tbuckley/cabot-search huggingface dataset:
Abstract 4145510: SLIT2 is a novel driver of doxorubicin cardiotoxicity through adipose-cardiac crosstalk
Authors: Mualla Ozcan, Aynaz Lotfinaghsh, Carla Valenzuela Ripoll, Ahmed Diab, Zhen Guo, Wentong Jia, Anahita Ataran, Hamidreza Hajirezaei, Lauren Pedersen, Alireza Sargazi, Babak Razani, Weining Lu, Aarti Asnani, Julio Chirinos, Carmen Bergom, Irfan Lodhi, Jonathan Brestoff, Bettina MITTENDORFER, Ali Javaheri
Journal: Circulation (2024)

Background: Dox cardiomyopathy remains a clinically significant problem. Alternate-day fasting has been shown to exacerbate Dox cardiomyopathy and cachexia. We sought to identify common disease mechanisms by comparing proteomics in mice vs. humans with Dox cardiomyopathy. Methods: Chow-fed C57BL/6 male mice (n=50) were treated with Dox (5 mg/kg intraperitoneal x 3 doses). One day after the last dose, mice were randomized to ad-lib feeding or ADF (24 hours of fasting followed by 24 hours of refeeding) for two weeks, followed by echocardiography, and body composition analysis. For aptamer-based human proteomics, we utilized banked blood from patients with Dox cardiomyopathy (n=47) and other cardiomyopathy (n=2167) from the Penn Heart Failure Study. For 2 group comparisons in mice and humans, we used Student’s t-test and false-discovery rate adjusted for covariates, respectively. For 3-group analyses, one-way ANOVA with Sidak’s correction for multiple comparisons was utilized. Results: Alternate-day fasting (ADF) decreased left ventricular (LV) ejection fraction (p=0.047, 95% CI of difference: -5.61 to -0.04) and LV mass (p=0.012, 95% CI of difference: -10.10 to -1.39) and increased end-diastolic volume/body weight (p=0.035, 9.5% relative reduction) in mice treated with Dox. Dox+ADF also increased adiposity (p=0.005, 95% CI of difference: 6.266 to 29.52) and brown adipose mass (p&lt;0.001, 95% CI: 1.231 to 3.206). Aptamer-based plasma proteomics showed that Dox+ADF upregulated SLIT2, which was the most significant and pronounced protein identifying human Dox cardiomyopathy (vs other cardiomyopathies, p&lt;0.0001, 95% CI of difference: 20307 to 25447). Furthermore, Dox+ADF stimulated SLIT2 and its target UCP1 in inguinal adipose tissue, while UCP1 knockout attenuates Dox cardiotoxicity. Further studies showed that SLIT2 was both necessary and sufficient for Dox cardiotoxicity. Conclusion: These findings suggest that adipose-cardiac crosstalk mediated by SLIT2 is a novel mechanism of Dox cardiomyopathy.
Abstract 4145767: Genetic impairment in myosin-5b related transport processes mediates cardiac dysfunction and sudden cardiac death
Authors: Melanie Ricke-Hoch, Maren Heimerl, Sergej Erschow, Mirco Mueller-Olling, Dietmar Manstein, Niels Decher, Silke Kauferstein, Tina Jenewein, Andreas Pich, Denise Hilfiker-Kleiner
Journal: Circulation (2024)

Background: Class-5 myosin motor proteins including the members MYO5a, b and c are responsible for intracellular sorting and trafficking of different cargoes, e.g. receptors, metabolites, mRNAs, proteins. Aim: The aim is to examine the expression and role of class-5 myosins in the heart with specific focus on MYO5b. Methods: By performing next-generation sequencing, a cohort of SCDY/SIDS patients was screened for variants in MYO5b. Expression analysis were performed using RNA-Seq, qRT-PCR, immunohistochemistry and Western blot. Protein binding partners were identified by proteomics following immunoprecipitation. Mice with a cardiac-specific knockout (KO) of MYO5b (aMHC-Cre tg/- ;MYO5b flox/flox ) and isolated cardiomyocytes were analysed regarding heart function, morphology and molecular alterations compared with controls. Results: MYO5a and MYO5b encoding the myosin-5a and -5b heavy chains show an expression pattern dependent on the developmental status. A reduction in myosin-5b protein expression was detectable in a cohort of human end-stage failing hearts. Human genetic analysis of a sudden cardiac death in the young/sudden infant death (SCDY/SIDS) cohort (n=95) revealed rare and likely pathogenic missense variants in MYO5b in 3%. Young MYO5b-KO mice showed no difference in heart function compared with WT mice, however, displayed impaired electric conductance, metabolism and reduced sarcomeric integrity. Aging KO mice developed heart failure (HF) ending fatal in all mice. RNA-Seq of left ventricular tissue prior to HF revealed deregulated gene expression of sarcomeric and metabolic genes, ion channel subunits and genes involved in Ca 2+ -homeostasis. Proteomic analysis of myosin-5b binding partners revealed them to be mostly ribosomal and mitochondrial in nature. The mitochondrial membrane potential in cardiomyocytes with reduced MYO5b was downregulated. RNA-Seq of MYO5b-bound ribonucleoprotein particles (RNPs) revealed mRNAs coding for sarcomere structure and function, ion channel subunits and metabolic proteins. Conclusion: Myosin-5b is involved in the transport of mRNA/ribosome complexes important for sarcomere function, metabolism, Ca 2+ homeostasis and ion channels. Genetic variants or pathophysiological conditions impairing cardiac MYO5b-related transport are associated with an increased risk for cardiomyocyte dysfunction, HF and sudden death.
Abstract 4145572: <i>LMNA</i> p.Q353R Mutation Causes Dilated Cardiomyopathy through Impaired Vitamin D Signaling
Authors: Masamichi Ito, Manami Katoh, Seitaro Nomura, Issei Komuro
Journal: Circulation (2024)

Introduction: Dilated cardiomyopathy (DCM) is one of the causative diseases of heart failure, caused by genetic mutations. Cases with mutations in the LMNA gene, which encodes lamin A/C protein and constitutes the nuclear lamina, are known to have a poor prognosis. We have previously shown that the DNA damage accumulation and the consequent activation of DDR in cardiomyocytes are the cause of cardiac function impairment. However, the method to reduce DNA damage in the heart has not been elucidated. Therefore, we decided to explore the compounds that could reduce it in the cardiomyocytes. Methods and Results: We generated iPS cells from DCM patients with a LMNA mutation (p.Q353R) and differentiated them into cardiomyocytes. The mutant cardiomyocytes showed severe deformation of nuclear morphology as well as reduced contractility. In addition, the number of positive foci for γH2AX, a DNA double-strand break marker, was increased in the nuclei of the mutant strain. These results indicate that in vitro disease modeling using iPS cell-derived cardiomyocytes was successfully achieved. We administered a library of 175 compounds to the mutant cardiomyocytes to search for compounds that reduce the positive foci of γH2AX. We found that vitamin D2 (VD2) significantly reduced DNA damage in the mutant strains. RNA-seq analysis revealed that VD2 restored the expression of DNA repair enzymes that were downregulated in the mutant strains. We then screened binding molecules of the mutant LMNA p.Q353R protein and wild-type LMNA protein using a protein array. The screening results showed that the binding to the vitamin D receptor (VDR) was significantly enhanced in the mutant protein compared to the wild-type protein. In the mutant cardiomyocytes, VDR was localized to the periphery of the nuclear membrane, and reporter assays showed decreased transcriptional activity of VDR. Finally, we examined the effects of VD2 on DNA damage accumulation and cardiac function in vivo. VD2 analog reduced DNA damage accumulation and improved cardiac function in two mouse models: a pressure-loaded heart failure model and a Lmna nonsense mutant cardiomyopathy model. Conclusion: Using patient-derived iPS cells, we could recapitulate various pathological processes in diseased cardiomyocytes, as well as identify therapeutic candidates through compound screening. One of the existing drugs, VD2, was a hit in this screening, and clinical trials for drug repositioning are expected.
One‐strength dose escalation of house dust mite depot product for subcutaneous immunotherapy is safe and tolerable
Authors: M. Jutel, C. Vogelberg, K. Duwensee, D. Troyke, L. Klimek
Journal: Allergy (2024)

Abstract Background Allergen immunotherapy (AIT) aims at modulating the immune response by administration of allergen preparations at regular intervals over several years (1). For subcutaneous AIT (SCIT), the treatment is initiated with a dose escalation phase followed by a maintenance dose administration. Over the last decade, there has been a trend towards shortening dose escalation regimens to increase patient adherence. This open‐label, phase II trial aimed to investigate the safety and tolerability of a house dust mites (HDMs) SCIT product when used in a newly designed one‐strength dose escalation scheme. Method Patients, aged 12–65, suffering from HDM‐allergic rhinitis/rhinoconjunctivitis ± asthma were included. Patients were randomized to the one‐strength (6 injections from the highest strength 3) or the Standard dose escalation regimen (14 injections from strengths 1 to 3) using the HDMs‐SCIT product. All adverse events were reported. Tolerability was assessed on the Likert scale. Results One hundred and forty‐three patients were randomized, 79 adults and 64 adolescents. In total, the one‐strength regimen caused more adverse drug reactions (ADRs) than the Standard regimen ( p = .0457). With both regimens most ADRs were local reactions which occurred more often in the one‐strength group ( p = .0393). But there was no significant difference in the number of patients affected by systemic or serious ADRs between both regimens. No relevant differences occurred between the two age groups and no other risks were observed for adolescents compared to adults. Conclusion The safety and tolerability of both regimens can be considered comparable, as most ADRs were local reactions, primarily rated as mild in intensity. Nevertheless, the one‐strength regimen caused more ADRs. Reducing the number of injections from 14 to 6 while using only one strength offers the potential to improve patient adherence which further might increase clinical efficacy. Future trials could confirm this hypothesis.
Abstract 4145483: Comparison of Micro Embolic Signals During Carotid Procedures in Patients With Diabetes Mellitus and Patients Without Diabetes Mellitus
Authors: Karlo Wiley, Allison Anker, Ana Martinez Torres, Guliz Kozdag Gold, Alejandro Vivoni, Cristina Sanina
Journal: Circulation (2024)

Introduction: The rate and significance of micro embolic events during carotid endarterectomy (CEA) and carotid artery stenting (CAS) remains unclear. We evaluated pre-procedural, intra-procedural, and post-procedural micro embolic signal (MES) rates in patients treated electively with CEA and transfemoral CAS with distal filter protection monitoring MES continuously with transcranial Doppler (TCD). The aims of the study were to determine if patients with diabetes mellitus (DM) had more MES than patients without DM during the procedures and if there were significant effects of the revascularizations on cognitive functions in the short term. Methods: Fifty-six patients (mean age 71±9 years; 35 male, 21 female) with significant carotid stenosis underwent successful TCD monitoring during the elective revascularization procedures [34 (61%) CEAs and 22 (39%) CASs]. 22 (39%) had DM when they were enrolled into the study. Ipsilateral MES were segregated into a total of 9 phases of pre-procedure, intra-procedure and post-procedure and the data were analyzed with IBM SPSS software. Cognitive functions were assessed with Mini Mental State Examination 2nd Edition questionnaire. The cognitive tests were administered within 1 day before and after the treatment. Results: There were no statistically significant differences in the MES rates in any stage of the procedures between the patients with DM and the patients without DM. There were also no differences in the Mini-Mental State Examination scores before and after the procedures between patients with DM and patients without DM. Conclusion: TCD recordings did not demonstrate any significant differences of MES rates during all phases of the carotid procedures between patients with DM and patients without DM. Interestingly, no difference was also found in cognitive function in pre and post procedure periods in both groups.
Abstract 4145460: Takotsubo syndrome and sports: a systematic review
Authors: Pengyang Li, Xiaojia Lu, Chenlin Li, Catherine Teng, Ao Shi, Bin Wang
Journal: Circulation (2024)

Takotsubo syndrome (TTS) is a rare cardiovascular condition characterized by reversible ventricular dysfunction and a presentation resembling that of acute myocardial infarction. An increasing number of studies has shown physical stress as a trigger for TTS. Here, we comprehensively reviewed the literature and examined the available evidence for TTS patients triggered by sports. After searching PubMed, Embase, Web of Science and Scopus databases, two investigators independently reviewed 837 studies published through July 24, 2023. Of these studies, 21 met the inclusion criteria (n = 23 patients), including 9 patients with exercise stress test, 14 patients with daily physical activity. In Sports-trigger TTS patients, the most common TTS symptom was dyspnea (69.57%), followed by chest pain (52.17%) and diaphoresis (13.04%). The most common type of TTS was apical, accounting for 69.57% of cases, followed by the midventricular (21.74%) and basal (8.70%) types. The overall mortality rate for Sports-trigger TTS patients was 0.00%. Exercise stress test (39.13%), swimming (21.74%) and diving (21.74%) are the most frequently identified physical activity triggers of TTS. Sports is a potential etiology of TTS patients, rare but it is associated with excellent prognosis. Furthermore, the diagnosis of TTS must be considered in patients with typical symptom after sports. Future prospective studies are needed to establish appropriate guidelines for avoiding TTS during sports and the appropriate exercise prescription for Sports-trigger TTS patients to recovery.
Abstract 4145509: Invasive Versus Conservative Management Strategy in NSTE-MI in ≥70-Year-Old Patients: A Meta-Analysis.
Authors: Akshat Banga, Fahimeh Talaei, Parth Munjal, Yash Vardhan Trivedi, Sawai Singh Rathore, Jaiprakash Gurav, Biki Sah, Hans Mautong, Vikas Bansal
Journal: Circulation (2024)

Background: Ambiguity surrounds invasive management of non-ST-segment elevation myocardial infarction (NSTE-MI) in older adults (≥70 years), and the number of elderly patients undergoing invasive treatment in clinical practice remains relatively low. Data comparing the efficacy of invasive versus conservative medical management for NSTEMI in this population is conflicting due to the under-representation or exclusion of the older population from randomized controlled trials (RCTs). Methods: We performed a meta-analysis of RCTs to evaluate the long-term outcomes of invasive versus conservative medical strategies in older patients with NSTEMI. Random effects meta-analysis was conducted to estimate the odds ratio (OR) with 95% CI for the individual endpoints of all-cause mortality, cardiovascular (CV) mortality, recurrent myocardial infarction (MI), unplanned revascularization, and readmission for cardiovascular causes. Results: A total of nine RCTs with 4,336 patients (Invasive: 2,368; Control: 1,968) with median follow-ups ranging from 6-63.6 months were included. Compared with a conservative strategy, an invasive strategy was associated with a significantly decreased risk of recurrent MI (OR 0.62, 95% CI 0.47-0.81; p&lt;0.001) (Figure 1) and unplanned revascularization (OR 0.38, 95% CI 0.25-0.56; p&lt;0.001). There was no difference in all-cause mortality (OR 0.81, 95% CI 0.39-1.35; p=0.42) (Figure 2), CV mortality (OR 0.72, 95% CI 0.43-1.23; p=0.23), or readmission for cardiovascular causes (OR 1.21, 95% CI 0.63-2.33; p=0.57) between invasive and conservative management strategies. Conclusion: In older patients ≥70 years old with NSTE-MI, an invasive strategy reduced the risk of recurrent MI and revascularization when compared with conservative management. However invasive strategy did not offer any benefit in mortality or cardiac-cause related readmission over conservative management.
Abstract 4145471: Global And Regional Burden Of Alcoholic Cardiomyopathy From 1980 To 2021: An Analysis Of Global Burden Of Disease (GBD) Study 2021
Authors: Wania Rehman, Muhammad Talha Shaukat, Aqeeb Ur Rehman, Aleenah Mohsin, Saad Ur Rahman, Jinnette Abbott, Navin Nanda
Journal: Circulation (2024)

Background: Alcoholic cardiomyopathy (ACM) is induced by chronic alcohol consumption and is a predominant cause of non ischemic dilated cardiomyopathy. Here we evaluate the trends of ACM from 1980 to 2021, while focusing on locoregional variations which will help identify the areas with the highest disease burden and guide future investigation into underlying causes. Methods: Data extraction from the Global Burden of Diseases (GBD) study encompassed age-standardized death rates (ASDR), Years of Lost Life (YLL), and disability-adjusted life years (DALYs). The dataset was globally stratified by continent and by World Bank income classification. Joinpoint Regression was employed to determine average annual percentage changes (AAPC). Results: Globally, the prevalence of alcoholic cardiomyopathy decreased from 1990 to 2021, with an AAPC of -0.80 (95% CI -0.82 to -0.78). However, the ASDR had a fluctuating trend from 1980 to 2021. Intermittent spikes in ASDRs could be observed, with the most prominent ones seen from 1991 to 1994 (Annual Percentage Change =9.71; 95% CI 6.1-11.3) and 2002 to 2005 (Annual Percentage Change =12.54; 95% CI 9.2-14.4). Overall, however, the global ASDR decreased from 1980 (ASDR=1.3) to 2021 (ASDR=0.7) with an AAPC of -1.48 (95% CI - 1.5 to -1.3). Similarly, disability-adjusted life years (DALYs) and age-standardized Years of Lost Life (YLL) also declined over this period [(AAPC=-1.03; 95% CI -1.25 to -0.82) and AAPC= -1.14 (95% CI -1.26 to -1.03) respectively]. In continent-wise analysis, North America and Europe had higher ASDRs, while Asia and Africa had lower ASDRs throughout the analysis. It was observed that irrespective of ASDRs, all continents independently had a decreasing trend in alcoholic cardiomyopathy mortality. According to world bank income levels, low- and lower- middle-income countries had higher death rates than high- and upper-middle income countries. Conclusions: Global trends in alcoholic cardiomyopathy (ACM) from 1980 to 2021 reveal fluctuating mortality rates, with substantial intermittent surges. Despite declining DALYs and prevalence, low-income and lower-middle-income nations have persistently high death rates which underscores the need for targeted interventions to address this concerning disparity.
Abstract 4145503: The Trifecta of Female Gender, LVAD and Sensitization: A Case for Higher Priority Listing for Heart Transplant
Authors: Gaurang Vaidya, Richard-Tien Ha, Sumanth Kidambi, Erna Nishime, Hemal Parekh, David Scoville, Brandon Varr, Sirtaz Adatya
Journal: Circulation (2024)

Background: Highly sensitized recipients are expected to have higher wait-time for heart transplant, however, their sensitization status does not grant them higher priority. Methods: UNOS database was analyzed for adult heart transplant recipients from Oct 2018 to April 2024 with reported calculated panel reactive antibodies (cPRA). Retransplant and multiorgan transplant recipients were excluded. Results: Total 10801 recipients were identified. High cPRA (≥70% cPRA) group constituted only 5% of the listed patients. However, 13% of listed female recipients fell in this category (compared to &lt;2% males, p &lt;0.01). Higher cPRA recipients were more likely to have a durable LVAD (27% vs. 19%, p= 0.01). There was no difference in blood group O (p= 0.5), BMI (p=0.9) and dilated cardiomyopathy etiology (35% in both groups). High cPRA recipients were younger (51 vs. 53 years, p= 0.01). High cPRA group had significantly longer wait time (115 vs. 98 days, p= 0.04). Rejection episodes requiring treatment in the first year were similar (11% in both). One-year survival was comparable (figure). In median follow-up period of 720 days, hospitalization for rejection (3% vs. 4%, p= 0.3), for infection (11% vs. 10%, p= 0.3) and coronary artery vasculopathy rates were similar (4% vs. 6%, p= 0.4). Conclusion: High cPRA patients tend to be females, resulting in a gender disadvantage. Additionally, LVAD can be a source of ongoing but temporary sensitization, which could improve with its removal during transplant surgery. But due to their high cPRA, these LVAD patients will wait longer than non-sensitized LVAD patients, due to a significantly smaller donor pool. A case is made to consider adding higher priority status for high cPRA patients to balance the disadvantage in donor pool, without any effect on post-transplant mortality.
Abstract 4145408: The Unexpected Heart Stopper: A Case of Ketamine-Induced Stress Cardiomyopathy Requiring Mechanical Circulatory Support
Authors: Syed Hyder, Akhilesh Gonuguntla, Vibhu Parcha, Samuel McElwee
Journal: Circulation (2024)

Background: Stress cardiomyopathy (SCM) is rarely triggered by ketamine and seldom leads to cardiogenic shock. Ketamine-induced catecholaminergic surge can lead to myocardial stunning with transient ischemia and subsequent reversible heart failure. Mechanical circulatory support can be successfully leveraged in SCM-associated cardiogenic shock while awaiting myocardial recovery. Case Presentation: A 28-year-old female with chronic pain was admitted for failure to thrive secondary to opioid-induced gastroparesis. The patient was weaned off opiates while on ketamine over 4 days. After halting ketamine, the patient had a cardiac arrest with eventual return of spontaneous circulation. After being extubated, she developed chest pain, hypotension, and ventricular tachycardia with anterolateral ST elevations, troponin leak, and lactic acidosis. TTE revealed an EF &lt;20% with severe mid-distal LV dysfunction with preserved basal segments, concerning for SCM. Cardiac catheterization revealed clear coronaries but elevated filling pressures and reduced cardiac index, requiring mechanical circulatory support by IABP and, eventually, VA-ECMO. By 1-week post-arrest, IABP was removed and the patient was decannulated off VA-ECMO. TTE at 1-week post-arrest showed an EF of 45-50% with moderate global hypokinesis. MRI at 1-month post-arrest revealed a normal heart with no abnormal myocardial edema, fatty infiltration, perfusion abnormalities, or scarring. TTE at 1-month post-arrest revealed an EF of 55-60% without wall motion abnormalities. Subcutaneous ICD did not reveal any events on follow-up. Conclusion: With the rise of ketamine use in pain management, the recognition of rare cardiac complications like SCM should be an important consideration even in patients without underlying cardiac risk factors. Early recognition of shock and initiation of mechanical circulatory support may lead to more favorable outcomes. Increased awareness and prompt intervention can significantly impact a patient’s recovery and prognosis in ketamine-induced SCM.