tbuckley/cabot-search huggingface dataset:
Abstract 12089: Dual Actions of β <sub>2</sub> AR-Agonism Confer Protection Against Heart Failure and Renal Dysfunction via Inotropic and Lusitropic Effects and Normalized Cholesterol Homeostasis in a Mouse Model of Alport Syndrome
Authors: AHMED CHAHDI, Keyvan Yousefi, Jose Manuel Condor Capcha, Camila Irion, Guerline Lambert, Serene A Shehadeh, Julian Dunkley, Yee-Shuan Lee, Aisha Khan, Melina Ramic, Nadja Andrade, Zane Zeier, Derek Dykxhoorn, Chryso Katsoufis, michael freundlich, Joshua M Hare, Mary Nabity, Carolina Rivera, Anastasios Lymperopoulos, Keith A Webster, Noam Zelcer, Lina A Shehadeh
Journal: Circulation (2021)

Introduction: Col4a3-/- Alport mice present a model of heart failure with preserved ejection fraction (HFpEF) secondary to chronic kidney disease(CKD) wherein etiological relationships have been established between hypertension, pulmonary edema, inflammation, cardiac hypertrophy and fibrosis, diastolic dysfunction and underlying abnormalities of elevated low-density lipoprotein receptor (LDLR) expression, excess LDL-cholesterol(LDL-C) accumulation, and mitochondrial dysfunction in renal tubules. Hypothesis: We tested the hypothesis that selective β2-Adrenoceptor (β2AR) modulation with salbutamol, a short-acting β2AR agonist, could alleviate symptoms of CKD and simultaneously augment cardiac function. Methods: Alport mice were injected i.p.with salbutamol or DMSO vehicle as a single bolus of 200μg/dose in short-term studies or daily with 100 μg/dose for 2 wks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection. N=3-8 for all experiments. Results: Short-term, salbutamol improved renal function in parallel with decreased LDLR levels and reduced uptake of LDL-C into renal tubules. Long-term, cardiac diastolic function assessed by isovolumetric relaxation time, filling pressures, and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP (p&lt;.05). Mechanistically, in the kidney, salbutamol activated IDOL and hence lysosomal ubiquitination and degradation of LDLR via a novel β2AR-mediated, cAMP-independent pathway involving the Rac1/Cdc42 β1PixGEF. β1Pix reversibly sequesters IDOL into a complex with LDLR, thereby blocking the degradation pathway. β2AR stimulation dissipates the complex reactivating IDOL-mediated LDLR degradation thereby re-establishing LDL-C homeostasis and renal function. Using flow cytometry in 293T cells, ectopic expression of bPix stabilized membrane LDLR, sensitive to IDOL- but not PCSK-mediated degradation. Conclusions: β2AR agonism represents a potential treatment strategy to alleviate progression of CKD and HF associated with HFpEF phenogroup 3.
Dissecting the Mechanisms of Hepcidin and BMP-SMAD Pathway Regulation By FKBP12
Authors: Alessia Pagani, Mariateresa Pettinato, Alessandro Dulja, Silvia Colucci, Mariam Aghajan, Valeria Furiosi, Martina U. Muckenthaler, Shuling Guo, Antonella Nai, Laura Silvestri
Journal: Blood (2021)
Abstract 9837: A Blunted Nocturnal Blood Pressure Decline is Associated with Total and Cardiovascular Mortality
Authors: Alejandro De La Sierra, Bryan Williams, Manuel Gorostidi, Ernest Vinyoles, Julian Segura, Luis M Ruilope
Journal: Circulation (2021)

Introduction: A blunted nocturnal BP decline is associated with an increased cardiovascular risk. Nevertheless, patients with a blunted BP dip usually have high levels of nighttime BP, being both parameters clearly related. Thus, it is unclear if an abnormal dipping is deleterious per se or it merely reflects an elevated BP during sleep. Hypothesis: We aimed to assess the prognostic value of nocturnal BP decline, independently of the presence or not of nocturnal BP elevation. Methods: Vital status and death due to cardiovascular causes were obtained from death certificates in 59110 hypertensives, enrolled in the Spanish ABPM Registry between 2004 and 2014, and having a valid 24-h ABPM at entry. On the basis of BP data, patients were classified into 4 groups: Normal (&lt;120 mmHg) night systolic BP (SBP) and normal (&lt;0.9) systolic night-to-day ratio (NDR). Normal night SBP with elevated (≥0.9) NDR. Elevated (≥120 mmHg) night SBP with normal NDR and both elevated night SBP and NDR. Association between NDR, dipping status and groups combining night SBP and NDR with total and cardiovascular mortality were assessed by Cox models, adjusted for clinical confounders. Results: The total number of deaths were 2866 (978 of cardiovascular causes) during a median follow-up of 5 years. NDR predicted total mortality (HR for 1 SD change: 1.19; 95%CI: 1.15-1.23). Both patients with reduced dipping (HR: 1.28; 1.17-1.41) and risers (HR: 1.59; 1.42-1.77) had increased risk of total mortality, whereas extreme dippers (NDR&lt;0.8) did not. With respect to patients with both normal night SBP and NDR, those with elevated NDR in the absence of elevated night SBP had increased risk of death (HR: 1.36; 1.19-1.55), as well as those with elevated night SBP and normal NDR (HR; 1.40; 1.21-1.62). Those combining both abnormalities had the highest risk (HR: 1.78; 1.60-1.98). Similar results were obtained for cardiovascular mortality. Conclusions: Abnormalities in the circadian dipping pattern are responsible for an increased risk of mortality, both total and cardiovascular. Increased mortality rates are observed in patients with a reduced nocturnal dip and, even more intensively, in those with a riser pattern. This abnormal dipping increases the risk of mortality even in the absence of BP elevation.
Abstract 11616: Seizures in Infants with Congenital Heart Disease
Authors: Safwat Aly, Hany Aly, Mohamed A Mohamed
Journal: Circulation (2021)

Background: Infants with congenital heart disease (CHD) may have an increased risk to develop seizures during hospitalization. Objectives: to examine the association of CHD with non-epileptic, non-traumatic seizures in hospitalized infants up to one year of age. Methods: We conducted a retrospective analysis of the U.S. National Inpatient Sample dataset (2015-2018). We used the international classification of disease-10 th version to identify infants with different types of CHD. We included infants up to one year of age. We excluded infants &lt;35 week gestational age, infants with central nervous system or with major congenital anomalies, common trisomy or genetic disorders. We used chi square testing to examine the association of subtypes of CHD with seizures excluding post traumatic and epileptic seizures. We calculated mortality in infants with CHD who developed seizures versus those who did not have seizures. Results: There was 12,023,781 infants in the weighted sample who met our inclusion criteria. Of them, 48.7% were females, 46.7% were Caucasians, 195,685 (1.63%) were identified with a CHD and 20,565 (0.17%) suffered at least one episode of seizure during hospitalization. Seizures occurred in 4225 (2.2%) of infants with any type of CHD compared to 16,340 (0.14%) in infants with no CHD, odds ratios for seizures is 15.6 (CI: 15.2-16.5, p &lt;0.001). The association of seizures with subtypes of CHD is shown in table-1. Among infants with CHD, 2205 infants expired during hospitalization. Mortality was higher in infants with CHD who suffered seizures (8.5%) vs. those who did not have seizures (1.0%), OR 9.6 (8.5-10.8, p &lt;0.001). Conclusion: Infants with CHD have a higher chance to experience seizure episodes during their hospitalization and those who have seizures have higher chances of mortality during hospitalization. Further analysis is required to understand the pathological correlation between seizures and CHD and its impact on long term developmental outcomes.
Association Between the <i>ACE</i> Insertion/Deletion Polymorphism and Risk of Lower-Limb Amputation in Patients With Long-Standing Type 1 Diabetes
Authors: Kamel Mohammedi, Yawa Abouleka, Charlyne Carpentier, Louis Potier, Severine Dubois, Ninon Foussard, Vincent Rigalleau, Jean-François Gautier, Pierre Gourdy, Guillaume Charpentier, Ronan Roussel, André Scheen, Bernard Bauduceau, Samy Hadjadj, François Alhenc-Gelas, Michel Marre, Gilberto Velho
Journal: Diabetes Care (2021)

OBJECTIVE The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes. RESEARCH DESIGN AND METHODS ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below-the-ankle amputation consisting of at least one ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic, and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] vs. II) and plasma ACE, after adjusting for confounders. RESULTS Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03–4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 1.16–13.67]). This association was driven by excess risk of minor, but not major, LLA. The D allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33–4.65]). LLA was associated with higher mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers. CONCLUSIONS This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes.
Abstract 13471: HFpEF in Spontaneously Obese Mice Due to Genomic Rearrangement in Non-Coding Region of Chromosome 1
Authors: Donnell White, Jian Wu, Rong Bao, Lothar Lauterboeck, Bob A Kesterson, Qinglin Yang
Journal: Circulation (2021)

Background: Obesity is the most common comorbidity and risk factor for heart failure (HF) in patients with preserved ejection fraction (HFpEF), a subclass containing more than 50% of HF cases. However, effective treatment of HFpEF remains scarce due to the incomplete understanding of the mechanisms. Methods: A mouse line (C57/B6J) of Floxed-stop Overexpression of IF1 (FEI) was generated and maintained for Cre-mediated conditional IF1 overexpression. We observed that severe obesity became a fixed phenotype in inbred FEI mice after inbreeding for 5-6 generations. Targeted-Locus-Amplification (TLA) analyses revealed that FEI inbreeding triggered a genomic rearrangement in a non-coding region of chromosome 1. A heterozygous line with genotype and phenotype fixation was obtained via outbreeding with wild type mice. In the present study, we focus on assessing the cardiac phenotype of FEI mice using echocardiography, histology, and exercise tolerance tests. Results: The early onset of obesity was consistent in the heterozygotes of obese FEI mice with increased peripheral fats and circulating tissue lipids, as well as reduced systemic metabolic rates. FEI mice also exhibited increased food intake, fasting blood glucose, insulin, and leptin with impaired glucose/insulin tolerance. Echocardiography revealed that the FEI mice developed concentric left ventricular hypertrophy with preserved ejection fraction. However, E/A ratio results from Doppler flow measurement at mitral valve suggest diastolic dysfunction in the FEI mice. Heart weight to tibial length ratio was significantly increased in FEI compared with WT mice. H&amp;E and Trichrome blue staining on heart sections exhibited increased cardiomyocyte hypertrophy and cardiac fibrosis. Treadmill exercise tolerance test revealed a significantly decreased exercise tolerance in FEI mice. Conclusions: We conclude that the cardiac phenotypes in the obese FEI mice closely recapitulate obese patients who suffer from HFpEF. Thus, further studies on these mice should yield novel and translational insight into the molecular and metabolic mechanisms underlying the HFpEF development, leading to improved treatments.
Abstract 11788: Tolvaptan Add-On Therapy on Efficacy Parameters and Outcomes in Patients Hospitalized With Acute Heart Failure
Authors: Tikal Kansara, Haresh Gandhi, Ashish Kumar, Monil Majmundar, Samarthkumar J Thakkar, Harsh P Patel, Savi Mushiyev, Aravind Kokkirala, Craig Basman
Journal: Circulation (2021)

Introduction: Even with the adequate use of diuretics and vasodilators, volume overload and congestion are the major causes of morbidity and mortality in patients hospitalized with acute heart failure (HF). Hypothesis: We aim to evaluate the additive effect of tolvaptan on efficacy parameters as well as outcomes in hospitalized patients with HF. Methods: We searched PubMed, EMBASE, Cochrane library, and Web of Science databases for randomized controlled trials that studied the effects of tolvaptan versus placebo in hospitalized patients with HF. Studies were included if they had any of the following endpoints: mortality, re-hospitalization, and in-hospital parameters like dyspnea relief, change in weight, sodium, and creatinine. Results: The meta-analysis analyzed data from 14 studies involving 5945 patients. The follow up duration ranged from 30 days to 2 years. Between tolvaptan and placebo groups, there was no difference in mortality [relative risk (RR) 0.73 (0.46, 1.18) p =0.2] and rehospitalization [RR 0.79 (0.51, 1.22) p = 0.28]. HF patients had a better dyspnea relief score (Likert score) in tolvaptan group [RR 1.19 (1.06, 1.33) p = 0.003] and mean reduction in weight in the first 48 hours (short-term) [mean difference (MD) -2.19 (-.35, -0.86) p = 0.001]. However, at 7 days (medium-term) the mean difference in weight was not significant [MD -0.67 (-1.45, 0.11) p = 0.09]. Serum sodium increased significantly in tolvaptan group [MD 3.75 (2.92, 4.58) p &lt; 0.00001]. There was no difference in creatinine [MD 0.00 (-0.08, 0.08) p = 0.98] among the two groups. (Figure 1) Conclusions: Our meta-analysis shows that during hospitalization of HF patients, tolvaptan can be useful in short-term symptomatic dyspnea relief and initial reduction in weight due to its additive diuretic effect. However, this benefit is short-lived and there is no advantage in reducing rehospitalization rates and mortality. Further, tolvaptan is not effective for sustained and long term weight loss.
PATH-46. DIAGNOSTIC IMPACT OF THE CNS TUMOR METHYLATION PROFILING IN A NEUROPATHOLOGY CONSULT PRACTICE
Authors: Zhichao Wu, Zied Abdullaev, Drew Pratt, Hye-Jung Chung, Shannon Skarshaug, Valerie Zgonc, Candice Perry, Svetlana Pack, Lola Saidkhodjaeva, Sushma Nagaraj, Manoj Tyagi, Liqiang Xi, Mark Raffeld, Antonios Papanicolau-Sengos, Kayla O’Donnell, Joseph Chinquee, Michael Newford, Mark Gilbert, Felix Sahm, Abigail K Suwala, Andreas von Deimling, Farshad Nassiri, Gelareh Zadeh, Eytan Ruppin, Martha Quezado, Kenneth Aldape
Journal: Neuro-Oncology (2021)

Abstract DNA methylation profiling coupled with the application of CNS tumor methylation classifier has contributed to precise and accurate diagnostics for a range of tumor types involving the central nervous system. The impact and characteristics of methylation profiling on tumor diagnosis has not been fully assessed in the setting of neuropathology consultation practice. A consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice were profiled over 2-year period and analyzed using the DKFZ/Heidelberg CNS tumor methylation classifier. Among the 1,045 cases received from outside institutions for consultation, the classifier was able to refine a histologically diagnosed entity (e.g. medulloblastoma) in 13.3% (n = 139) cases. A substantially new diagnosis was able to be rendered in an additional 17.9% (n = 187) cases, many of which could be confirmed using orthogonal methods. A “suggestive” (0.30-0.84) classifier score was found in 23% (242) cases and we found that complementary methods (UMAP, t-SNE and nearest-neighbors) were able to resolve this uncertainty in 118 cases. We found tumor purity significantly associated with varied classifier score (p = 1.53e-11). Computational tumor purity adjustment by deconvolution on a subset of gliomas provided a proof-of-concept to resolve diagnostics in the setting of low tumor purity. Overall, this work directly assesses the benefit of methylation classification in a set of diagnostically challenging CNS tumors, addresses tumor purity diminished methylation signal and provides complementary approaches to address diagnostics in cases of low-confidence classifier scores.
Abstract 9862: Correlation of Lipoprotein(a) and Plaque Morphology in Very Young Acute Coronary Syndrome Patients Using Optical Coherence Tomography
Authors: prachi sharma, Saurabh Nagar, Sharad Chandra, Gaurav K Chaudhary, Vikash Jaiswal, Akhil Kumar Sharma, Monika Bhandari, Pravesh Vishwakarma, Akshyaya Pradhan, rishi sethi, Sudhanshu Dwivedi
Journal: Circulation (2021)

Background: Levels of lipoprotein (Lp) (a) are a useful marker for risk stratification of cardiovascular diseases. This genetic biomarker is suggestive of patient predisposition to an acute coronary event. Its correlation with the plaque morphology is yet to be explored with optical coherence tomography (OCT). Aim: To study the correlation of Lp(a) levels and plaque morphology in very young (&lt;35 years) patients presenting with acute coronary syndrome(ACS). Methods: A prospective, single-centre, observational study was conducted at a tertiary-care centre. Very young patients with acute coronary syndrome and fit for OCT guided invasive coronary angiography were included. Lp(a) levels were compared between healthy controls and these very young ACS patients. Correlation of Lp(a) levels and plaque characteristics in very young ACS patients was done using OCT imaging. Results: A total of 80 subjects were enrolled in the study. Out of these 40 were very young ACS and 40 were age matched healthy controls. Mean levels of Lp(a) were 28.10±13.96 nmol/l and 61.20±55.88 nmol/l in healthy controls and very young patients with ACS respectively (p=0.022). In very young patients, plaque rupture and erosion were the mechanism of acute coronary syndrome in 67.5% and 32.5% patients, respectively. Among very young ACS patients, those with Lp(a) levels &lt;75 nmol/l had a mean thin cap fibroatheroma thickness of 96.89±65.52 μm and those with Lp(a) levels ≥75 nmol/l had a mean thin cap fibroatheroma thickness of 67.85±53.80 μm (p=0.158). Conclusion: It was revealed that patients with higher Lp(a) levels had lesser thickness of fibrous cap on OCT imaging compared with lower levels of Lp(a). Lp(a) levels were independently associated with ACS in very young (&lt;35 years) patients, with plaque rupture being the commonest mechanism. Hence, we conclude that higher Lp(a) levels predispose to ACS at a very young age associated with lowering of fibrous cap thickness.
Characterization of Indolent Chronic Myelomonocytic Leukemia Phenotypes and Identification of Dynamic Disease Features of Progression and Need for Treatment
Authors: Luis E. Aguirre, Somedeb Ball, Akriti G Jain, Najla Al Ali, David A. Sallman, Andrew T. Kuykendall, Kendra Sweet, Jeffrey E. Lancet, Eric Padron, Rami S. Komrokji
Journal: Blood (2021)
Abstract P505: Rv Sarcomeres From Lv-hfref Patients With Low Papi Have Abnormal Rv Thick Filament Structure
Authors: Vivek Jani, Mohammed I Aslam, Weikang Ma, Henry Gong, Anthony Cammarato, Thomas Irving, David A Kass, Steven Hsu
Journal: Circulation Research (2021)

Patients with left heart failure and reduced ejection fraction (HFrEF) have variable RV failure that, if present, drastically worsens outcomes. In a cohort of 21 HFrEF patients from two hospital sites, we have previously shown (Aslam et al, Eur J HF; 2020: volume 23, pages 339-341) that like global function, RV myocyte maximum calcium-activated myocyte tension (T max ) is quite variable (COV 27%). To determine if a relationship between RV myocyte function and indices of RV chamber function exists, we trained a random forest classifier based on 41 clinical variables, including hemodynamic, laboratory, and echocardiographic data, and queried the importance of each. This revealed that the most predictive model for reduced T max was based on the pulmonary artery pulsatility index (PAPi), an established clinical index of RV failure. To gain insight into potential mechanisms for depressed T max in HFrEF patients with a low PAPi, we obtained small angle x-ray diffraction patterns in 5 HFrEF patients with depressed PAPi and T max and compared this to 5 non-failing (NF) controls. The equatorial intensity ratio I(1,1)/I(1,0) was reduced in low T max RV muscle fibers vs. controls (0.250.06 vs. 0.180.02, P&lt;0.0001), suggesting myosin heads are more associated with the thick filament backbone. In meridional reflections, we find a significant decrease in M3 band spacing (14.340.03 nm in NF vs. 14.300.01 nm in HFrEF; P=0.0013) suggesting more myosin heads are in the “OFF” configuration. The latter may underly tension reduction in RV myocytes from failing RV HFrEF patients. Ongoing studies will examine these structural changes in HFrEF patients with a broader range of PAPi and T max to test if this association applies. These findings focus attention on thick filament structural and configuration abnormalities as potential culprits underlying RV disease in HFrEF. Further studies using novel sarcomere enhancers will test if these changes can be remedied, and if so, in which patients.
Daily low-dose prednisolone during upper respiratory tract infection in children with relapsing steroid sensitive nephrotic syndrome does not prevent associated relapse: the PREDNOS 2 randomized controlled trial
Authors: Martin Christian, Nicholas Ja Webb, Samir Mehta, Rebecca Woolley, Nafsika Afentou, Emma Frew, Elizabeth Brettell, Adam Khan, David Milford, Detlef Bockenhauer, Moin A Saleem, Angela S Hall, Ania Koziell, Heather Maxwell, Shivaram Hegde, Hitesh Prajapati, Rodney D Gilbert, Caroline Jones, Karl McKeever, Wendy Cook, Natalie Rowland
Journal: JAMA Pediatrics (2021)
Humoral Immunity and Adverse Events after Vaccination Against COVID-19 By a Vector Based Vaccine Sputnik V in Patients with Chronic Myeloid Leukemia
Authors: Ekaterina Yu. Chelysheva, Anna Petrova, Oleg A. Shukhov, Margarita Gurianova, Anastasiya Bykova, Irina Nemchenko, Nikolay Tsyba, Dmitry S. Tikhomirov, Anna G. Turkina
Journal: Blood (2021)