tbuckley/cabot-search huggingface dataset:
Abstract 4141908: Variant Burden and Severity of Cardiac Phenotype in Duchenne Muscular Dystrophy Cardiomyopathy
Authors: Gabrielle Geddes, Stephanie Ware, Tae-Hwi Schwantes-An, Marco Abreu, John Parent, Jennifer Howell, Conner Earl, Jonathan Soslow, Larry Markham
Journal: Circulation (2024)

Introduction: Duchenne muscular dystrophy (DMD) has cardiac phenotype variability ranging from mild ventricular dysfunction to death from heart failure in the second decade. This variability has not been explained by specific DMD variants. Question: This study was designed to identify target genes, other than DMD , as cardiomyopathy (CMP) severity modifiers. Methods: Genome sequencing results were analyzed from 54 well phenotyped DMD males and either severe CMP (cardiac mortality or left ventricular ejection fraction (EF) &lt; 40% at &lt; 20 years of age, n = 18) or mild CMP (EF &gt; 40% at &gt; 20 years of age, n = 36). We compared variants within CMP groups as follows: 1) all study subjects, 2) siblings discordant for CMP severity, and 3) subjects without relatives. Combined Annotation-Dependent Depletion (CADD) was used to assess individual rare variant burden by filtering to retain coding variants with a raw CADD-generated C-Score &gt;2.5. Using the C-Score, we calculated the difference between group mean (DBGM) between the CMP groups for each gene. For each of the three analyses groups, we normalized DBGM summative C-Score and determined which genes had a DBGM summative C-Score &gt;3 standard deviations from the mean (SDM). We evaluated genes that were present on the gene list for all three analyses. Results: The cohort by CMP severity is depicted in Figure 1a. Comparisons yielded 8,155 genes with a C-Score &gt; 2.5 in at least one patient. Number of genes with DBGM &gt;3SDM in respective CMP group analysis above: 1) 159 genes 2) 134 genes 3) 136 genes. Nine genes had DBGM summative C-Scores &gt;3 SDM in all three analyses. Of these, 5 genes, ANKLE1 , ESRRA , GXYLT1 , MTCH2 , and QRFPR, had scores suggestive that these genetic variants could be protective against severe CMP. Whereas 4 genes, FRAS1 , GEMIN4 , PKD1L2 , and PRSS2 had scores suggestive that these genetic variants could be a risk factor for severe CMP. Conclusion: DBGM summative C-Scores from DMD genome sequencing generated 9 candidate genes from 8,155 genes for stratifying CMP phenotypic variability. Further translational evaluation of these genes as modifiers of DMD CMP severity is warranted. If confirmed, these modifiers could provide therapeutic insight specific to DMD CMP.
Abstract 4141960: Quality of Life Outcomes after the Dual Epicardial&amp;Endocardial Procedure Approach for Treatment of Non-Paroxysmal Atrial Fibrillation
Authors: Ali Khoynezhad, Vigneshwar KASIRAJAN, Mark La Meir, Carlo de Asmundis, Jayanthi koneru, John Johnkoski, Kevin Rist, Mubashir Mumtaz, Michael Link, Joris de Groot, Antoine Driessen, Mark Lee, Steven Hoff, David Bello, Gansevoort Dunnington, Susan Eisenberg, Margot Vloka, Benedict Taylor, Stephen Jones, Jonathan Philpott, Thomas Beaver, William Miles, junaid khan, Steven Kang, Gaurang Gandhi, Eric Okum, Nitesh Badhwar, Tina Baykaner, Anson Lee, Paul Vesco, J Michael Smith, Sydney Gaynor, Ken Frazier, Kenneth Ellembogen
Journal: Circulation (2024)

Background: Quality-of-life (OQL) is recognized as a proven benefit of atrial fibrillation (AF) ablation. The DEEP trial (NCT02393885) showed safety (6.7%) and efficacy (71.8%) of an epicardial-endocardial hybrid ablation (HA) approach with left atrial appendage exclusion (LAAE) for non-paroxysmal AF; results were consistent with two randomized trials comparing HA+LAAE to catheter ablation (CA). Limited data exist on QOL after HA+LAAE. Goal: To evaluate QOL changes from baseline to 12-months post-HA+LAAE in the DEEP trial. Methods: DEEP is a 17-site prospective, international, single arm trial. Key eligibility: adults with non-paroxysmal AF, left atrial diameter ≤5.5cm, failed class I/III anti-arrhythmic drugs, and ≤2 prior failed CA. Stage 1 was thoracoscopic radiofrequency epicardial ablation to isolate the pulmonary veins and left atrial posterior wall, and LAAE. Stage 2 was endocardial mapping and touchup ablation. QOL was measured via the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire at baseline and 12-months post-HA+LAAE. AFEQT yields scores from 0 to 100 (0 as complete disability and 100 as no disability) and includes an overall and four subscale scores. A 5-point AFEQT change is clinically important. Mean differences with 95% CIs were calculated; p-values are from paired t-tests. Results: Of 85 patients, 82 completed both baseline and 12-month AFEQT. The mean change in overall score was 30.1 ± 19.8 (95% CI: 25.8-34.5; median 29.5, min, max: -15.4, 78.2; p&lt;0.0001) (Figure). The greatest improvement was in the Treatment Satisfaction subscale with a mean score of 53.2 ± 29.9 (95% CI: 46.6-59.7; median 58.3, min, max: 0.0, 100.0; p&lt;0.0001), followed by Treatment Concern, Daily Activities, and Symptoms subscale scores. All mean improvements from baseline exceeded a clinically meaningful 5-point change. Conclusion: In the DEEP trial, HA+LAAE resulted in patient-reported QOL improvements at 12-months post-procedure.
Abstract 4141955: A Case of Dilated Cardiomyopathy and Systemic Thromboembolism in a Young Patient on Testosterone Replacement Therapy
Authors: Muhammad Sabri, Naila Ijaz, Ramsha Nadeem, Lucy Checchio, Faiza Riaz
Journal: Circulation (2024)

Introduction: Whereas low testosterone levels have been associated with poor cardiovascular outcomes and testosterone replacement therapy (TRT) in middle-to-older age adults with cardiovascular risk factors is considered safe, there is little data on the adverse cardiovascular effects of TRT in young adults. Case Report: A 38-year-old male with a past medical history of hypogonadism, recently started on intramuscular testosterone cypionate injections, presented to the hospital with altered mentation. Laboratory workup was remarkable for hemoglobin of 19 g/dL. Computed tomography (CT) angiogram of the head demonstrated a left middle cerebral artery infarct with a filling defect, requiring mechanical thrombectomy. A transthoracic echocardiogram (TTE) was done which revealed a dilated left ventricle (LV) with severely reduced LV systolic function, EF 20%, and global hypokinesis. There was no LV thrombus or evidence of a patent foramen ovale with contrast saline injection. He did not have any episodes of atrial fibrillation on telemetry monitoring. His hospital course was further complicated by an inferolateral ST elevation myocardial infarction (STEMI) due to distal left anterior descending (LAD) artery occlusion. He underwent drug-eluting stent placement and was started on dual antiplatelet therapy. Repeat TTE demonstrated new apical akinesis along with an LV apical thrombus of 1.1 x 0.8 cm. CT abdomen/pelvis with contrast demonstrated left renal and right iliofemoral thrombosis and the patient was also started on systemic anticoagulation. Discussion: Data suggests that physiologic levels of testosterone exhibit cardioprotective effects and low testosterone levels are associated with increased cardiovascular mortality. However, studies have also shown that testosterone use is associated with an increased risk of thrombosis and coronary artery disease. Additionally, testosterone use has been associated with myocardial apoptosis and adverse cardiac remodeling from dysregulation of androgenic receptors, which results in dilated cardiomyopathy. There is an ongoing debate on the safety of TRT, however, studies on TRT have largely included the middle and older male population and there is little data on younger patients. Herein, we demonstrate a case of TRT in a patient with several cardiovascular risk factors, who developed evidence of possible TRT-associated cardiomyopathy in addition to hypercoagulability.
Abstract 4141921: Hydration to prevent acute kidney injury after pulsed field ablation: importance of timing and fluids amount
Authors: Vincenzo Mirco La Fazia, Sanghamitra Mohanty, Prem Geeta Torlapati, carola gianni, Domenico Della Rocca, Weeranun Bode, Joseph Gallinghouse, Amin Al-Ahmad, Luigi Di biase, Andrea Natale
Journal: Circulation (2024)

Previous studies have highlighted the risk of acute kidney injury (AKI) development, underlining the need for strategies to mitigate this complication. We analyzed 208 consecutive patients who underwent pulsed field ablation (PFA) for post-FDA approval. All patients received pulmonary vein isolation. Ablation of extra-PV sites was performed per the operator’s choice, with no contrast agents . Serum creatinine was measured in all patients at baseline and 24 after ablation. The aim of our study was to evaluate the impact of hydration timing and the amount of fluids on incidence of AKI in patients undergoing PFA. Group means for continuous variables were compared using the Student t-test. Categorical variables were compared using the Chi-square test. A ROC analysis was done to evaluate the predictive model of PFA applications to evaluate AKI. All tests were two-tailed and conducted at an α level of 0.05. We divided patients into two groups: Group 1 (n=102) received either one liter of saline pre-procedure or one liter pre-procedure followed by a liter post-procedure; Group 2 (n=106) was preemptively hydrated with two liters of saline before the procedure, followed by additional 500cc if the patient had received more than 100 PF applications. Baseline Characteristics of population are described in Fig.1a . In the comparative analysis of the two groups, there was no significant difference regarding the number of PFA applications administered. None of the patients in Group 2 experienced AKI, while Group 1 AKI occurred in 9 patients. (0/106 vs 9/102, p-value=0.0034). The ROC analysis yielded an area under the curve of 0.709 ± 0.107 with a 95% confidence interval ranging from 0.498 to 0.919 (p-value=0.035). An optimal PF application cutoff point of 105.50 was determined, associating a higher probability of AKI with PFA applications exceeding this threshold (sensitivity:0.667, specificity:0.735, Youden's index:0.402) ( Fig.1b ). Among the 9 patients who developed AKI, we observed that 7 received more than 100PF applications; the remaining 2 patients, each with baseline stage 3 chronic kidney disease and prior episodes of AKI following surgeries, received 54 and 50PF applications, respectively. In this series of patients, pre-procedural hydration with two liters of fluids eliminated the risk of AKI even in patients who received a high number of PFA applications.
Abstract 4141922: Development of prediction models in heart failure lacks quality: a systematic review
Authors: Seth Bergstedt, Ellen Cravero, Katianna Feldewerd, Evan Walser-Kuntz, Andrew Willett, Larissa Stanberry
Journal: Circulation (2024)

Advances in modeling methodology and increased democratization of software led to rapid increase in novel prediction models. In clinical research, these models proclaim novel predictors, promise superior accuracy and meaningful improvements in patient outcomes. Developing an accurate prediction model requires rigorous methodology with great attention to study design and conduct. Failure to adhere leads to prediction bias and may result in harmful decisions. We conducted a systematic review of research articles in heart failure listed in PubMed 2018 – 2023 and presented by their authors as developing prediction models, either diagnostic or prognostic. The study variables were selected based on PROBAST and TRIPOD (Table 1). These were summarized and the study conducts were evaluated against the gold standard of prediction modeling per PROBAST and TRIPOD. For each study, we calculated the optimal sample size, i.e. the minimal size required for at least 5% prediction accuracy and 90% shrinkage in parameters. Sentiment analysis was performed to estimate the prevalence of promotional language in the abstract corpus. From 6,429 studies, 212 studies were presented as developing prediction models. Of those, 83 (39%) were truly about developing prediction models (TPM) and the rest were impostors, i.e. inferential models misrepresented as predictive. Mostly, TPMs were prognostic, modeled binary outcomes, and employed machine-learning methods (Table 1). Commonly, essential data volume summaries were lacking and handling of missing data was inadequate. The deficit in the number of samples in model training was 1499 (-316, 3866) samples with 52(71%) studies below the optimal size. Model validation or testing was not performed in 30% of the studies. Discrimination statistics were reported often in testing but not in validation. The calibration was rarely assessed at either phase. Thirty (36%) studies had enough information to implement risk score calculations. The sentiment analysis showed increased use of hype words in both TPMs and impostors relative to 2020-rates in Millar et al (2022). Most TPM studies exhibit poor design, insufficient sample size, mishandling of missing data, and inadequate model evaluation. These deficiencies result in biased risk estimates, degrade the performance in external data limiting generalizability and clinical utility of the developed models. Excessive use of hype can be misleading and may impede objective evaluation by the readers.
Abstract 4141936: Neurocognitive and vascular dysfunction in a murine model of atrial fibrillation is attenuated by mitochondrial catalase
Authors: Pavithran Guttipatti, Ruiping Ji, Najla Saadallah, Uma Mahesh Avula, Parmanand Dasrat, Samantha Parsons, Elaine Wan
Journal: Circulation (2024)

Background: Atrial fibrillation (AF) increases the risk of cognitive decline and dementia independent of stroke or comorbidities. However, the mechanism is poorly understood and there is no animal model studying the effects of persistent AF on the brain. Objectives: We studied a genetic mouse model with spontaneous and persistent AF to assess cognitive performance, brain structure, and vascular function and to investigate if expression of mitochondrial catalase can improve these deficits in AF mice. Methods: We have previously established a double transgenic mouse model expressing modified human Na + channel SCN5A with spontaneous prolonged AF (DTG-AF mice). We have shown DTG-AF-mCAT mice expressing mitochondrial catalase (mCAT) have greatly reduced AF burden. We used the automated touchscreen test to assess visual discrimination and learning. Selection of the correct stimulus between two screens results in a reward. Number of trials and time to achieve a performance criterion of 80% correct was compared between control (n=15), DTG-AF (n=18), and DTG-AF-mCAT mice (n=12) via one-way ANOVA and Mantel-Cox test respectively. Brain imaging was performed with T2-weighted MRI on control (n=7) and DTG-AF (n=7) mice. Vascular function was assessed by measuring myogenic tone of cannulated third order mesenteric arteries ex-vivo (n = 9, 9, 9 vessels). * p&lt;0.05, *** p&lt; 0.001. Results: DTG-AF mice show significantly impaired visual learning on the touchscreen test, requiring greater trials to reach performance criterion than control mice (mean difference 133.6 ± 53.8). Brain MRI did not reveal microinfarcts but demonstrated increased lateral ventricle size in DTG-AF mice suggestive of ventriculomegaly (1.83 ± 0.19 vs 1.27 ± 0.17). Mesenteric resistance arteries in DTG-AF mice demonstrated loss of myogenic tone with increasing intraluminal pressure. Importantly, reducing AF burden with mitochondrial catalase significantly improved touchscreen test performance and restored myogenic tone. Conclusion: DTG-AF mice model the neurocognitive dysfunction seen in AF and display loss of myogenic tone and vascular dysfunction which may be the cause of altered cerebral autoregulation. Reducing mitochondrial ROS is sufficient to improve cognitive performance and reverse vascular dysfunction.
Abstract 4141772: “SETDB2 regulates the Innate Immune Memory response and influences Inflammatory Immune landscape in Atherosclerosis”
Authors: ANANT JAISWAL, Laszlo Halasz, Yajaira Suarez, Carlos Fernandez-Hernando, Timothy Osborne
Journal: Circulation (2024)

Background: Several pro-inflammatory signals, including microbial cell components such as β-glucan or metabolites produced during western-diet feeding, function as initial “triggers” that train macrophages to respond more robustly to a later secondary inflammatory challenge. This crude “memory” response in innate immune cells is termed as “trained immunity." This memory response is mediated, at least in part, through epigenomic changes to the chromatin landscape. Aim: Role of SETDB2 in trained immunity and atherosclerosis. Results: Our preliminary findings suggest that SETDB2, a putative epigenomic enzyme that is a member of the KMT1 family of lysine methyltransferases, is induced by β-glucan training in macrophages, and knocking out SETDB2 in myeloid cells (SETDB2mKO) altered the magnitude of the secondary pro-inflammatory response in the two-step training protocol described in Background. RNA sequencing revealed a dynamic profile of transcripts that were altered in SETDB2mKO with different gene clusters, consistent with SETDB2 positively regulating some genes while negatively regulating others. We also developed SETDB2 knock-in (SETDB2KI) mice that crippled its potential enzymatic function. Interestingly, SETDB2KI data suggested that SETDB2’s enzyme activity is essential for its role in negatively regulating genes, while positively regulated genes require SETDB2 but not its enzyme activity. Several metabolic and inflammatory pathway genes were regulated by SETDB2, as were several genes known to be involved in immune cell infiltration. Bone marrow transplantation from global SETDB2-deficient mice into LDLRKO resulted in more severe atherosclerotic plaques following western diet feeding, and single-cell RNA sequencing revealed increased neutrophil and reduced CD4+ T-cell populations in lesions from the SETDB2-deficient plaques. When combined together, the positive and negative regulation of different gene clusters by SETDB2 in the in-vitro training study and the more severe atherosclerosis with altered immune profiles in the SETDB2-deficient plaques in vivo suggest that SETDB2 positively and negatively regulates CD4+ T cell and neutrophil recruitment to atherosclerotic plaques, respectively. Conclusion: Our preliminary findings show that SETDB2 regulates immuno-metabolic pathway genes via two different mechanisms, which might also influence the immune cell inflammatory landscape and severity of atherosclerosis.
Abstract 4141929: Genetic Evidence for GIP as a Therapeutic Target for Peripheral Artery Disease
Authors: Sabina Sorondo, Shaunak Adkar, John Depaolo, Michael Levin, Nick Leeper, Scott Damrauer, Derek Klarin
Journal: Circulation (2024)

Background: Peripheral arterial disease (PAD), when comorbid with type 2 diabetes (T2D), is associated with increased risk of adverse limb events, and therapeutic options for these patients are limited. The STARDUST trial recently demonstrated that Liraglutide significantly improves lower limb perfusion in PAD patients with concomitant T2D in an open label randomized setting, potentially expanding the use of Glucagon-like Peptide-1 Receptor (GLP1R) agonists to this population. Using data from the Million Veteran Program (MVP), we aimed to estimate the effects of GLP1R and gastric inhibitory peptide (GIP) agonists on PAD using genetic proxies. Methods: We obtained previously published GWAS summary statistics for T2D from the DIAMANTE consortium, and performed an association analysis for PAD in MVP at the GLP1R and GIP loci. For our primary analysis in MVP, association testing was performed with clinical PAD using logistic mixed models controlling for age, sex and population structure. We performed a colocalization analysis of PAD and T2D association signals at these loci using hyprcoloc, and then tested the association with PAD stratified by T2D status. Genome-wide significance (5x10e-8) was used to determine statistical significance for our primary analysis. Results: We identified 51330 participants with and 256807 participants without PAD in MVP. Among the European population, we observed evidence of association for PAD at the GIP locus (lead variant rs35895680, OR = 1.048, P = 1.723e-10 for the C risk allele), but not at the GLP1R locus (lead variant rs113678890, OR = 1.6434, P = 1.150e-3). The lead PAD variant at the GIP locus was observed to be the lead T2D variant in the recent DIAMANTE consortium GWAS analysis, and we observed evidence of colocalization between T2D and PAD at the GIP locus, (Posterior Probability of the same causal variant = 0.99). Logistic regression for rs35895680 in the MVP PAD data revealed significant associations in both diabetics (OR=1.04, P = 9.02e-5) and non-diabetics (OR 1.04, P = 1.35e-3), without evidence of heterogeneity (P = 0.60281). Conclusions: These findings highlight GIP as a promising target for PAD intervention, potentially benefiting a broader patient population beyond those with concomittent diabetes. Consequently, future trials incorporating therapies inhibiting both GLP1R and GIP, such as tirzepatide, could offer superior therapeutic benefits for PAD compared to GLP1R agonists alone.
Abstract 4141931: Effect of Storage Temperature on Myocardial Tissue Preservation in Rat Hearts
Authors: Zachary Kiernan, Gina Marie Labate, Qun Chen, Mohammed Quader
Journal: Circulation (2024)

Background: Cold static storage of the heart in ice for transportation is thought to cause post-transplantation graft dysfunction secondary to freeze injury. No basic science or randomized clinical trial has objectively evaluated this concern. Hypothesis: Hearts stored at 0°C for four hours do not sustain freeze injury. Aim: To quantify the myocardial damage and resulting function in hearts stored at 0 o C, 4 o C and 8 o C for four hours. Methods: Male Sprague-Dawley rat hearts were procured under general anesthesia and immediately stored in University of Wisconsin solution at 0 o C, 4 o C and 8 o C for four hours (n = 6-8/group). Hearts were then re-perfused on a Langendorff apparatus for 90 minutes using oxygenated Krebs-Henseleit buffer (37 o C) at a perfusion pressure of 73 mmHg. Functional parameters were recorded via a balloon tip catheter in the left ventricle. Coronary flow rate was monitored with timed collection of effluent. At the end, hearts were collected for infarct size quantification using triphenyltetrazolium chloride staining. Results: Infarct size in hearts stored at 0°C, 4°C, and 8°C were 28±1%, 32±2%, and 39.7±2%, respectively. There was no significant difference in infarct size between hearts stored at 0°C and 4°C. Hearts stored at 8°C had a significantly larger infarct size compared to both 0°C and 4°C ( P = 0.0004 and 0.0178, respectively). Left ventricle developed pressure in hearts stored at 0°C, 4°C, and 8°C were 55±4 mmHg, 51±3 mmHg, and 55±2 mmHg, respectively (all P &gt; 0.05). Negative dP/dt in hearts stored at 0°C, 4°C, and 8°C were -2505±274 mmHg/sec, -1969±186 mmHg/sec, and -1861±175 mmHg/sec, respectively (all P &gt; 0.05). Coronary flow at 4°C (22 mL/min) was higher compared to 0°C (19 mL/min) and 8°C (16 mL/min) ( P= 0.0371 and P =0.0003, respectively). Cardiac troponin I levels in the coronary effluent from hearts stored at 0°C, 4°C, and 8°C were 0.88±0.1 ng/ml, 0.86±0.1 ng/ml, and 1.24±0.2 ng/ml, respectively (all P &gt; 0.05). Conclusion: Hearts stored at 0°C for four hours showed no signs of freezing, they showed similar functional parameters and comparable levels of biochemical markers for injury compared to hearts stored at 4°C. Hearts stored at 8°C had a larger infarct size compared to 0°C or 4°C.