bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4143363: Direct Left Ventricular Unloading Vs Counter Pulsation Support Exhibits Differential miRNA Expression In The Left Ventricle Of Cardiogenic Shock Patients
Authors: Krishnamoorthi Muthu Kumar , Patel Khush , Bhimaraj Arvind
Published: November 2024

Background:
Various temporary mechanical circulatory support device (t-MCS) options are available for supporting patients in cardiogenic shock. While each device has a different physiological impact on the heart, limited studies compare genetic changes in the heart t-MCS. Here, we compare the impact of a percutaneous left ventricular assist device (pVAD) vs an Intra-aortic balloon pump (IABP) on miRNA expression of the left ventricle in patients being bridged to cardiac replacement.

Hypothesis:
Difference in genetic signature exists between patients treated with pVAD vs IABP

Methods:
Myocardial tissue was collected at the time of cardiac surgery from 4 patients bridged with a pVAD (Impella 5.5) and 4 bridged with IABP. Samples from each strategy of support were combined. Bulk sequencing was performed on an Illumina Hiseq 4000. Raw data was processed to identify unique sequences with lengths of 18-26 nucleotides and were mapped to miRBase to identify known and novel microRNAs (miRs).

Results:
The top upregulated (Fig. 1A) and downregulated (Fig. 1B) miRs had functionality related to endothelial pathology and cell transitions (miR 422,378 &92a, miR-653, miR-144). For example, miR 21 has been shown to represent a pathogenic state in cancer and cardiac disease and was found to be significantly lower in heart failure patients supported with pVAD when compared to patients supported with IABP. Gene set enrichment analysis of all the downregulated miRs was performed using miRNA enrichment analysis and annotation tool (miEAA). UpSet plots (Fig. 1C) of the downregulated miRs exhibited a regulatory role in inflammatory and cancer-based genes. KEGG enrichment analysis of

target genes

of the differentially expressed miRs exhibited that 1000 genes were associated with metabolic pathways (hsa01100), followed by 500 genes in cancer pathways (hsa05200) (Fig. 1D).

Conclusion:
Our results suggest that direct cardiac unloading using a p-VAD might have a better improvement of the pathological milieu of heart failure when compared to counter-pulsation unloading. The choice of t-MCS to support myocardial recovery might be important. Our future work will include a prospective study with temporal evaluation of patient’s blood for miRNA profiling.
Abstract 4143423: Pulmonary Valve Replacement-Related Change in Biventricular Global Function Index in Repaired Tetralogy Of Fallot
Authors: Sterling Shanique , Sperotto Francesca , Lu Minmin , Sleeper Lynn , O'Leary Edward , Valente Anne , Geva Tal
Published: November 2024

Background:
Reduced biventricular global function index (BVGFI)—a novel indicator of ventricular performance—is associated with adverse clinical outcomes in patients with repaired tetralogy of Fallot (rTOF). The impact of pulmonary valve replacement (PVR) on BVGFI has not been characterized.

Research Question:
What is the impact of PVR on BVGFI in rTOF?

Objectives:
To characterize the impact of PVR on BVGFI and identify pre-PVR determinants of depressed BVGFI after PVR in rTOF.

Methods:
This is a single-center retrospective cohort study of rTOF patients fulfilling the following criteria: 1) Cardiac magnetic resonance (CMR) prior to and after PVR, utilizing the most proximal CMR to PVR within 2 years before and 3 years after the procedure; and 2) No interval cardiac procedure other than PVR. Patients with rTOF were compared with a control group free of heart disease. Based on the distribution of BVGFI in the control group, BVGFI was categorized as normal (>46), intermediate (40-46), or depressed (<40). Associations between pre-PVR characteristics and post-PVR depressed BVGFI were explored.

Results:
Compared with controls (n=136), BVGFI was lower in rTOF (n=141) pre-PVR (46.6±7.6 vs 56.5±5.1, p<0.001). In rTOF, right ventricular volumes, mass, and ejection fraction decreased after PVR while BVGFI did not differ (46.6±7.6 vs 45.5±6.8, p=0.051). Individual changes in BVGFI from pre- to post-PVR varied as shown in Figure 1. In multivariable analysis, pre-PVR factors independently associated with depressed post-PVR BVGFI were lower BVGFI (adjusted-OR 0.81, 95% CI 0.76-0.89; p<0.001), male sex (OR 3.56, 95% CI 1.47, 8.66; p=0.005), ≥moderate pulmonary regurgitation (OR 7.01, 95% CI 1.33, 37.1; p=0.022), and left ventricular end-systolic volume index >41 ml/m
2
vs < 33 ml/m
2
(OR 2.8, 95% 1.33-7.31; p<0.001).

Conclusions:
On average, pre-PVR BVGFI remained stable after PVR with notable variation among individual patients. Lower pre-PVR BVGFI, ≥moderate pre-PVR pulmonary regurgitation, male sex, and higher pre-PVR left ventricular end-systolic volume index are independently associated with depressed post-PVR BVGFI. Further research is warranted to elucidate the role of BVGFI in informing timing of PVR.
Abstract 4143488: POCUS Guided Diuresis in Acute Decompensated Heart Failure – Quality Improvement in the Cardiac Care Unit
Authors: Pargaonkar Sumant , Sunil Kumar Sriram , Chen Yi-Yun , Borkowski Pawel , Flatow Elie , Satish Vikyath , Brown Donclair , Kharawala Amrin , Maliha Maisha , ZOUMPOURLIS PANAGIOTIS , Adhikari Anurag , Garg Vibhor , GAshi Eleonora , Faillace Robert
Published: November 2024

Background:
Patients with acute decompensated heart failure (ADHF) often require admission to the Cardiac Care Unit (CCU). Clinical examination alone may be inadequate for management, leading to suboptimal diuretic regimens and prolonged hospital stays. The use of Point-of-care ultrasound (POCUS) to evaluate the lungs for pulmonary edema and inferior vena cava (IVC) for size and collapsibility can enhance volume status evaluation.

Aim:
Reduce the average duration of IV diuresis by 20% among patients admitted to the CCU for ADHF in 1 year

Methods:
An algorithm for POCUS guided diuretic regimen escalation was implemented across three Plan-Do-Study-Act (PDSA) cycles. Patients who were intubated, on dialysis, or with isolated RV failure were excluded. PDSA-1 introduced the algorithm and provided training to a team of 5 residents. PDSA-2 included weekly reminders and recruitment of 14 residents to increase buy-in. PDSA-3 focused on incorporating POCUS assessments into nighttime care to facilitate early morning decision-making.

Results:
Process Measure: Quarterly compliance rates using the number of POCUS orders that were completed- Baseline (0%, n=23), PDSA-1 (0%, n=35), PDSA-2 (19%, n=15), PDSA-3 (31%, n=46).

Outcome Measure: The average duration of IV diuresis progressively decreased through the year: Baseline (5 days), PDSA-1 (5.3 days), PDSA-2 (4.4 days), PDSA-3 (3.5 days). There was an increase of 6% in PDSA-1 compared to baseline, but PDSA-2 and 3 showed a progressive reduction of 12% and 30% respectively.

Balancing Measure: The mean potassium supplementation showed variation throughout the year: Baseline (63.3 mg), PDSA-1 (141 mg), PDSA-2 (151.7 mg), PDSA-3 (75.7 mg), reflecting no significant negative impact from the intervention.

Equity Lens: The duration of IV diuresis, which at baseline ranged from 3 to 8 days across different races, standardized to approximately 5 days for all races by PDSA-3.

Conclusion:
We progressively reduced the duration of IV diuresis using POCUS-guided lung and IVC assessments with a structured diuretic regimen. This demonstrated improved patient care from early decongestion and symptomatic relief. Additionally, we demonstrate that POCUS plays a crucial role in promoting health equity by providing an objective assessment of volume status across diverse racial groups. This integration promises optimized heart failure management and potential cost reductions from reduced length of stay, highlighting the value of POCUS in clinical practice.
Abstract 4143506: Inflammation but not Coronary Atherosclerotic Burden Is Related to Oxygen Uptake On-Kinetics in the 6-Minute Walk Test
Authors: Rocco Isadora , Gomes Walter , Bublitz Caroline , Krainer Isis Begot , Hossne Nelson , Arena Ross , Guizilini Solange
Published: November 2024

Background:
Anatomic burden of coronary artery disease (CAD) has been considered a consistent prognostic marker. Inflammation also increases the cardiovascular risk and plays a significant role in the evolution of atherosclerosis. The progression of CAD impacts the responses to exercise, reducing functional capacity. Despite this knowledge, the specific interplay between inflammation and atherosclerotic burden in influencing submaximal exercise capacity, particularly oxygen uptake (VO
2
) kinetics, remains underexplored in CAD. This study aims to investigate how these factors correlate with VO
2
on-kinetics in the Six-minute Walk Test (6MWT) in patients with CAD.

METHODS:
Patients with obstructive CAD, confirmed by coronary angiography, underwent a 6MWT using a mobile telemetric cardiopulmonary monitoring to assess functional capacity and the VO
2
on-kinetics through the mean response time corrected by work (wMRT). Inflammatory markers were analyzed by dosage of high-sensitivity C-reactive protein, interferon-gama, tumor necrosis factor alpha and interleukins (IL), IL-6, IL-8 and IL-10. Coronary atherosclerotic burden was evaluated by the Grading Scale for Anatomic Burden of Disease from COURAGE Trial. Correlation analyses were performed according to the symmetric distribution of data, using Pearson’s (r) or Spearman’s rank correlation coefficients(r
s
).

RESULTS:
A total of thirty-four patients aged between 60.3±8.0 years were enrolled, presenting body mass index of 26.0±3.7kg/cm
2
, left ventricular ejection fraction of 0.50±0.14, walking distance of 443±66m, VO
2
at steady-state (VO
2SS
) of 896±240ml/min and wMRT of 1.64x10
-3
± 1.00x10
-3
min
2
/ml. Although correlated with distance and VO
2SS
(r=-0.472;p=0.002 and r=-0.434;p=0.015, respectively), atherosclerotic burden was not associated with wMRT (p=0.17). High-sensitivity C-reactive protein and IL-8 were negatively associated with both distance and VO
2SS
(r
s
=-0.428;p=0.001/ r
s
=-0.543;p=0.001 and r
s
=-0.438;p=0.014/ r
s
=-0.407;p=0.019) and positively correlated with wMRT (r
s
=0.412;p=0.022/ r
s
=0.505;p=0.003).

CONCLUSION:
In contrast to anatomic burden, inflammatory markers were associated with both walking intensity and VO
2
kinetics. Therefore, inflammation may be more crucial to exercise response mechanisms than coronary stenosis, suggesting a paradigm shift in our understanding of clinical repercussions of obstructive CAD. Actions able to attenuate the inflammatory profile may improve exercise capacity and prognosis.
Abstract 4143515: Microbubble Cavitation Under Ultrasound Causes Microvessel Deformation at Mega-Hertz Frequency: Insights into Microvascular Mechanics
Authors: Jang Sae , Chen Cheng , Chen Xucai , Helfield Brandon , Villanueva Flordeliza
Published: November 2024

Background:
There is growing interest in understanding microbubble (
MB
) behavior under ultrasound (
US
) in complex
in vivo
environments, to optimize safety and efficacy for various clinical applications,
e.g.
, large molecule drug delivery, temporary blood-brain-barrier opening, and thrombus disintegration. However, there have been few mechanistic
in vivo
studies due to the challenges of visualizing vibrating MBs in the circulation at high temporal resolutions. Our study elucidates MB interactions with surrounding microvessels using ultra-fast intravital imaging of the rat cremaster muscle.

Hypothesis:
MB vibration-induced stress deforms surrounding microvessels
in vivo.
Deformations are influenced by not only the US parameters, but also the biomechanical properties of the vessel wall.

Methods:
Definity® was injected via the femoral artery of anesthetized rats and imaged in externalized cremaster muscle using an ultrafast microscope (up to 12 Mfps). Concurrently, a single US pulse of 6-10 cycles [1 MHz, peak negative pressures (
PNP
) 0.5-2.0 MPa] was delivered. Images were analyzed to calculate MB and vessel dimensions and to perform Fourier analyses. Stress-strain curves were generated using normal stress exerted by the MB (derived from the linearized Euler’s equation) and measured circumferential vessel strain (Diameter/initial Diameter-1).

Results:
MBs expanded in both circular and elliptical shapes (Fig 1A), and vibrated nonlinearly under US. Vessels vibrated in-phase with the MBs at higher PNP (Fig 1B). Fourier analyses revealed nonlinear vessel vibration (Fig 1C) at fundamental and harmonic US frequencies. Calculated normal stress exerted by the MB of three MB-vessel pairs displayed linear relationships with measured circumferential vessel strain (Fig 1D), with slopes (representing Young’s modulus, or stiffness) between 0.6-1.7 MPa.

Conclusions:
We demonstrate, for the first time, microvascular harmonic behavior in response to MB vibration under US; the associated bioeffects warrant further investigation. Finally, we introduce a novel method for measuring
in vivo
microvessel stiffness using MBs as mechanical probes, where vessel stiffness is represented by the slope of the presented stress-strain curve.
Abstract 4143616: A Silent Murmur: Incidental Finding of a Cardiac Paraganglioma
Authors: Min Kyung , Srikanth Kishan , Lien Tann , Hernandez Salvador , Colicci Steven , Wheeler Amber , Ting Jennifer
Published: November 2024

Background:
Paragangliomas are rare neuroendocrine tumors, arising from neural crest cell lines in the autonomic system. The detection of these tumors has risen in recent years with the growing availability and use of intrathoracic imaging.

Case Presentation:
A 59-year-old male with a past medical history of HTN, HIV, syphilis, and treated prostate cancer presented to the clinic for a new-patient evaluation and was incidentally found to have a 2/6 diastolic murmur, reportedly present since childhood. He was asymptomatic apart from brief episodes of dizziness when leaning forward or standing during exercise. Family history was notable for an aortic aneurysm in his father and valvular disease in his mother.

Clinical Decision Making:
A TTE showed a 5.7 x 5.9 cm echogenic mass pushing against the RV and RA. Prospective ECG-gated CT scan of the chest revealed a highly vascular intrapericardial mass (6.0 x 7.7 mm) anterior to the RA and RV with the RCA leading into it. Cardiac MRI showed a large, circumscribed mass moving within the RV-free wall without evidence of depressed RV ejection fraction or significant coronary artery compression. Coronary angiogram found an engorged acute marginal branch feeding the highly vascular mass and the RCA continuing under the mass to give off a small PDA and a small RPL. There were normal filling pressures and no significant obstructive CAD. A multidisciplinary team determined a high concern for cardiac paraganglioma. Serological workup was notable for elevated serum epinephrine (335 pmol/L). 24-hour urinary dopamine was elevated (831.5 ug/TV) while 24-hour urinary catecholamines/metanephrines were normal. A DOTATATE PET/CT scan confirmed presence of a cardiac paraganglioma. Genetic workup did not reveal presence of any succinate dehydrogenase (SDH) mutations.

Conclusion:
Here we present a highly unusual case of an asymptomatic intra-pericardial paraganglioma in a 59-year-old male. Given the lack of guidelines for management and the complexity of the case due to the location of the tumor, a multidisciplinary team comprising cardiology, endocrinology, and surgery is evaluating the patient, with considerations of surgical removal and CABG to PDA after neurohormonal blockade.
Abstract 4143638: Donation After Circulatory Death in Pediatric Heart Transplant Recipients: A Lost Opportunity for Donor Pool Expansion
Authors: Shikhare Anuja , Vaidya Gaurang , Aquino Liliam , Cocalis Mark , Aljohani Othman
Published: November 2024

Background:
Donation after circulatory death (DCD) is underutilized in pediatric heart transplant (HTx).

Methods:
UNOS database was analyzed for HTx with reported DCD donors (1/2020-4/2024). Data is reported as median (interquartile range). Multiorgan and retransplant recipients were excluded from outcome analysis.

Results:
The youngest DCD heart donor was <1 year old and the median age was 15 years. During the study period, 86 (4%) pediatric donors were DCD. However, in terms of pediatric recipients, DCD accounted for only 12 (0.9%) of the total pediatric HTx. The remaining pediatric DCD donors (74) were assigned to adult recipients. In the same period, all DCD donors accounted for 10% of adult HTx.

The pediatric donor cohort was subdivided into 4 categories based on the recipient's age-group and whether the donor was DCD or not (table 1). Pediatric DCD hearts were allocated to lower priority listed recipients and those with blood group O (in both pediatric and adult recipients). Despite this, the total waitlist time was shorter among DCD recipients, suggesting the potential role of DCD to lower wait times. Distance travelled between donor to transplant center can be longer with DCD due to the use of a different organ care system. Table 1 summarizes the findings.

Few UNOS regions (4, 5, 10, 11) are using pediatric DCD hearts for pediatric recipients (figure A). For outcome analysis, adult recipients who received pediatric DCD hearts were compared to those who received pediatric non-DCD hearts. No difference was noted in the one-year survival (figure B).

Conclusion:
Pediatric DCD heart for pediatric recipients represents an unexplored strategy for donor pool expansion.
Abstract 4143671: Transcatheter annuloplasty of tricuspid regurgitation with the K-Clip system: one-year results from the TRISTAR study.
Authors: JIN QINCHUN , ZHANG XIAOCHUN , ZHOU DAXIN
Published: November 2024

Background:
Despite progressively high morbidity and mortality rates associated with severe tricuspid regurgitation (TR), limited treatment options are available.

Aims:
The single-arm, multicenter, prospective TRISTAR study(K-Clip Transcatheter Annuloplasty System in Tricuspid Regurgitation(TRISTAR) Early Feasibility Study) evaluated the 1-year outcomes of the novel transcatheter K-Clip reconstruction system in treating secondary TR.

Methods:
Between May 2022 and October 2022, patients with ≥severe secondary TR at 11 centers, despite medication therapy, were deemed candidates for transcatheter tricuspid repair by the local Heart Team and a multidisciplinary screening committee.

Results:
Ninety-six patients were enrolled(mean age 72.7±7.1 years, 60.4% female, mean TRISCORE 5.3±2.1). Technical success and procedural success were achieved in 97.9% and 93.8%. At 1 year, echocardiography showed average reductions of annular septolateral diameter by 11.3% (41.9mm vs. 37.1mm, p < 0.001) with increases in stroke volume(60.8±18.5mL vs 67.6±19.8mL, p < 0.001) and cardiac output(4.3±1.5 vs 5.3±2.0, p < 0.001). Tricuspid regurgitation was reduced to ≤moderate in 82.5% with ≥1-grade reduction in 97.7% and ≥2-grade reduction in 66.3%. Patients experienced significant clinical improvements in New York Heart Association (NYHA) functional class I/II (32.6% to 96.5%, p < 0.001). Six-minute walk test increased by 31.9m(304.3±81.2, p<0.001), and overall Kansas City Cardiomyopathy Questionnaire (KCCQ) score improved by 7.6 points(66.7±16.89 vs 74.4±13.6, p<0.001). No cardiovascular mortality was reported while severe bleeding was reported in 5 patients. Kaplan-Meier estimated of survival and freedom from heart failure re-hospitalization were 97.8% and 95.1%, respectively.

Conclusions:
One-year experience using the K-Clip tricuspid annuloplasty system demonstrated high survival rates, low complications and durable improvements in TR reduction, functional status, and quality of life for patients with severe secondary TR.
Abstract 4143686: Unipolar and omnipolar voltage mapping of the pediatric sino-atrial node
Authors: van Schie Mathijs , Zwijnenburg Roxanne , Linderhof Manouk , DAI LIXIA , Zhang Can , Taverne Yannick , van den Bosch Annemien , de Groot Natasja
Published: November 2024

Introduction:
Sinus node dysfunction (SND) commonly occurs in pediatric patients with congenital heart disease (CHD). It includes disturbances in sino-atrial node (SAN) impulse generation and/or its propagation from SAN exit sites towards the atrial myocardium. Various voltage mapping techniques i.e., unipolar, bipolar and omnipolar, are available to explore the degree of electrical remodeling. However, the interrelationship between unipolar and omnipolar voltages and the added value of either technique with respect to SAN mapping is unknown. Therefore, we performed epicardial high-resolution voltage mapping of the SAN area in pediatric CHD patients.

Methods:
Intra-operative mapping (128 electrodes; interelectrode distance 2mm) was performed in 45 patients (0.6[0.4-3.1] years). Unipolar morphology characteristics were computed, including peak-to-peak voltages and R/S ratios. Bipolar potentials were constructed from unipolar potentials in both horizontal and vertical directions. Omnipolar potentials were constructed from each orthogonal bipolar pair. Omnipolar peak-to-peak voltages were compared to the corresponding unipolar voltages. Low-voltage areas were defined as unipolar voltage <1 mV (U-LVA) and omnipolar voltage <0.5 mV (O-LVA).

Results:
In total, 2313 unipolar electrograms were recorded from which 7831 omnipolar electrograms were derived. Omnipolar voltages surrounding the SAN area were larger than unipolar voltages (6.2[4.8-7.6] vs 5.2[3.6-6.3]mV,p<0.001). There was also a strong linear correlation between omnipolar and unipolar voltages (r=0.890,p<0.001). O-LVAs near the SAN were identified in only 9 patients (20%), while U-LVAs were present in 34 patients (76%); 8 patients had combined U/O-LVAs. U-LVAs were larger than O-LVAs (6.5[4.6-10.5] vs 0.7[0.5-2.2]%,p<0.001). At the SAN exit site, there were no differences between unipolar and omnipolar voltages (4.1[2.8-5.7] vs 3.7[2.6-5.5]mV,p=0.453). However, unipolar potentials at the SAN exit site consistently consisted of full S-waves (R/S ratio: 0.99[0.94-1]), while omnipolar potential morphology was highly variable.

Conclusions:
At the SAN area, a considerable amount of U-LVAs could be identified. These unipolar potentials typically consisted of full S-waves, which were easily recognizable but probably led to an overidentification of U-LVAs. By utilizing combined omnipolar voltage mapping, LVAs near the SAN may be more accurately identified and used to identify patients at risk for developing SND.
Abstract 4143704: Systemic Arterial Aneurysms in Kawasaki Disease: An Important Evidence Gap
Authors: Orr William , Raghuveer Geetha , Portman Michael , Dionne Audrey , Fabi Marianna , Misra Nilanjana , Sundaram Balasubramanian , El Ganzoury Mona , Tierney Seda , Prasad Deepa , Lee Simon , Elias Matthew , Harris Tyler , Caro Ana , Norozi Kambiz , Mauriello Daniel , McHugh Kimberly , Lang Sean , Manlhiot Cedric , McCrindle Brian
Published: November 2024

Introduction:
Non-coronary artery systemic arterial aneurysms (SAA) are a rare and under-reported sequelae of Kawasaki disease (KD), for which data and guidance are limited.

Methods:
A survey was sent to members of the International KD Registry (IKDR) regarding their experiences and practices with SAA in KD patients. For comparison, a systematic review was conducted following PRISMA methodology; after evaluation, a total of 21 studies with 75 patients total were included. Results were compared qualitatively.

Results:
Surveys were completed by 48 (56%) of 86 IKDR investigators; 35 (73%) respondents had >10 years of experience caring for KD patients. Experience with SAA was limited, with 33% not having cared for a patient with SAA. Reported screening practices included 81% screening only patients with coronary artery (CA) involvement, 8% reporting screening all patients with KD, and with 11% using other criteria. The degree of CA involvement influenced screening, with 56% screening only those with giant CA aneurysms, 20% also small/medium aneurysms, 6% included dilation and 18% not using any specific CA criteria. Additional factors reported included multiple or rapidly expanding CA aneurysms, clinical features such as prolonged/persistent fever, progressing/persistent elevation of inflammatory markers, and resistance to standard treatment. These screening practices were somewhat concordant with the characteristics of patients with SAA reported in the literature (
FIGURE
). Initial preferred assessment method was CT angiography for 48%, ultrasound 28% and MRI for 24% of respondents. In contrast, SAA reported in the review were most commonly assessed with conventional coronary artery angiography. From the review, SAA were associated with a high rate of regression (62-93%). Longer-term complications reported included SAA thrombosis, calcification, stenosis, occlusion and collateral formation. Clinical and management factors associated with SAA outcomes were not defined.

Conclusion:
While the development of SAA is a known but rare complication of acute KD, there remains a gap in evidence as to which patients are at risk, best practices for screening and management, and outcomes. Protocol driven cohort studies are needed.
Abstract 4143723: Thrombocytosis is Prevalent and Associated with Greater Inflammation and Coronary Artery Involvement in Both Kawasaki Disease and Multisystem Inflammatory Syndrome in Children Associated with COVID-19
Authors: Harahsheh Ashraf , Wehrmann Melissa , grcic michelle , Nowlen Todd , Dahdah Nagib , Jain Supriya , Garrido Luis , Khoury Michael , Szmuszkovicz Jacqueline , Jone Pei-Ni , Barnes Benjamin , Harris Kevin , Hicar Mark , Hidalgo Corral Nicolas , choueiter nadine , Ballweg Jean , Mondal Tapas , Manlhiot Cedric , McCrindle Brian
Published: November 2024

Introduction:
Thrombocytosis, sometimes extreme, after acute Kawasaki disease (KD) is common and felt to be pathognomonic of this diagnosis, although has also been reported after multisystem inflammatory syndrome in children (MIS-C), a clinically similar condition. We sought to determine differences in factors associated with thrombocytosis for each condition.

Methods:
From 01/2020 to 10/2023 across 41 sites in 8 countries from the International KD Registry, 1674 MIS-C and 1290 contemporaneous KD patients with adequate laboratory data were included in the analysis. Age-related cutpoints (derived from the CALIPER Study of normal children/adolescents; AJCP 2020; 154:342) were applied to peak platelet counts to define thrombocytosis (age <1 year, >647 x10
9
/L; age 1 to <12 years, >434; age 12 to <21 years, >371). Associations of demographic, clinical, laboratory and outcome factors with thrombocytosis were determined for each diagnosis group.

Results:
Thrombocytosis was more prevalent after KD (57%) than MIS-C (49%; p<0.001), with higher median peak platelet count (492 vs. 413 x10
9
/L; p<0.001). The difference remained significant after adjustment for age. Thrombocytosis was significantly associated with greater total days of fever for both KD (median 8 vs. 7 days; p=0.005) and MIS-C (median 7 vs. 6 days; p<0.001), but not with any symptoms/signs or presentation with shock in either group. For both groups, thrombocytosis was associated with significantly greater laboratory abnormalities, specifically higher markers of inflammation, lower hemoglobin and lower albumin. Cardiac biomarkers (peak NTproBNP, peak troponin I) were significantly lower for KD patients with thrombocytosis. While there was no significant association of thrombocytosis with ventricular function in either group (FIGURE A), coronary artery involvement was worse for both groups if thrombocytosis occurred (FIGURE B), with an overall lower prevalence and severity for patients with MIS-C, despite more severe clinical presentation and greater laboratory abnormalities.

Conclusions:
Thrombocytosis has a high prevalence for both KD and MIS-C, and is associated with both more severe inflammation and greater coronary artery involvement for both diagnoses.
Abstract 4143732: Mitochondrial DNA heteroplasmy and incident cardiovascular disease
Authors: Hong Yun Soo , Shi Wen , Puiu Daniela , Lake Nicole , Guallar Eliseo , Arking Dan
Published: November 2024

Background:
Variants of mitochondrial DNA (mtDNA) may exist in heteroplasmy and have been associated with increased risk of mortality and cancer. While variation in mtDNA has been associated with cardiomyopathy in mitochondrial disease, the association between mtDNA heteroplasmy and cardiovascular disease (CVD) in the general population has not been well studied.

Methods:
We quantified mtDNA heteroplasmy from whole genome sequencing data in 476,434 participants in the UK Biobank. We defined a variant allele frequency of 5–95% as heteroplasmic. We functionally characterized mtDNA single nucleotide variants using a constraint-based score, mitochondrial local constraint score sum (MSS). We evaluated the associations of MSS and incident CVD, defined as fatal or non-fatal myocardial infarction (MI) or ischemic stroke (IS), using Cox proportional hazards models adjusted for demographic, lifestyle, and clinical factors in 463,705 participants free of CVD. We further tested the interactions with clonal hematopoiesis of indeterminant potential (CHIP) and leukocyte telomere length (LTL) in the association between heteroplasmy and CVD. We performed additional analysis stratified by MSS for each complex/region in the mtDNA, and subgroup analysis by sex and C-reactive protein (CRP; ≥3mg/L). Lastly, we performed analysis separately for MI and IS.

Results:
During a median (1
st
and 3
rd
quartiles) follow-up of 13.6 (13.1–14.5) years, there were 24,723 incident CVD events (16,959 MI and 9671 IS cases). 28.3% of the study population had 1 or more heteroplasmies. We found that higher MSS was associated with CVD (adjusted hazard ratio [aHR] for a 1-unit increase in MSS 1.08; 95% confidence interval 1.00–1.17). In particular, a higher MSS was associated with MI (aHR 1.13; 1.02–1.24) but not with IS (aHR 1.03; 0.90–1.17). The association between MSS and MI was stronger for fatal MI (aHR 1.52; 1.10–2.10) than for non-fatal MI (aHR 1.10; 0.99–1.21). When stratified by complex/region, higher MSS in Complex I increased the risk of MI by 27% (aHR 1.27; 1.06–1.53) but not in other complexes/regions. Although LTL was inversely associated with CVD outcomes, there were no associations with CHIP. Furthermore, there was no interactions by LTL, CHIP, sex, and CRP in the association between MSS and CVD outcomes.

Conclusion:
These results indicate that mitochondria may have a functional role in the development of CVD, particularly MI, and MSS may serve as a biomarker for CVD risk.
Abstract 4143746: Single Center Rates and Trends in Diagnosis of Necrotizing Enterocolitis in Pediatric Shunt-Dependent Congenital Heart Disease
Authors: Payne Jarae , Baxelbaum Keith , Olsen Robert , Gunturi Deepthi , Ostapenko Svetlana , Savoca Melanie , Sullivan Erin , Gaynor J , Kozyak Benjamin , Gardner Monique
Published: November 2024

Background:
Necrotizing enterocolitis (NEC) is a rare comorbidity in infants with heart disease, specifically those with shunt-dependent congenital heart disease (SDCHD). We aimed to describe NEC incidence and cofactors in our center’s SDCHD population and diagnostic practice changes.

Methods:
A retrospective case-control study in patients who underwent first staged palliation for SDCHD between 1/1/2013 and 6/30/2022. Palliation procedures included stage one Norwood with a BTTS or RV to PA conduit, hybrid, BTTS only or PDA stent. Demographics, clinical factors, and diagnostics including abdominal ultrasound (AUS) were abstracted for subjects for 21 days after palliation. NEC was defined with Bell’s criteria from databases and AUS was assessed by chart review. Hierarchical logistic regression models assessed surgical era rates into three cohorts 2013-2016, 2017-2019, and 2020-2022. Groups were compared with Chi-square, Fisher’s exact test, Wilcoxon rank-sum tests, and trends over time with logistical regression.

Results:
Of 531 patients included, 77 (14.5%) had NEC. There was no association of NEC diagnosis with sex, race, and ethnicity, presence of genetic syndromes or extracardiac abnormalities. The primary and majority SDCHD diagnosis was hypoplastic left heart syndrome and variants (61%). On univariate analysis, risks significantly associated with NEC include younger gestational age, delayed sternal closure, catheter reintervention, ECMO, cardiac arrest, seizures, >/= moderate ventricular dysfunction, increased pre- and post-procedural VIS scores, and postoperative anemia. Logistic regression found a significant increase in NEC by year, with a 23% increase in odds for each increasing year across the time range (OR 1.23, 95% CI 1.12-1.36, p<0.001) and odds of AUS use significantly increased by year (OR 1.14, 95% CI 1.05-1.24, p=0.003). When controlling for gestational age, procedure type, presence of a genetic syndrome and chromosomal abnormality the odds of having a NEC diagnosis increased by 1.24 on average with each change in era.

Conclusions:
Rates of NEC diagnoses at our institution have increased over time with ultrasound as a diagnostic indicator. Clinical risks factors suggesting higher acuity of illness were associated with higher rates of NEC. Further studies are needed to assess AUS sensitivity and its contribution to NEC rates, as well as a multicenter analysis to collate risk factors for this fragile patient population.
Abstract 4143749: Impact of SGLT2 Inhibitors on Cardiovascular Outcomes Following Acute Myocardial Infarction with Heart Failure with Preserved Ejection Fraction: A Propensity-Matched Registry Study
Authors: Calcagno Tess , Issa Rochell , MAHALWAR GAURANGA , Issa Ryan , Brateanu Andrei , Kaelber David , Menon Venu , Tang Wai Hong , Griffin Brian , Kwon Deborah , Wang Tom Kai Ming
Published: November 2024

Background:
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have effectively reduced cardiovascular mortality and hospitalizations in heart failure with preserved ejection fraction (HFpEF). This study investigates their effects on patients with HFpEF after an acute myocardial infarction (AMI), focusing on long-term outcomes.

Aims:
The study aims to determine whether an SGLT2 inhibitor (SGLT2i) can improve cardiovascular morbidity and mortality.

Methods:
Using TriNetX, a health research network accessing data from over 100 million patients globally, AMI patients with HFpEF (identified by NYHA Class 2-4, diagnosis code, and EF>50%) treated with and without SGLT2i were identified. Equal cohorts of 1,675 patients were created, and propensity scores were matched for demographics, medical history, medications, and lab values. Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Survival analysis was conducted at intervals ranging from 30 days to 5 years post-AMI to determine the efficacy of SGLT2i, examining MACE and its component outcomes.

Results:
The analysis included 3,350 post-AMI patients between 2014 and 2023, with a mean age of 69.7 ± 11.4 years, 46.1% female. Of the SGLT2i group, 90.8% had T2DM compared to 91% of the non-SGLT2i group. The SGLT2i group had significantly lower 30-day mortality (2.6% versus 7.4%, P<0.0001) and MACE (58.6% versus 64.3%, P=0.002). Over a 5 year period, the SGLT2i group exhibited lower mortality (32.5% versus 55.8%, HR 0.767, P<0.0001) and a lower rate of MACE (58.6% versus 64.3%, HR 0.818, P<0.0001). Other outcomes, including MI, stroke, and bleeding events, also favored the SGLT2i group at both 30 days and 5 years (P<0.0001).

Conclusions:
SGLT2i use post-AMI in HFpEF patients was associated with improved survival and reduced rates of MACE and further MI. These results support further investigation into the inclusion of SGLT2i in therapeutic strategies for HFpEF patients post-AMI.
Abstract 4143778: ROS-dependent SUMOylation of Copper Chaperone Atox1 Orchestrates Endothelial Inflammatory and Angiogenic Signaling, Promoting Neovascularization Following Ischemic Injury
Authors: Das Archita , Varadarajan Sudhahar , Yadav Shikha , Fulton David , Kelley Stephanie , McMenamin Malgorzata , Abe Junichi , Kaplan Jack , Ushio-Fukai Masuko , Fukai Tohru
Published: November 2024

Background:
Neovascularization in response to ischemia relies on reactive oxygen species (ROS), inflammatory, and angiogenic signaling in endothelial cells (ECs). Our prior study suggested that the copper (Cu) chaperone Atox1 acts as a Cu-dependent transcription factor for p47phox, facilitating ROS-NFkB-dependent inflammatory responses in ECs stimulated by inflammatory cytokine TNFα. However, the precise mechanism of Atox1’s nuclear translocation during inflammatory angiogenesis is unknown. Posttranslational SUMOylation and deSUMOylation by SENP1 in the cytosol and nucleus play crucial roles in regulating gene expression, protein subcellular localization and signal transduction.
In silico
analysis identified a conserved potential SUMOylation motif at Lys(K3) of Atox1.

Results:
Here we show that TNFα or hypoxia stimulation in human aortic ECs, as well as mouse hindlimb ischemia model that promotes inflammatory angiogenesis, significantly increased Atox1-K3 SUMOylation. Mechanistically, ROS induced by TNFα or hypoxia led to the oxidation/inactivation of SENP1 at Cys603 in the cytosol, thereby elevating Atox1 K3-SUMOylation (3.6-fold). Unexpectedly, Atox1siRNA or overexpression of “SUMO-dead” Atox1K3R mutant in ECs inhibited TNFα or hypoxia-induced, activation of NFkB (increased cytosolic p-NFkB and its nuclear translocation) as well as Cu-dependent Atox1 nuclear translocation. Additionally, in the nucleus under reducing conditions, ChIP and promoter analysis revealed that deSUMOylation of Atox1 by nuclear active SENP1 is required for Atox1’s transcriptional activity on inflammatory and angiogenic genes VCAM/ICAM, IL-8 and RANTES. Functionally, siAtox1 and “SUMO-dead” Atox1K3R mutant reduced inflammatory and angiogenic responses, including monocyte adhesion, migration and capillary tube formation. In vivo, EC-specific Atox1
-/-
mice or CRISPR/Cas9-generated “SUMO-dead” Atox1K3R knock-in mutant mice exhibited significantly reduced blood flow recovery, Mac3+ inflammatory cells, and angiogenesis (CD31+ capillary) in hindlimb ischemia and sponge implant inflammatory angiogenesis models.

Conclusions:
SUMOylation of Atox1 via oxidative inactivation of SENP1 in the cytosol promotes p-NFkB and the nuclear translocation of both Atox1 and NFkB. Within the nucleus, deSUMOylated Atox1 and NFkB synergistically enhance the expression of inflammatory and angiogenic genes in inflamed or hypoxic ECs, thereby driving neovascularization in ischemic cardiovascular diseases.
Abstract 4143791: Second Chances: Outcomes of Left Atrioventricular Valve Re-intervention Following Initial Repair of Atrioventricular Septal Defect
Authors: O'Connor Mario , Stauber Catherine , Venardos Neil , Fraser Charles , Mery Carlos , Well Andrew
Published: November 2024

Background:
Outcomes after initial atrioventricular septal defect(iAVSD) repair are excellent in the current era. The need for left atrioventricular valve(LAVV) intervention and further reinterventions after iAVSD repair are common and poses significant clinical and surgical challenges. Data on the outcomes after initial LAVV repair remain limited.

Research Question / Hypothesis:
What is the incidence and outcomes of LAVV reintervention after initial LAAV repair following iAVSD repair?

Methods:
Retrospective review of the Pediatric Health Information System from 1/2004-12/2023. All patients who underwent AVSD repair were included. LAVV reintervention was defined as LAVV repair or replacement after iAVSD repair. ICD 9/10 codes were used to identify diagnoses and procedures.

Results:
A total of 7,745 patients underwent AVSD repair. Following iAVSD repair, 503(7%) required LAVV reintervention. Of those, 292(58%) were White Non-Hispanic, 310(62%) female, 255(51%) government insured, and 267(53%) had Down syndrome. Median age was 4.3[2.9-6.7] months at iAVSD repair[cm1] . 405(81%) underwent LAVV repair and 98(20%) replacement. 127(31%) had LAVV repair and 26(27%) had LAVV replacement during the same admission as iAVSD repair. Of the 503, 73(15%) had a second reintervention; 19(26%) had a repeat LAVV repair and 54(74%) LAVV replacement. Freedom from a second reintervention at 15 years was 77%(95%CI:72.1-82.2). Of the 98 patients that underwent initial replacement, older age at initial valve replacement was associated with a decreased risk for second replacement (HR:0.78;95%CI:0.65-0.93,p=0.007). Freedom from re-replacement at 15 years was 44.1%(29.3-67.6) and differed by age at initial replacement.(Figure 1.)

Conclusion:
LAVV reintervention after iAVSD repair is common and frequently followed by a need for additional LAVV reintervention. Need for early LAVV repair is associated with increased risk of further interventions. These data reinforce the chronic nature of LAVV pathology in AVSD and helps inform counseling for families and patients.
Abstract 4143796: Inpatient Mortality Trend in Obese Versus Non-Obese Patients With Acute Coronary Syndrome: “An Obesity Paradox” – 15-Year Nationwide Sample Analysis
Authors: Abood Zaid , Bajwa Tanvir , Sokhal Balamrit , Tunink Kirsten , Hommeida Mohamed , Allaqaband Suhail , Jan M. Fuad
Published: November 2024

Background:
Obesity is endemic in the United States. Previous studies have reported an obesity paradox in mortality associated with acute coronary syndrome (ACS). However, percutaneous coronary intervention (PCI) and inpatient mortality trends over a long period of time in this group of patients remain unknown.

Aim:
To evaluate PCI and inpatient mortality trends among ACS patients with obesity over a 15-year period.

Methods:
We used the National Inpatient Sample from 2005 to 2019 to identify the study population using the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification. The primary outcomes were (1) the trend in PCI use among obese patients admitted for ACS and (2) in-hospital mortality trends in these patients compared to non-obese ACS patients treated with PCI. The secondary outcome was total hospital costs over the years.

Results:
We evaluated 9,259,932 patients hospitalized in the United States for ACS. Of those, 1,345,937 (14.5%) were obese. Obese patients were younger (mean age 61 years) and had a higher percentage of females (41.3%) compared to non-obese counterparts (mean age 68 years, P<.001; 38.4% female, P<.001). Overall mortality among the obese patients was lower than in non-obese patients (3.0% vs 5.6%, P<.001). A total of 663,128 (49.2%) obese patients underwent PCI compared with 45% in the non-obese group (P<.001). From 2005 to 2019, the number of PCI procedures in the obese group increased approximately threefold (Figure 1A). During this period, the mortality rates among obese patients with ACS treated with PCI increased from 2.0% in 2005 to 2.9% in 2019 (P<.001), yet remained lower than those in the non-obese group, which experienced a slight decrease in mortality from 4.3% in 2005 to 3.8% in 2019 (P<.001) (Figure 1B). Length of stay and total cost were relatively similar, around 3.8 days and $23,000, respectively, in both groups.

Conclusion:
Over the past 15 years, an increasing trend of PCI adoption has been observed in obese patients. In these PCI-treated obese patients, we observed lower mortality rates compared with their non-obese counterparts. This obesity paradox suggests a potential protective effect of obesity, warranting further research to understand the underlying pathophysiology to improve treatment strategies for this demographic.
Abstract 4143819: The Cardiotoxic Effect of Androgen Deprivation Therapy on the Genome of Men Diagnosed with Prostate Cancer
Authors: Mullen McKay , Guha Avirup , Weintraub Neal , Nain Priyanshu , Simon Abigayle , Elsayed Omar , Hyma Kunhiraman Harikrishnan , Harris Ryan
Published: November 2024

Background:
Prostate cancer (PC) is the second leading cause of cancer-associated mortality among men. In addition, cardiovascular disease (CVD) is the most common cause of death in men with prostate cancer who survive chemotherapy. Conventional chemotherapy is often paired with androgen deprivation therapy (ADT) to prevent metastasis. Although ADT has increased cancer survival rates, the presence of CVD has increased substantially. From an epidemiological perspective, genetic diversity is related to disease predisposition; however, the causal factors remain unknown. Thus, this study sought to (1) evaluate the cardiotoxic effect of ADT using drug screening on differentiated cardiac stem cells, and (2) determine whether affected genes identified in the cell experiment were present in samples collected from men with PC before and following ADT.

Methods:
First, induced pluripotent stem cells (iPSCs) from 4 men were differentiated into endothelial cells and cardiotoxicity screening was conducted by comparing the gene response of ADT treated and untreated cells using RNA seq and gene ontology. Next, 19 men with PC were enrolled for the human experiment, and blood samples were collected at baseline, and 4 and 12 weeks following ADT. O-link proteomics was performed at all time points to determine overlap between biomarkers associated with increased CVD risk during ADT identified in the cell experiment.

Results:
The iPSC RNA seq data identified 301 genes that were significantly altered by ADT. Specifically, in the ADT treated cell lines, there was overexpression (
p
<0.001) among members of the cyclin-dependent kinase (CDK) and transforming growth factor (TGF) families when compared to the untreated cells. In the human samples, there was an increase in the normalized plasma expression of CDK1 (0.428±0.9 to 1.036±1.0;
p
=0.133) and TGFBR2 (0.789±0.6 to 1.128±0.6;
p
=0.058) from baseline to 12 weeks, respectively.

Discussion:
CDK and TGF, genes known to play a role in CVD, were upregulated following ADT in both cell and human experiments. Different CDKs have been linked to various aspects of heart disease. Similarly, TGFβ isoforms are known to be upregulated and activated in myocardial diseases, playing an important role in regulating the heart phenotype and function. Therapies to reduce CDK and TGF isoforms represent a novel approach to decrease the CVD risk associated with ADT in men with prostate cancer; however, future studies are certainly warranted.