tbuckley/cabot-search huggingface dataset:
Abstract 4145315: Are We Including Everybody? A Systematic Review On Reporting Of Transgender and Gender-Expansive Populations in Cardiovascular Clinical Trials
Authors: Aishwarya Yamparala, Amir Joshi, Warren Fernandez, Shreyash parajuli, Kannu Bansal, Tariq Ahmad, Nihar Desai
Journal: Circulation (2024)

BACKGROUND: Transgender and gender expansive (TGE) people constitute a vulnerable population with added cardiovascular risk and frequently experience health inequalities and obstacles to care. However, they are nonetheless underreported and underrepresented in clinical trials. We aim to understand inclusion and representation of TGE population in clinical research by examining the volume and caliber of reporting in certain disciplines of CV clinical trials. METHODS: A systematic review of clinical trials from January 2020 to March 2024 was conducted across 4 cardiovascular areas (heart failure, stroke, dyslipidemia, electrophysiology) using ClinicalTrials.gov focusing on the inclusion and reporting of TGE populations in the United States with published results. Trials were evaluated for explicit mention of TGE participants, use of gender-inclusive language, and provision of disaggregated data by gender identity. Equity metrics, such as the proportion of trials including TGE participants were calculated. RESULTS: A total of 32,583 participants were included(Table).We collected reporting of populations for sex and gender descriptions, as well as the inclusion and exclusion criteria. Almost all studies reported sex or gender as a single outcome variable. We inferred this to denote sex unless it was specified otherwise. All studies reported sex, with women representing 54% of all participants. Women represented the minority of study participants in stroke (39%), dyslipidemia (45%), and electrophysiology (37%) clinical trials, but majority of participants in heart failure trials (64%). Gender identity, including the option “other”, was reported in only 3 trials (4.1%), of which 2 were heart failure and 1 was a dyslipidemia trial. Most trials had pregnant women, lactating women, and age &lt;18 years as exclusion criteria, and had adults aged &gt;18 years as the inclusion criteria. CONCLUSION: Our findings confirm that there is still a lack of commitment in current clinical trials to the Sex and Gender Equity in Research guidelines. The impact of the differences in this population can never be fully understood unless gender identification data is carefully gathered. Current national guidelines mandate that in randomized clinical trials, gender should be fully reported and that gender-inclusive language be used appropriately. To properly represent and care for these populations, future cardiology studies should adhere to the Sex and Gender Equity in Research principles.
Abstract 4144825: 4-Hydroxy-2-Nonenal Alters Alternative Polyadenylation to Regulate mRNA Isoform Diversity in the Transition from Human Cardiac Fibroblasts to Myofibroblasts
Authors: Kartiga Natarajan, Rahul Neupane, Hari Krishna Yalamanchili, Suresh Palaniyandi, Eric Wagner, Ashrith Guha, Rajarajan Amirthalingam Thandavarayan
Journal: Circulation (2024)

Background: Cardiac fibrosis involves excessive deposition of extracellular matrix (ECM) proteins, leading to myocardial stiffness and remodeling, exacerbating diastolic and systolic dysfunction. Notably, cardiac fibroblast (CF) differentiation into myofibroblasts drives ECM deposition, contributing to adverse remodeling. Lipid peroxidation by 4-hydroxynonenal (4HNE) is crucial in fibrosis initiation. Our research explores the role of alternative polyadenylation (APA) in ECM production specifically the impact of 4HNE on APA-mediated modifications in CF activation. Objective: To investigate global APA events during the transition of human CFs to myofibroblasts induced by 4HNE, using the PolyA miner algorithm. Methods: Human CFs were treated with 1 or 2 µM 4HNE or vehicle control to investigate 4HNE induced heterogeneity in 3’UTR lengths. Poly(A)-click RNA sequencing and PolyA-miner analysis were used to examine 3’UTR length changes in genes related to myofibroblast activation. Results: Our analysis revealed cells treated with 1 µM 4HNE altered 236 differential APA genes (DAGs), of which 169 genes exhibited PolyAIndex and among them, 77 underwent 3’ UTR lengthening, and 92 genes underwent 3’UTR shortening. Whereas cells treated with 2µM 4HNE altered 461 DAGs of which 345 genes exhibited PolyAIndex, with 127 genes exhibiting elongation and 218 genes showing shortening. This shows, 4HNE altered 3’UTR lengths in dose dependent manner. Importantly, pathway analysis unveiled that the shortened 3’UTR lengths of genes in 4HNE treated fibroblasts were associated with TGF-β, hippo, and focal adhesion signaling pathways implicated in myofibroblast activation, whereas genes with altered elongated 3’UTR lengths were mostly linked to hedgehog signaling. Furthermore, 4HNE promoted differential APA of fibrotic genes, including fibronectin, collagen 1 α, and α-smooth muscle actin, correlating with increased protein expression. Altogether, our results identify 4HNE as an APA regulator during cardiac myofibroblast activation, though the exact mechanism remains unknown. Conclusion: This study provides novel insights into the molecular mechanisms by which 4HNE governs the transition of human CF to myofibroblasts through regulation of 3'UTR length of fibrotic genes and subsequent translational control. Understanding 4HNE-mediated APA-mediated changes in CFs may pave the way for the development of targeted therapeutic strategies to mitigate adverse outcomes in cardiac fibrosis.
Abstract 4144794: Effects of Myectomy on Cardiac Magnetic Resonance Parameters in Obstructive Hypertrophic Cardiomyopathy
Authors: Myra Lewontin, Olivia Ondigi, Robyn Goodrich, Cristiane De Carvalho Singulane, Matthew Thomas, Karen McClean, Allison Perry, Kenneth Bilchick, Amit Patel, Christopher Kramer, Michael Ayers
Journal: Circulation (2024)

Introduction: Cardiac magnetic resonance (CMR) analyses in patients from the EXPLORER-HCM study showed that cardiac myosin inhibitors (CMIs) have favorable effects in obstructive hypertrophic cardiomyopathy (oHCM) characterized by decreased left ventricular (LV) maximal thickness, decreased left ventricular mass index (LVMI), decreased left atrial volume index (LAVI), and cessation of replacement fibrosis progression based on late gadolinium enhancement (LGE). Question: Do surgical and alcohol myectomy lead to less favorable LV remodeling and cessation of scar formation than CMIs using CMR findings from EXPLORER-HCM as the comparison reference? Hypothesis: We hypothesized that the extent of CMR changes observed with CMIs in oHCM would not be observed with myectomy. Methods: We identified patients who underwent surgical or alcohol myectomy at our center of excellence with pre- and postprocedural CMR. We analyzed changes in LAVI, LVMI, LV maximal thickness, LV ejection fraction (LVEF), percent scar volume (LGE%), and scar mass by LGE (LGE% x LV mass). We normalized these changes by LV mass for comparison with CMR findings with CMIs reported in EXPLORER-HCM. Results: Characteristics of five patients with CMR before and after surgical or alcohol myectomy are shown in Table 1. Median (IQR) time to postprocedural CMR was 6.6 (2.5-28.9) months. LV maximal thickness decreased by 2.0 ± 1.4 mm (p = 0.03) following myectomy (EXPLORER-HCM: 2.4 mm decrease), LVMI decreased by 13.2 ± 15.5 g/m 2 (p = 0.13)(EXPLORER-HCM: 15.8 g/m 2 decrease), LAVI decreased by 11.9 ± 13.3 g/m 2 (p = 0.12)(EXPLORER-HCM: 10.3 g/m 2 decrease), and LVEF decreased by 6.4 ± 9.2% (p = 0.20)(EXPLORER-HCM: 6.4% decrease). Myectomy patients had an increase in LGE% of 2.5 ± 3.3% (p = 0.16) and in LGE mass of 2.4 ± 6.9 g (p = 0.48). Corrected for LV mass change, there was decreased mean LV maximal thickness (-1.7 mm), trends toward decreased mean LVMI (-11.3 g/m 2 ), LAVI (-10.2 g/m 2 ), LVEF (-5.5%), and trends toward increased mean LGE% (2.1%) and LGE mass (2.0 g). Conclusions: Surgical or alcohol myectomy resulted in trends toward positive remodeling, with overall similar effects to those seen with CMIs. Limitations include small sample size and variable timing of CMRs. There was an increase in LGE during follow-up with myectomy, consistent with continued disease activity with myectomy compared to CMI. This plausible difference in scar formation merits further prospective investigation with a larger sample size.
Abstract 4144840: Current Status and Challenges of Cardiac Transplantation in the MENA Region: A Narrative Review
Authors: Mohammad Tanashat, Mohammed Ayyad, Laith Alhuneafat, Mouath Abu Daoud, Jana Nusier, Omar Al Taani, Mutaz Abu-Laila, Yazan Al-Ajlouni
Journal: Circulation (2024)

Background: Cardiac transplantation has significantly evolved since its inception in 1967. While the USA and Europe lead in transplant numbers and innovations, the Middle East and North Africa (MENA) region is progressively developing its programs. Countries such as Saudi Arabia, Turkey, the UAE, and Jordan have made notable advancements; however, challenges including donor organ shortages, cultural and religious barriers, and economic constraints persist. Research Question: What is the current status of cardiac transplantation in the MENA region, and what are the main challenges and advancements faced by these programs? Goals: This narrative review aims to provide a comprehensive overview of the development, challenges, and outcomes of cardiac transplantation programs in the MENA region. Methods: A thorough literature review was conducted, examining scholarly articles, clinical reports, and data from national and international transplant registries. Key topics reviewed include the establishment and growth of cardiac transplant centers, advancements in surgical techniques and immunosuppressive therapies, patient outcomes, and barriers specific to the MENA region. Results: The review found variability in the development and outcomes of cardiac transplantation programs across the MENA region. Saudi Arabia has one of the most developed programs, with 1-year survival rates of 85% and 5-year rates of 75%. Turkey reports 1-year survival rates of approximately 80%. The UAE has recently expanded its transplant capabilities, yet faces challenges in donor organ availability and long-term patient follow-up. Jordan’s program shows promising outcomes with a 1-year survival rate of around 80%, but financial constraints are significant hurdles. Common challenges include low donor registration rates, lack of public awareness about organ donation, and high operational costs. Disparities in healthcare infrastructure also hinder progress. Innovations such as ex-vivo heart perfusion and new immunosuppressive therapies are being adopted selectively, with Saudi Arabia and Turkey at the forefront. Conclusions: Enhancing public education on organ donation, establishing robust organ procurement systems, and developing specialized heart failure clinics are crucial. Addressing these issues could potentially improve cardiac transplantation success, leading to a subsequent reduction of cardiovascular disease burden in the MENA region.
Abstract 4144933: Telomeric Repeat-Binding Factor 2 Interacting Protein (TERF2IP) S205 Phosphorylation Orchestrates LATS1/2 Degradation under Disturbed Flow Conditions
Authors: Sivareddy Kotla, Venkata Subrahman K Samanthapudi, Abigail Osborn, Jonghae Lee, Oanh Hoang, Gilbert Mejia, Keila Carolina Ostos Mendoza, Keri Schadler, Khanh Chau, NHAT TU LE, James Martin, Junichi Abe
Journal: Circulation (2024)

Background: While the shelterin complex, including TERF2IP, is established in its role of telomere protection, its interaction with the Hippo pathway, which also regulates senescence and inflammation, has not been reported. Our research aims to investigate whether TERF2IP influences the Hippo pathway, potentially linking it to endothelial cell (EC) responses under disturbed flow (d-flow). Methods: ECs were transduced with TERF2IP variants, and subjected to d-flow or static conditions. Post-transfection with makron-1 ubiquitin E3 ligase (MKRN1)/control siRNA, ECs underwent d-flow or remained static. Protein turnover was analyzed using cycloheximide (CHX) treatment. TERF2IP-MKRN1/LATS1/2 interactions were assessed via co-immunoprecipitation after d-flow exposure. Results: LATS1/2 depletion led to endothelial cell (EC) senescence and apoptosis, prompting investigation into the regulatory role of TERF2IP S205 phosphorylation on d-flow-induced LATS1/2 degradation. Adenoviral transduction with the TERF2IP S205A mutation significantly mitigated the d-flow-mediated decrease in LATS1/2 levels. The absence of changes in LATS1/2 mRNA post-d-flow and the protective effect of the protease inhibitor MG132 against LATS1/2 reduction implicate protein degradation mechanisms. Furthermore, MKRN1 depletion markedly curtailed the d-flow-induced decline in LATS1/2 and senescence, underscoring the involvement of the MKRN1 Ub E3 ligase in regulating LATS1/2 protein stability and d-flow-mediated EC senescence. CHX runoff assays following MKRN1 or control siRNA transfection revealed that MKRN1 is pivotal for LATS1/2 stability. The interaction between TERF2IP and MKRN1, enhanced by d-flow and attenuated by the TERF2IP S205A mutation, along with the inhibitory effect of TERF2IP c-myb domain overexpression on their association, indicates a binding site for MKRN1 on TERF2IP. Persistent TERF2IP-LATS1/2 binding until LATS1/2 expression declined suggests the formation of a TERF2IP-MKRN1-LATS1/2 complex that facilitates LATS1/2 degradation mediated by the recruitment of TERF2IP-MKRN1 complex. Conclusion: D-flow triggers the phosphorylation of TERF2IP at S205, leading to the formation of a TERF2IP-MKRN1-LATS1/2 complex. This complex initiates the degradation of LATS1/2, a key regulator of EC senescence. Thus, TERF2IP S205 phosphorylation under d-flow conditions is a crucial step in the pathway leading to LATS1/2 proteolysis, impacting our understanding of EC senescence and atherothrombosis.
Abstract 4145229: Outcomes among hospitalized patients with stress-induced cardiomyopathy and concomitant Coronavirus Disease 2019 (COVID-19) infection: Insight from the US National Inpatient Sample
Authors: John Malin, Bruce Adrian Casipit, Phuuwadith Wattanachayakul, Rasha Khan, Abiodun Idowu, Evan Isaacs, Andrew Geller, Carlo Gabriel Casipit, Aman Amanullah
Journal: Circulation (2024)

Background: Stress-induced cardiomyopathy (CM) is a form of acute transient left ventricular dysfunction triggered by underlying physiological stress which often leads to increased morbidity and mortality. Coronavirus disease 2019 (COVID-19) is thought to cause stress-induced CM due to overwhelming systemic inflammation. There is paucity of data regarding the impact of COVID-19 on in-hospital outcomes of patients with stress-induced CM. The purpose of this study is to investigate in-hospital outcomes, including mortality and cardiogenic shock, of patients with concomitant COVID-19 and stress-induced CM. Methods: We queried the 2020 USA National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified hospitalized adult patients ≥ 18 years old with stress-induced CM and concomitant COVID-19 using ICD-10 CM codes. We used a survey multivariable logistic and linear regression analysis to calculate adjusted odds ratios (aORs) for outcomes of interest. A p value of &lt;0.05 was considered statistically significant. Results: A total of 30,705 hospitalized patients with stress-induced CM were identified in 2020, of which 2.41% had concomitant COVID-19. The overall in-hospital mortality rate among patients with stress-induced CM was 10.15%. Among those with concomitant COVID-19, the mortality rate was significantly higher to 39.86% (P=0.00). Using a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, concomitant COVID-19 among patients with stress-induced CM was associated with increased risk for in-hospital mortality (aOR 5.50; p=0.00), development of CS (aOR 2.40; p=0.00) and AKI (aOR 1.84; p=0.00), use of MV (aOR 3.88; p=0.00), and longer LOS (aOR 4.93; p=0.00). (See table 1) Conclusion: Our analysis showed that concomitant COVID-19 among hospitalized patients with stress-induced CM increased the risk for in-hospital mortality, risk for the development of CS and AKI, utilization of MV, and longer LOS, but was not significantly associated with the utilization of RRT. This highlights the potential for COVID-19 as a predictor for worse outcomes among hospitalized patients with stress-induced CM.
Abstract 4144795: Air pollution exposure and effect of finerenone treatment in patients with chronic kidney disease and type 2 diabetes: A FIDELITY analysis
Authors: Sadeer Al-Kindi, Zhuo Chen, Jean-Eudes Dazard, Youssef Farag, Gerasimos Filippatos, Peter Rossing, Katja Rohwedder, Pedro Salerno, Charlie Scott, Zihe Zheng, Sanjay Rajagopalan
Journal: Circulation (2024)

Background: Finerenone significantly reduced the risk of CV and adverse kidney outcomes vs placebo in patients with CKD and T2D in FIDELITY, a prespecified pooled analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials. Exposure to particulate matter air pollution ≤2.5 microns (PM 2.5 ) is established as the world’s leading environmental risk factor and is implicated in CV and kidney events. This FIDELITY post-hoc subanalysis aimed to examine the effect of finerenone across varying levels of PM 2.5 exposure. Methods: Patients in FIDELITY were on optimized renin–angiotensin system inhibition and randomized 1:1 to finerenone or placebo. Key outcomes included composite CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline over at least 4 weeks, or kidney-related death), and combined composite CV and kidney. Participants were assigned to antecedent PM 2.5 exposure using site location at the time of enrollment (annual PM 2.5 using an integrated exposure model). The effect of finerenone vs placebo was assessed on outcomes across strata of PM 2.5 exposure (quartiles, ≤ vs &gt; median) and as a continuous variable. Results: A total of 12,990 participants were included. Median PM 2.5 exposure was 15.5 (IQR 9.8–21.0) µg/m 3 . PM 2.5 exposure was associated with higher CV and kidney event rates (Fig 1). Although finerenone had a similar beneficial impact on composite CV and renal outcomes across strata of PM 2.5 exposure (P interaction =NS), the numbers needed to treat to prevent one composite CV/kidney event were 34 and 29 for participants at low (≤ median) and high (&gt; median) PM 2.5 exposure, respectively. The finerenone safety profile was generally similar across PM 2.5 quartiles. Conclusions: In FIDELITY, finerenone lowered the risks of CV and kidney outcomes vs placebo in patients with CKD and T2D irrespective of PM 2.5 exposure levels. Given the association between PM 2.5 and risk of CV and kidney events, finerenone may be particularly beneficial in those exposed to higher air pollution levels.
Abstract 4145173: Neighborhood Socioeconomic Deprivation is Associated with Mortality and Readmission for Common Cardiovascular Conditions: a Nationwide Cohort Study of &gt;2 Million Patients
Authors: Jay Lusk, Beau Blass, Hannah Mahoney, Molly Hoffman, Amy Clark, Jonathan Bae, Robert Mentz, Tracy Wang, Manesh Patel, Bradley Hammill
Journal: Circulation (2024)

Introduction/Background: Understanding the relationship between neighborhood socioeconomic environment and cardiovascular outcomes is important to implement effective quality strategies to ensure health equity. Goals/Aims: To determine the association of neighborhood socioeconomic deprivation with 30-day mortality and readmission for patients admitted with common cardiovascular conditions. Methods/Approach: We examined claims data from fee-for-service Medicare beneficiaries aged &gt;=65 with 1 year of preceding fee-for-service eligibility between 2017-2019 admitted for heart failure, valvular heart disease, ischemic heart disease, or cardiac arrhythmias. The primary exposure was the Area Deprivation Index, and outcomes were 30-day all-cause mortality and unplanned readmission. We used logistic regression models and adjusted for demographics, medical comorbidity burden, access to healthcare resources, and characteristics of admitting hospitals. Results/Data: A total of 2,064,426 admissions were included. Patients from socioeconomically deprived neighborhoods generally had higher observed mortality and readmission (Table 1). After full adjustment, neighborhood socioeconomic status was associated with increased 30-day mortality and readmission for all cardiovascular conditions studied. Unadjusted and sequentially adjusted models for 30-day mortality are shown in Table 2. Figure 1 visualizes the adjusted association between neighborhood deprivation and 30-day mortality and readmission. Conclusions: Neighborhood socioeconomic deprivation was independently associated with increased 30-day mortality and readmission for several common cardiovascular conditions.
Abstract 4144814: A novel small molecule synthesized based on a snail hibernation model induces hibernation in mouse fibroblasts and perfused hearts
Authors: JIYUAN PIAO, Yongneng Zhang, Yuan Yuan Zhao, Patrick Hannington, Seyed Amirhossein Tabatabaei Dakhili, John Ussher, Gopinath Sutendra, Evangelos Michelakis
Journal: Circulation (2024)

Animals during hibernation suffer no ischemic consequences from their very much decrease heart/respiration rates, otherwise incompatible with life, but humans lost the ability to hibernate (presumably when their ancestors gained independence from the weather) and are highly vulnerable to ischemia. In a snail hibernation model, we isolated a brain metabolite only present in the plasma and brain of hibernating snails, and we characterized it with HPLC/MS. We found it is an activator of PHLPP1, a critical phosphatase in the conserved AMPK/mTOR signaling networks implicated in hibernation and fuel sensing (O 2 , glucose, amino acids). We synthesized it chemically and named it Snail Neurometabolite Activator of PHLPP1 (SNAP). We hypothesized that SNAP may induce hibernation in snails as well as mouse cells and organs that normally do not exhibit hibernation. We utilized in vivo, in vitro and ex vivo models, using Alberta snails, mouse-derived fibroblasts and ischemia and reperfusion (IR) injury model with Langendorff-perfused mouse hearts, to assess the effects of SNAP on snail hibernation, as well as the fuel deprivation-induced stress resistance in mouse-derived cells and hearts. SNAP injections in snails induced reversible hibernation indistinguishable from physiologic. SNAP specifically dephosphorylates the PHLPP1 targets p-S6K and p-AKT (downstream of mTOR and AMPK respectively) in fibroblasts cultured in hypoxic and low-glucose conditions for 3 days, significantly suppressed O 2 consumption, apoptosis, and cell-cycle progression, but enhanced autophagy formation. Upon discontinuation of SNAP and return to normal culture conditions, the SNAP-treated cells had preserved metabolism and re-entered the cell cycle at much higher rates compared to the vehicle, suggesting protection from ischemia and reperfusion (IR) injury and entrance in a reversible hibernation-like state. Furthermore, SNAP conferred cardioprotective effects during IR injury by preserving LV pressure, max and min dp/dt and re-entering normal function much earlier at reperfusion compared to the vehicle. SNAP offers protection from IR injury, inducing a hibernation-like state in mice cells and hearts, with wide implications for heart attack/stroke, preservation of donated organs for transplantation or even ultra-long space travel.