 years) and proportion of women (57.1 vs.45.0%) did not significantly differ. Similarly, groups did not differ on mean CD4 count (665 vs. 568 cells/uL, p=0.40), % with undetectable Viral Load (85.7% vs. 71.6%, p=0.41), or antiretroviral therapy use (100.0% vs. 92.8%, p=0.46). Of note, the prevalence of coronary artery disease (CAD) (14.3% vs. 1.6%, p=0.009), myocardial infarction (28.6 vs. 1.8%, p<0.001), abnormal stress testing (14.3% vs. 0.8%, p=0.001), PCI (14.3% vs. 0.9%, p=0.001), type II diabetes (57.1% vs. 16.0%, p=0.003), HbA1C (8.0±2.9% vs. 5.9±1.4%, p=0.004) and chronic kidney disease (57.1% vs. 10.2%, p<0.001) were higher in PWH with HFpEF. Of note, the groups had comparable mean EF (55.0 vs. 56.0%, p=0.66), diastolic dysfunction (33.3% vs. 41.9%, p=0.68), left ventricular (LV) hypertrophy (28.6% vs. 20.9%, p=0.62) and LV mass index (86.4±30.8 vs. 79.1±23.2 g/m2, p=0.34).

Conclusions:
The overall prevalence was similar to that reported in persons 45 years of age or more in the general population. Risk markers for atherosclerotic disease were significantly higher in PWH with HFpEF. HIV disease severity did not appear to be associated with HFpEF prevalence. Further studies evaluating the pathophysiology of HFpEF in PWH are needed.
Abstract 15618: Cardiac Magnetic Resonance Evaluation of Diastolic Indices in Boys With Duchenne Muscular Dystrophy
Authors: Weiner Jeffrey , GeorgeDurrett Kristen , Crum Kimberly , Chew Joshua , Spurney Christopher , Hor Kan N , Cripe Linda , Parra David , Markham Larry W , Soslow Jonathan H
Published: May 2021

Introduction:
Cardiomyopathy (CM) is the leading cause of death in boys with Duchenne Muscular Dystrophy (DMD). Diastolic dysfunction precedes systolic dysfunction in DMD, but while CMR is used routinely to assess fibrosis and left ventricular ejection fraction (LVEF), CMR measures of DMD diastolic dysfunction have not been reported.

Hypothesis:
Boys with DMD have diastolic dysfunction based on CMR indices when compared with healthy controls.

Methods:
Prospectively enrolled DMD patients (n = 54) and healthy male controls (n = 40) underwent CMR. Standard volumes and function were calculated. LV filling curves were generated by contouring every phase in the short axis. Indices were compared between groups using a Wilcoxon rank sum and within DMD using a Spearman’s rho test.

Results:
There was no difference in LVEF between DMD and controls, though DMD patients had significantly smaller indexed left ventricular end diastolic volume (LVEDVi) (see data in Table 1). Peak ventricular filling rates (PFR) were significantly slower in DMD vs controls as were peak ventricular emptying rates (PER). Mean time to PFR (tPFR) and mean time to PER (tPER) were significantly shorter in DMD patients vs controls. In a subset analysis excluding patients with LVEF < 55%, observed differences in PFR, PER, tPFR and TPER remain statistically significant. In DMD patients, tPER correlates negatively with LVEF (rho = -0.57, p <0.001). PER corrected to LVEDVi correlated strongly with LVEF (rho = 0.74, p <0.001). PFR corrected to LVEDVi also correlated strongly with LVEF (rho = 0.75, p <0.001).

Conclusions:
Despite having normal baseline systolic function, boys with DMD have significantly different CMR diastolic indices compared with controls. CMR diastolic indices may help detect subclinical dysfunction in DMD. Future analyses should evaluate for correlation between diastolic dysfunction and clinical outcomes.
Abstract 15621: Checkpoint Kinases Important Players in Lung Fibrogenesis and Pulmonary Vascular Remodeling: A Translational Study
Authors: Wu Wenhui , Vitry Geraldine , Nadeau Valerie , Omura Junichi , Orcholski Mark , Marsolais David , Tremblay Eve , Martineau Sandra , Breuils Bonnet Sandra , Paulin Roxane , Provencher Steeve , BOUCHERAT Olivier , Bonnet Sebastien
Published: May 2021

Introduction:
Pulmonary fibrosis (PF) is an important commonality in pathogenesis of interstitial lung diseases, and pulmonary hypertension (PH) is a well-recognized severe complication of PF. Both significantly impact patients’ survival and functional status, but without validated treatments. In the lung, parenchymal and vascular remodeling share pathomechanisms, mainly including excessive proliferation and resistance to apoptosis of fibroblasts (LFs) and pulmonary arterial smooth muscle cells (PASMCs). In cancer, sustained cell proliferation is ensured, in part, by a fine tuning of cell cycle and DNA repair machinery, of which checkpoint kinases (CHK1 and CHK2) are critical regulators. They are upregulated in cancer and their inhibition are currently tested in clinical trials. However, these pathways have never been explored in PF-PH. We thus hypothesized that CHK1/2 are upregulated in PF and contribute to both fibrotic and vascular lesions in PF-PH patients.

Methods and Results:
Increased DNA damage (γH2Ax and p(S4/S8)-RPA32) as well as augmented expression and activity of CHK1/2 was observed by WB in lung and isolated LFs from PF patients compared to controls (p<0.05, n=8~15 per group) with marked expression in fibroblastic foci. Similarly, increased levels of CHK1/2 and DNA damage were detected by WB and IF in remodeled pulmonary arteries (PA) of PF patients with or without PH. Similar findings were noted in mice exposed to bleomycin. In isolated PF-LFs and PASMCs, dual inhibition of CHK1/2 using MK-8776 and LY2606368 significantly reduced expression of TCTP and RAD51 (two factors required for efficient DNA repair), leading to exacerbation of DNA damage and resulted in reduced cell proliferation (Ki67 labeling, WB PCNA) and resistance to apoptosis (Annexin V assay, WB Survivin). Furthermore, inhibition of CHK1/2 mitigated the hyper-activated state of PF-LFs, as illustrated by reduced expression of FN, CTGF, and pSTAT3 (WB). Similar results were observed in control LFs exposed to TGF-β1; all p<0.05.

Conclusions:
Our data provide compelling evidence that CHK1/2 are involved in lung fibrogenesis and PA remodeling in PF. Current experiments aim to determine whether CHK1/2 inhibitors elicit beneficial effects in animal models of PF-PH.
Abstract 15632: Phenotypic Overlap Between Left Ventricular Noncompaction and Hypertrophic Cardiomyopathy: A Case Report
Authors: Senser Ethan , Hawkins Madison , Williams Eric M , Gilstrap Lauren
Published: May 2021

Introduction:
Left ventricular non-compaction (LVNC) is characterized by extensively trabeculaed myocardium adjacent to normal compacted myocardium of the left ventricle (LV). Hypertrophic cardiomyopathy (HCM) typically appears as diffuse or segmental LV hypertrophy, with or without outflow tract obstruction. Cardiac sarcomere mutations are present in most HCM cases and have also been identified in LVNC. Whether or not there is clinically significant phenotypic overlap between the two diseases is less well understood. We present a case of known HCM that met criteria for both LVNC and HCM by cardiac MRI.

Case:
A 49-year old man with HCM due to a c.3742_3759dup variant in MYBPC3 presented to clinic after an episode of syncope and ICD firing. In clinic, the device was interrogated and he was found to have had ventricular flutter which was successfully treated with one shock and a new, high (>20%) burden of premature ventricular beats. An echocardiogram showed a stable ejection fraction at 42%, mild concentric LV hypertrophy without obstruction and a newly dilated LV with an end diastolic diameter of 7.1cm (previously 6.2cm). A cardiac MRI was performed (
Figure
) and showed LV noncompaction and diffuse transmural and mid myocardial hyperenhancement/fibrosis of the septum, basilar lateral wall, anterior wall, and distal right ventricle consistent with patient's long-standing history of hypertrophic cardiomyopathy.

Discussion:
This case highlights the phenotypic overlap between HCM and LVNC by cardiac MRI. Had this patient not already carried a genetic diagnosis of HCM, he would likely have been diagnosed with LVNC based on this cardiac MRI. The phenotypic overlap in these diseases raises questions about ICD guidelines, the role of anticoagulation and prognosis.
Abstract 15633: Clinical Features and Prognosis of Acute Cardiac Injury in Hospitalized Patients With Covid-19: A Retrospective Cohort Study
Authors: XIE Mingxing , Zhang Li , Xie Yuji , zhang yanting , Sun Wei , WU CHUN , Wang Bin , Zhang Danqing , Yuan Hongliang , Zhang Yongxing , Li He , He Lin , Cui Li , Zhu Shuangshuang , Li Meng , Zhang Yiwei , Zhang Yu , Wang Lufang , Cai Yu , Wang Rui , Yang Yun , Li Yuman , Wang Jing , Yang Yali , Lv Qing
Published: May 2021

Background:
The number of fatalities due to coronavirus disease 2019 (COVID-19) is escalating. However, information on critical complications in hospitalized patients of COVID-19 is scant. We aimed to explore the prevalence of acute cardiac injury and its association with in-hospital mortality in COVID-19 patients.

Method:
This retrospective study analyzed patients confirmed with COVID-19 in Union Hospital (Wuhan, China) from Jan 24 to March 18, 2020. Clinical outcomes (discharge, or death) were monitored to April 9, 2020, the latest date of follow-up. Demographic, clinical, laboratory, echocardiographic data as well as treatment and prognosis were analyzed. Comparisons were made between patients with acute cardiac injury and those without. An association of acute cardiac injury and in-hospital mortality was identified.

Results:
A total of 235 COVID-19 patients were included in the final analysis. Their median age was 66 years (interquartile range 57 - 73 years), and 131 (55.7%) were men. 98 (41.7%) patients were diagnosed with acute cardiac injury, of whom 60 (61.2%) died. There were more comorbidities in those who had acute cardiac injury than those who did not have. A higher proportion of patients with acute cardiac injury received glucocorticoid therapy (68.0% vs 37.0%; P < 0.001), immunoglobulin (53.1% vs 30.1%; P < 0.001), high-flow oxygen (79.6% vs 43.1%; P < 0.001), and invasive mechanical ventilation (40.8% vs 6.6%; P < 0.001) than those without acute cardiac injury. The percentage of patients who were admitted to intensive care unit (39.8 % vs 8.0%; P < 0.001) or died during hospitalization (61.2% vs 8.0%, P < 0.001) were also higher in those with acute cardiac injury. Plasma high-sensitivity troponin I levels correlated significantly with plasma interleukin -6, procalcitonin and C-reactive protein levels in COVID-19 patients. Echocardiography showed the cardiac function was attenuated in acute cardiac injury patients. Multivariable Cox proportional hazards regression analysis showed acute cardiac injury was an independent risk factor for higher in-hospital mortality in COVID-19 patients (HR, 3.393; 95% CI, 1.647- 6.987, P <0.001).
Abstract 15635: Myocardial Function Index Predicts Mortality in Amyloid Light Chain Cardiomyopathy
Authors: Akhiyat Nadia S , Anand Vidhu , Ryu Alexander , Kumar Vinayak , Borlaug Barry A , Abouezzeddine Omar F , Gibbons Raymond J , Gersh Bernard J , Anavekar Nandan S , Chandrasekaran Krishnaswamy
Published: May 2021

Introduction:
Cardiovascular disease remains the leading cause of morbidity and mortality in patients with amyloid light chain (AL) amyloidosis. Current prognostic evaluation in AL cardiomyopathy (AL-CM) largely relies upon disparate proxy measurements to assess mortality. With respect to observed myocardial volume changes between systole and diastole, we describe a single measurement derived from cardiac MRI (CMR) to assess mortality of AL-CM.

Methods:
A cohort of 129 consecutive patients with AL-CM undergoing CMR with amyloid protocol from the years 2001 - 1997 was reviewed. Myocardial volume change at end systole and end diastole was assessed by disc summation with CMR. The myocardial function index (MFI) was calculated by consolidating blood pool and myocardial volume measures as confluent components of myocardial function utilizing operator tracings. The association of MFI and death was assessed with adjusted hazard ratios (HR) derived by a Cox model.

Results:
Data at time of CMR was reviewed. The mean age was 60 ±10; 68% subjects were female. Median survival from CMR was 47 months. Mean LVEF was assessed by echocardiography to be 55% ± 12. Mean calculated MFI was 19.8% ±7. Univariate analysis suggested MFI is strongly associated with death (HR 0.004; 95%CI 0.00002-0.0838; p = 0.0003). A multivariate analysis re-demonstrated the strong predictive value of MFI when controlled for age (HR 0.006; 95%CI 0.00003 - 0.1156; p = 0.0006).

Conclusion:
MFI strongly correlates with mortality in AL-CM. In contrast to previously described assessments of ventricular function (extracellular volume imaging, myocardial perfusion imaging, and myocardial contraction fraction), MFI is easily derived from CMR and considers blood pool and myocardial volumes as confluent components of myocardial function. Further studies are needed to assess MFI amongst patients with varying etiologies of heart failure.
Abstract 15636: Effect of COVID-19 Public Health Measures on Activity and Quality of Life in Patients With Pulmonary Arterial Hypertension
Authors: Middleton Jennifer T , Konganige Shiran , Dahaghin Payman , Zafar Hamza , Reddy Ashwin , Martin Claire , Thompson A.A.R , Swift Andy J , Morris Paul , Condliffe Robin , Morrell Nicholas W , Kiely David G , Toshner Mark , ROTHMAN Alex M
Published: May 2021

Background:
Limitation of physical activity has been widely enforced to reduce COVID-19 transmission, however it is a critical measure in the prevention of cardiovascular disease. In patients with pulmonary arterial hypertension (PAH), exercise capacity relates to clinical outcomes and exercise training improves cardiopulmonary function. Here, we describe the temporal effects of UK government restriction measures on daily activity and quality of life (QoL) in patients with PAH.

Methods:
Patients Enrolled in The United Kingdom National Cohort Study of Idiopathic and Heritable PAH Study were implanted with insertable cardiac monitors (LinQ, Medtronic) in the clinic setting. Data were transmitted and reviewed in accordance with established clinical protocols. Standard questionnaires were administered remotely to assess QoL (EmPHasis-10), anxiety (GAD-7) and depression (PHQ-9).

Results:
Median age of the 26 patients was 49 years, 23 (88%) were female and 5 (19%) had heritable PAH with mutations in BMPR2. At enrolment 10 (38.5%) patients were low risk (<5% 1-year mortality), 10 (38.5%) were intermediate risk (5-10%) and 6 (23%) were high risk (>10%). The mean duration from insertion to census date was 21.1 weeks (SD 5.7). No complications were reported. Completeness of remote monitoring data was 100%.

Following lockdown, mean activity was reduced compared to pre-lockdown levels (3.16 vrs 2.68 hours/day, -0.48 hours, 95%CI -0.27- -0.69, 16%, p<0.0001). This reduction was present each week following lockdown. Although not statistically significant the greatest reduction in activity was observed in patients in the low-risk group. Following lockdown QoL was reduced (26 (18-38) vrs 32 (17-47), p<0.01) and anxiety (1 (0-9) vrs 10 (5-18), p<0.001) and depression scores increased (3 (1-16) vrs 11 (3-17), p<0.001) compared to pre-lockdown levels. No change in day or night heart rate, or heart rate variability was observed and no patients developed COVID-19.

Conclusion:
In this cohort of patients with PAH, protective health measures were effective in preventing COVID-19 in patients thought to be highly vulnerable. However, these measures resulted in reduced daily activity and QoL and were associated increased anxiety and depression indicators.
Abstract 15644: Proinflammatory Diet Independently Predicts Shorter Event-free Survival in Patients With Heart Failure
Authors: Kang Junghee , Moser Debra K , Biddle Martha J , Lennie Terry A
Published: May 2021

Introduction:
Inflammation is a common biological process accompanying chronic conditions, such as heart failure (HF) that can be moderated by diet. The association between foods thought to promote inflammation and event-free survival in patients with HF has not been investigated.

Hypothesis:
The inflammatory potential of individuals’ diets, measured using the dietary inflammatory index (DII), will be associated with event-free survival in patients with HF.

Methods:
The DII scores were calculated from 4-day food diaries recorded at baseline by 213 patients with HF (age 61±12years, 35% female, 43% NYHA III/IV). Patients were followed for a median of 365 days by monthly phone calls, medical record review, and death records to determine time to all cause-hospitalization or death. The DII scores were dichotomized using median value for the Cox regression model. Hierarchical multivariate Cox proportional hazards model was used to determine whether DII scores predicted event-free survival after controlling for age, gender, body mass index, prescribed angiotensin-converting-enzyme inhibitor, beta-blocker, cholesterol lowering agent, antiinflammatory agent, N-terminal pro B-type natriuretic peptide, comorbidity, depressive symptoms, and the New York Heart Association functional classification.

Results:
The DII scores independently predicted event-free survival in the model constant (
p
= 0.012). Higher DII scores were associated with more than double the risk of an event compared to lower DII scores (HR: 2.28, 95% Confidence Interval =1.21-4.36).

Conclusions:
Greater intake of foods considered to promote inflammation was associated with shorter event-free survival in patients with HF. These results provide further evidence of the importance of diet to HF outcomes.
Abstract 15645: The Prognostic Impact of Left and Right Atrial Segmental Strain Analysis in Cardiac Amyloidosis Patients
Authors: Soyama Yuko , Zhang Kathleen , Huntjens Peter , Karmpalioti Maria , Lenihan Daniel , Gorcsan John
Published: May 2021

Introduction:
Little is known about global and segmental atrial function in cardiac amyloidosis. Atrial function plays an important role to maintain adequate ventricular filling.

Hypothesis:
We hypothesized left atrial (LA) and right atrial (RA) segmental strain analysis is prognostic in patients with cardiac amyloidosis.

Methods:
We studied 121 patients with biopsy-proven cardiac amyloidosis and speckle-tracking strain echocardiography. The LA and RA were divided into 6 segments each (basal, mid, and apical segments of free wall and septum). We determined LA and RA free wall/septal wall peak strain ratios. The primary outcome was all-cause mortality (median follow-up; 5.0 years).

Results:
Regional LA strain analysis was feasible in 104 patients (86%) and RA in 92 patients (76%). Average LA global peak strain was 18.3±12.1% and RA global peak strain was 20.0±15.0%. We compared LA and RA strain free wall and septal wall segments. Atrial septal strain was significantly reduced compared to free wall strain in RA (10.8±9.9 % vs 30.7± 23.8%, p< 0.01). Free wall/septal wall strain ratio of LA was significantly reduced compared with the ratio of RA (p< 0.01). During the follow up, 60 patients died. All atrial regions showed reduction in peak strain in non-survivors compared with survivors. When dividing patients into 2 groups using LA free wall strain and RA free wall strain median values, low atrial free wall strain was associated with worse prognosis (Log-rank p < 0.001, HR 4.9, 95% CI= 2.6-9.3).

Conclusions:
LA and RA atrial strain have significant prognostic value in patients with cardiac amyloidosis. Free wall/septal wall strain ratio in LA was significantly reduced compared with RA. Assessment of atrial dysfunction has promise for clinical applications cardiac amyloidosis patients.
Abstract 15646: Pathological Assessment of Primary Graft Dysfunction Does Not Suggest a Prominent Role for an Adaptive Immune Response
Authors: Benck Lillian , Manzoor Daniel , Kransdorf Evan P , Patel Jignesh K , Luthringer Daniel , Kobashigawa Jon A
Published: May 2021

Introduction:
Primary graft dysfunction (PGD) is a major cause of mortality following heart transplant (HT). Pathological characteristics of PGD have not been well characterized. We sought to describe the clinical and pathological characteristics of patients who died or were re-transplanted due to PGD.

Methods:
We identified a cohort of 161 HT recipients between 3/7/2012 to 12/31/17 who developed PGD. Of these, 40 patients had severe PGD, and 16 died in the first month post-transplant. Autopsy or explant pathology was available in 6 patients, which was compared to pathology from the first endomyocardial biopsy in 24 patients with severe PGD that survived.

Results:
Of the 6 patients for whom pathology was available, mean age was 54, four were male and five were white. Half had non-ischemic dilated cardiomyopathy. Two were sensitized. Five patients had severe PGD and one patient had moderate PGD. There were five deaths and one re-transplant. On pathologic examination, most patients (4/6) had broad areas of myocardial necrosis with diffuse vascular thrombosis. Two patients had focal areas of myocardial necrosis. In no cases was there evidence of cellular rejection (ACR) or antibody-mediated rejection (AMR). In the 24 survivors of severe PGD, median age was 54 , twenty were male and half were white. Five were sensitized. On pathologic examination, ischemic changes were found in 10 patients (42%). While there was no significant ACR, 7/24 (30%) of cases showed evidence of either AMR 1 or AMR 2.

Conclusions:
In patients succumbing to moderate or severe PGD, PGD was associated with diffuse myocardial necrosis and vascular thrombi. In survivors of severe PGD, the most prominent finding was diffuse ischemic changes on routine heart biopsy. In both, there was no evidence of cellular rejection, however there was significant incidence of AMR, possibly induced by ischemic changes. These findings suggest that severe PGD may have an ischemic component characterized by vascular thrombosis.
Abstract 15686: Early Intervention versus Conservative Management for Asymptomatic Severe Aortic Stenosis: An Updated Systematic Review and Meta-analysis
Authors: Kumar Ashish , Majmundar Monil , Doshi Rajkumar P , Kansara Tikal , Shariff Mariam , shah Palak , adalja devina , Vallabhajosyula Saraschandra , PANAICH SIDAKPAL S , Thourani Vinod H
Published: May 2021

Introduction:
The management of asymptomatic severe aortic stenosis (AS) is controversial and guidelines for the management of the same is not updated based on recently available evidence.

Hypothesis:
The main objective is to determine the optimal strategy for the management of asymptomatic severe AS between early intervention versus conservative management.

Methods:
We performed a systematic electronic search of the PubMed and Cochrane databases from the inception of the database to May 31
st
, 2020. We used the Mantel Haenszel method with the Paule-Mandel estimator of Tau
2
and Hartung-Knapp adjustment to calculate relative risk (RR) with a 95% confidence interval (CI) and 95% prediction interval (PI). We used P curve analysis to assess publication bias and estimate the true effect of an intervention. All analysis was carried out using R version 3.6.2.

Results:
A total of seven studies were included in the final analysis, consisting of 1213 patients with early intervention and 2601 patients with conservative management. Early intervention as compared to conservative management was associated with reduced risk of all-cause mortality (RR: 0.32, 95% CI: 0.21-0.48)
(Panel A)
, cardiac mortality (RR: 0.36, 95% CI: 0.27-0.48)
(Panel B)
and non-cardiac mortality (RR: 0.40, 95% CI: 0.28-0.56)
(Panel C)
. There was no difference in the risk of sudden cardiac death (RR: 0.46, 95% CI: 0.15-1.40), stroke (RR: 0.79, 95% CI: 0.17-3.64), myocardial infarction (RR: 0.44, 95% CI: 0.01-16.82) or heart failure hospitalization (RR: 0.18, 95% CI: 0.01-5.29) between the groups. The pooled estimate for all the outcomes was associated with low-moderate heterogeneity.

Conclusions:
Among asymptomatic severe AS patients, early intervention is associated with reduced mortality without increasing any procedure-related clinical outcomes. Hence, this meta-analysis supports early intervention as opposed to watchful waiting for the management of asymptomatic severe AS.
Abstract 15703: Cardiac Magnetic Resonance Imaging Can Non-invasively Detect Rejection in Pediatric Heart Transplant Recipients
Authors: Soslow Jonathan H , Godown Justin , Bearl David , Crum Kimberly , George-Durrett Kristen , Chrisant Maryanne , Dodd Debra A , Hernandez Lazaro E
Published: May 2021

Introduction:
Pediatric heart transplant recipients (PHTx) undergo frequent surveillance endomyocardial biopsies (EMB). Non-invasive screening for acute rejection (AR) could decrease morbidity, improve quality of life, and decrease healthcare costs.

Hypothesis:
We hypothesized that cardiac magnetic resonance (CMR) extracellular volume (ECV), native T1, and T2 mapping can detect AR in PHTx.

Methods:
PHTx (n=29) were prospectively enrolled at two sites at time of surveillance EMB or EMB for AR. AR was defined as a clinical change or positive EMB requiring intensification of immunosuppression. Subjects with cardiac allograft vasculopathy (n=3) were excluded; ECV was not measured in 2 subjects without rejection (no IV, poor breathholds). CMR without sedation included standard volumetrics, modified Look-Locker inversion recovery before and after contrast, and T2 mapping. A Wilcoxon rank sum was used to assess for a difference between groups.

Results:
Median age was 17 y/o (range 9-19). There were 9 subjects with and 17 subjects without AR. Base ECV, mid ECV, 4-ch ECV, and average ECV were increased in AR vs non-rejection (Table 1, Fig 1). Native T1 and T2 times were also increased in patients with AR (Table 1). A cut-off of 29% for mid ECV and 1070ms for mid native T1 identifies all patients with rejection with 6 false positive results in non-rejection (Fig 1) and could potentially decrease the need for EMB by 65%.

Conclusions:
ECV, native T1, and T2 mapping can non-invasively distinguish between PHTx with and without AR and have potential to decrease the required number of surveillance EMBs.
Abstract 15704: Morbidity and Mortality After Anatomic Repair of Congenitally Corrected Transposition of the Great Arteries: Understanding Risks for Patient and Family Counseling
Authors: Watkins Kimberly J , Hartog Rebecca R , Wilde Megan , Lim Tiffany R , Rodenbarger Andrew , Lowery Ray , Yu Sunkyung , Afton Katherine , Goldberg Caren S , Ohye Richard G , Gaies Michael G
Published: May 2021

Introduction:
Anatomic repair of congenitally corrected transposition of the great arteries (ccTGA) generally poses short-term risk for presumed long-term functional benefit by restoring the left ventricle to the systemic circulation. Understanding early and late surgical outcomes is crucial for counseling patients and families.

Methods:
All patients with anatomic repair at a single institution from 1993-2018 were included. Follow-up data was obtained by contact with patients’ primary cardiologists. The primary outcome was long-term survival and the secondary outcome was freedom from reintervention. Univariate Cox proportional hazard model was used to identify risk factors for mortality. In-hospital mortality and morbidity were compared between the most recent (2010-2018) and past surgical eras.

Results:
Anatomic repair was performed in 118 patients: 64 Senning/arterial switch operations (ASO) and 54 Senning/Rastelli operations. Survival was 85%, 82%, and 70% at 1, 10, and 20 years after repair, respectively, and was significantly lower in the Senning/Rastelli group compared to Senning/ASO (Hazard ratio 3.0, p=0.01; Figure 1). Preoperative factors associated with mortality were heterotaxy syndrome (p=0.03) and right ventricular systolic dysfunction (p=0.01). During a median follow up of 9.4 years, 47 of 98 patients (48%) required surgical or catheter-based reintervention; median freedom from reintervention was 11.7 years. For the most recent era, 30 of 32 patients (94%) with Senning/ASO and 19 of 22 patients (86%) with Senning/Rastelli operations survived to hospital discharge. In-hospital morbidity was similar between eras (30% in 1993-2009 and 28% in 2010-2018, p=0.82).

Conclusions:
Short- and long-term outcomes are favorable following Senning/ASO. Mortality following Senning/Rastelli operations remains high, highlighting the need for careful patient selection and family counseling.
Abstract 15706: Association of Blood Pressure Level With Left Atrial Size and Function in Adolescents (SHIP AHOY)
Authors: Binka Edem , Manlhiot Cedric , Urbina Elaine M , ALSAIED Tarek , Brady Tammy M
Published: May 2021

Introduction:
Left atrial (LA) enlargement and dysfunction are risk factors for stroke, atrial fibrillation and death in adults, and are associated with hypertension (HTN). In children, left ventricular hypertrophy is the most common manifestation of cardiac-specific organ damage in those with HTN, but gaps in knowledge remain regarding the association of HTN with LA size and function.

Hypothesis:
Increasing blood pressure (BP) is associated with increased LA volume and abnormal LA strain in children.

Methods:
Echocardiographic images of youth, aged 11 to 18 yrs from 5 clinical sites were obtained. LA strain and strain rate were analyzed using 2-D speckle tracking imaging with R-R gating in the apical 4 and 2-chamber views and averages of both views were used. Subjects were grouped by SBP as low-risk (L; <80th %ile), mid-risk (M; 80-<90th %ile), or high-risk, (H;≥90th %ile). Linear regression models were used to determine the association between BP z-score and LA size and function adjusting for age, sex, race and ethnicity.

Results:
N=347 youth (median age 15.7 yrs) 60% (n=208) male and 40% (n=139) non-white were included. BP groups differed by age (L&H<M) and BMI (LL), stroke volume (M&HH), mitral E/e’ (H>L) and pulse wave velocity (H>L), each indicating worse CVD risk in the H vs. L group (Table). Multivariable analyses revealed DBP z-score to be independently associated with LA conduit strain (beta 0.73, 95% CI 0.01, 1.45, p<0.05). No other LA size or function variables were associated with BP.

Conclusions:
Greater BP is associated with increased CVD risk among youth as assessed by non-invasive measurements of CV structure and function. DBP is independently associated with LA conduit strain, a finding associated with CV events in adults. Future studies to determine the long-term association of abnormal DBP with LA strain are needed.
Abstract 15737: Deficiency of Mitochondrial Calcium Uniporter Protects Mouse Hearts From Iron Overload by Attenuating Ferroptosis
Authors: Fefelova Nadezhda , Wongjaikam Suwakon , Siri-Angkul Natthaphat , Gwathmey Judith , Chattipakorn Nipon , Chattipakorn Siriporn , Xie Lai-Hua
Published: May 2021

Iron (Fe) plays essential roles in many physiological processes. Hereditary hemochromatosis and frequent blood transfusions result in iron overload (IO) and dysfunction of iron-deposited organs including the heart. Although IO-induced cardiomyopathy remains a significant clinical challenge, the underlying mechanism is not well defined. In the present study, we aim to assess the involvement of the mitochondrial Ca uniporter (mCU) in IO-induced cardiac contractile dysfunction and ferroptosis. In a chronic IO model, after receiving Fe (dextran, i.p. 0.6 mg/g, 3 days/wk) for 6 weeks, systolic function (LVEF and LVFS) was reduced in mCU
+/+
(WT) compared to mCU
-/-
(mCU KO). This observation was confirmed in isolated ventricular myocytes where we similarly detected a significant decrease in cell shortening in WT, but not mCU KO myocytes. We found lower Fe levels in mitochondria from mCU KO myocytes compared to WT, while observing the same level of Fe deposition in heart tissue from both groups. The mitochondrial ROS level was lower in mCU KO myocytes vs. WT. Long term cardiac dysfunction may result in myocyte cell death, however, we did not detect apoptosis (TUNEL) in either mCU KO or in WT hearts with cardiac dysfunction after chronic IO. The lipid oxidation level was increased with Fe load suggesting ferroptosis may be involved in IO-induced cardiomyopathy, which was supported by the observation that administration of the selective ferroptosis inhibitor ferrostatin-1 reduced lipid oxidation (4-HNE) and maintained heart function. To further determine the role of mCU in IO-mediated ferroptosis in the heart, we used isolated myocytes from WT and mCU KO and conducted Live/Dead cell viability assays. While Fe (FAC, 0.1-5 mM) induced ferroptosis in a dose-dependent manner, it was prevented by ferrostatin-1 (10 μM), the Fe chelator 2,2'-bipyridyl (2 mM), and MitoTEMPO (5 μM), respectively. Fe-induced ferroptosis in mCU KO myocytes did not occur while the lipid oxidation level (Liperfluo) remained low. In conclusion, mitochondrial Fe uptake, presumably mediated by mCU, accounts for the molecular/cellular mechanisms for Fe-induced myocyte ferroptosis and cardiomyopathy. Cardiac-specific deficiency of mCU prevents the development of Fe induced cardiomyopathy.
Abstract 15740: Concomitant Use of Dronedarone and Direct Oral Anticoagulants and Risk of Bleeding in Patients With Atrial Fibrillation: An Analysis of the U.S. Truven Health MarketScan Database
Authors: Gandhi Sampada K , Ezekowitz Michael D , Reiffel James A , Boiron Rania , Wieloch Mattias
Published: May 2021

Introduction:
Dronedarone (DR), a P-gp and CYP 3A4 inhibitor may increase exposure and the risk of bleeding when combined with direct oral anticoagulants (DOACs).

Objective:
To examine the association between concomitant use of DR and the DOACs, apixaban (A), dabigatran (D), and rivaroxaban (R), and risk of bleeding compared to DOAC monotherapy in patients with atrial fibrillation (AF).

Methods:
A retrospective cohort study using a U.S. claims database, Truven Health MarketScan identified new users of A, D, and R in patients with AF ≥18 years from Jan 1, 2007 to Sep 30, 2017. Bleeding was defined as hospitalization or emergency room visit with a primary diagnosis of gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), or bleeding at other sites. Risk of overall and by type of bleeding was examined in concomitant users of DOAC and DR compared to patients using DOAC alone after adjusting for covariates of interest and applying propensity score (PS) trimming via Cox proportional hazards modeling.

Results:
Among concomitant users of DR and A (1,932), D (3,117), and R (2,395), crude incidence rates of bleeding per 1,000 person-years were 17.2, 37.8, 61.8, respectively versus 26.8, 31.3, and 44.9 in users of A (51,420), D (42,312), and R (57,300) alone. Incidence rates stratified by PS showed higher bleeding incidence in concomitant users of DR with D or R, but not with A. No increased bleeding risk was associated with use of DR and A vs A alone [Adjusted Hazard ratio (aHR): 0.69 (95% CI: 0.40, 1.17), p=0.16]. A modestly increased risk of GI bleeding but not overall bleeding was associated with combined use of DR and D vs D alone [aHR bleeding: 1.18 (95% CI: 0.89, 1.56), p=0.26; aHR GI bleeding: 1.40 (95% CI: 1.01, 1.93); p=0.04]. An increased risk of overall bleeding, driven by GI bleeding, was associated with combined use of DR and R vs R alone [aHR bleeding:1.31 (95% CI: 1.01, 1.69); p=0.04; aHR GI bleeding:1.39 (95% CI: 0.98, 1.95); p=0.06]. There was no increase in the risk of ICH associated with combined use of DR and any DOAC.

Conclusions:
Concomitant treatment with DR and A showed no increased risk of bleeding, but DR increased the risk of GI bleeding when given with D or R, and of overall bleeding only with R. Concomitant treatment with DR and any DOAC did not increase ICH risk.
Abstract 15747: The Sarcoplasmic Reticulum Calcium ATPase Pump Modulates Whole-body Glucose Homeostasis Through a Protein Disulfide Isomerase-dependent Pathway
Authors: Rochowski Matthew , Maria Zahra , Campolo Allison , Shoop Shanell , Hartson Steven D , Lopaschuk Gary D , Lacombe Véronique A
Published: May 2021

Introduction:
The heart is a very active metabolic organ which exerts endocrine effects by secreting cardiokines. However, its role in regulating whole-body metabolism has received scarce attention.

Hypothesis:
We hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis by secreting cardiokines during healthy and diabetic states.

Methods:
Diabetes was induced by streptozotocin in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=6-10/group). Translocation of glucose transporters (GLUTs) to the cell surface was measured via a photolabeling biotinylation assay. Glucose and palmitate oxidation rates, cardiac work and ATP production were quantified in isolated working hearts.

Results:
Blood glucose levels were lower in diabetic TG mice compared to diabetic WT mice (P=0.023). Diabetes induced a downregulation of cell surface GLUT4 protein content in cardiac and skeletal muscle (by 56% and 79%, respectively, P<0.05), as well as in white and brown adipose tissue of WT mice (by 68% and 74%, respectively, P<0.05), which was rescued in TG diabetic mice. WT diabetic hearts had decreased cardiac glucose oxidation rates and cardiac efficiency, and increased palmitate oxidation rates (P<0.05), which were restored in TG diabetic hearts. Using quantitative mass spectrometry, we found protein disulfide isomerase (PDI) upregulated in the heart of TG mice (by 1822%, P<0.0001), which was confirmed in the serum of TG mice via an ELISA assay (by 243%, P=0.03). Inoculation with exogenous PDI reduced blood glucose in WT healthy mice and partially rescued hyperglycemia in WT diabetic mice compared to untreated counterparts (P=0.009 and P=0.044, respectively).

Conclusions:
These data suggest that cardiac-specific SERCA overexpression rescues hyperglycemia by improving glucose transport in striated muscle and adipose tissue of diabetic TG mice. Identification of the pathways by which the SERCA pump and cardiac secreted proteins (i.e. PDI) are involved in the regulation of whole-body glucose homeostasis could lead to the identification of novel pharmacological targets in diabetic patients.
Abstract 15749: Sex-differences in Coronary Heart Disease Between Individuals With Familial Hypercholesterolemia and Controls in Norway During 1992-2017
Authors: Svendsen Karianne , Igland Jannicke , Krogh Henriette W , Tell Grethe S , Mundal Liv J , Holven Kirsten B , Bogsrud Martin P , Leren Trond P , Retterstol Kjetil
Published: May 2021

Introduction:
During the last 30 years, treatment of familial hypercholesterolemia (FH) has been revolutionized, but it is not known if both sexes equally benefit in these advances, and whether this could have affected the sex difference in risk of coronary heart disease (CHD). We aimed to study sex difference in the risk of CHD between men and women with FH compared to non-FH men and women.

Methods:
We obtained data on CHD hospitalization and death from Norwegian health registries in 4,525 individuals diagnosed with FH between 1992 and 2014 and an age and sex matched control population of 88,892. The sex distribution was about 50/50 between women and men, and the mean age at start of follow-up was 36 years.

Results:
The cumulative incidence of CHD (FH vs. non-FH controls) in women and men are shown in Figure 1 with a clear increased risk in FH compared to controls. The cumulative incidence starts to increase at a younger age in men compared with women, both in FH and non-FH controls. This corresponds to an age adjusted 2.6-fold higher risk of CHD in men compared with women in both the FH and control population. In the FH population, men aged 20-39 years had a hazard ratio (HR) of 5.3 (95% CI: 2.6-10.9) compared with women, whereas the corresponding HR between women and men in non-FH controls was 3.7 (95% CI: 2.6-5.3). There was no significant interaction between sex and FH status, indicating that the excess risk in men was similar in FH and non-FH controls. Stratified by sex and adjusted for age, we found that both men and women with FH had a 2-fold higher risk of CHD than controls. The highest excess risk was observed in ages 20-30 years with a of HR= 4.5 (95% CI: 2.2-9.2) and a HR of= 5.5 (95%CI: 4.60-9.34) in women and men, respectively.

Conclusions:
The risk of CHD among individuals with FH was higher in men than in women in all age groups presented, with no differences between the FH sample and the non-FH controls. However, the relative risk in FH compared with controls was similar for both sexes.
Abstract 15756: Vascular Guidance of Cardiomyocyte Proliferation During Growth and Regeneration
Authors: DeBeneditts Paige , Karpurapu Anish , Brezitski Kyla , Thomas Michael C , Karra Ravi -
Published: May 2021

Introduction:
Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance.

Hypothesis:
We hypothesized that CECs are required for CM proliferation during growth and regeneration.

Methods and Results:
We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express
Vegfr2
. To functionally link CEC and CM proliferation, we generated

Cdh5-CreER
T2

;

Vefgr2
flox/flox

mice to genetically delete
Vegfr2
from CECs. Compared to mice with intact
Vegfr2
, loss of
Vegfr2
from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when
Vegfr2
is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor,
Vegfa
can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14).

Conclusions:
CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.