tbuckley/cabot-search huggingface dataset:
Abstract 12001: Atrial Fibrillation Induces Ventricular Dysfunction via Altered Ca <sup>2+</sup> Handling and Oxidative CaMKII Activation in the Human Heart
Authors: Steffen Pabel, Maria Knierim, Thea Stehle, Felix Alebrand, Michael Paulus, Marcel Sieme, Melissa Herwig, Thomas Koertl, Brisca Wenner, Senka Ljubojevic-Holzer, Nataliya Dybkova, Simon Sedej, Daniel Scherr, Christoph Brochhausen, Gerd Hasenfuss, Lars S Maier, Nazha Hamdani, Katrin Streckfuss-Bömeke, Samuel Sossalla
Journal: Circulation (2021)

Introduction: The effects of atrial fibrillation (AF) on left ventricular (LV) function are poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to LV dysfunction. This study investigated the effects of AF on the human LV. Methods and Results: LV myocardium from patients with preserved LV function (EF&gt;50%) with sinus rhythm (SR, n=31) or rate-controlled AF (n=24) obtained during surgery for aortic stenosis was studied. Clinical data were mostly balanced without changes in LV function and remodeling. LV myocardium from SR and AF patients showed no changes in fibrosis. In functional studies, systolic Ca 2+ transient amplitude of human LV cardiomyocytes (CM) was reduced in AF patients, while diastolic Ca 2+ levels and Ca 2+ transient kinetics were unaltered. These results were confirmed in LV CM from non-failing donors with AF (n=4) vs. SR (n=8). In addition, normofrequent AF was simulated in vitro using arrhythmic or rhythmic electrical culture pacing (both at 60 bpm). After 24h of AF-simulation, human LV CM from non-failing donors (n=9) showed also an impaired Ca 2+ transient amplitude. For a standardized chronic AF-simulation, human iPSC-CM (n=22 differentiations/5 individuals) were tested. 7 days of AF-simulation caused reduced systolic Ca 2+ transient amplitude and sarcoplasmic reticulum Ca 2+ load, which could be explained by an increased diastolic Ca 2+ leak. Mechanistically, oxidative stress markers were higher in the LV of AF patients. Ca 2+ /calmodulin-dependent protein kinase IIδ (CaMKII) was found to be more oxidized at Met281/282 in the LV of AF patients leading to an increased CaMKII activity. Thus, RyR2 phosphorylation was elevated, which likely underlies the depression of LV Ca 2+ handling in AF. In translational contractility experiments of human ventricular trabecula from patients with heart failure (n=8), in vitro AF-simulation for 8h worsened systolic and diastolic contractile function. Conclusions: Here we could firstly show that AF impairs human LV function via increased oxidative stress and CaMKII activity in different patient populations and models. Thus, this translational study demonstrates the detrimental effects and mechanisms of AF in the absence of tachycardia on the human LV.
Abstract 13097: Diabetes and Obesity Are Causally Associated With Pulmonary Hypertension and Right Ventricular Function
Authors: Minoo Bagheri Naraghi, Vineet Agrawal, Jeffrey S Annis, Jane F Ferguson, Jonathan D Mosley, Evan L Brittain
Journal: Circulation (2021)

Background: Observational studies have shown overlap between pulmonary pressure, right ventricular (RV) function, and metabolic function, but causality has not been established. We used genetic variants associated with metabolic phenotypes to test for causality between metabolic function, pulmonary pressure, and RV function. Methods: We included all European ancestry subjects in Vanderbilt University’s de-identified DNA biobank (BioVU) with an echo reporting pulmonary pressure (RVSP) and RV function (TAPSE). To investigate causal relationships, two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted using genetic variants associated with phenotypes and echo measures. Significant phenotypes by univariate MR were included in multivariable MR models. We also tested echo measures for associations with polygenic risk scores (PRS) for metabolic phenotypes [score threshold: 5x10 -8 ]. Results: We identified 17,221 men and women (mean age: 62yr) with RVSP and 6,209 men and women (mean age: 61yr) with TAPSE. Diabetes genetic risk was associated with higher RVSP (β=0.015, p=0.016) [Figure 1A] and lower TAPSE (β=-0.028, p&lt;0.05) [Figure 1C]. BMI genetic risk was positively associated with RVSP (β=0.06, p=7.18 x 10 -6 ) [Figure 1C] but not TAPSE. In multivariable MR models, genetic risk for diabetes and BMI remained directly associated with RVSP (p&lt;0.05) and only diabetes genetic risk was inversely associated with TAPSE (β=-0.031, p=0.005). PRS for diabetes and BMI were associated with higher RVSP (β=0.01, p=0.001 for diabetes and β=0.01, p=2.04x10 -5 for BMI) but only PRS for diabetes was linked to lower TAPSE (β=-0.015, p=0.057). Conclusions: Genetic determinants of BMI and diabetes are causally associated with pulmonary pressure and RV function in a large, unselected population referred for echocardiography. These may be modifiable risk factors in the treatment and prevention of pulmonary hypertension and RV dysfunction.
DDRE-49. TRANSIENT OPENING OF THE BLOOD-BRAIN BARRIER BY VASOACTIVE PEPTIDES TO INCREASE CNS DRUG DELIVERY: REALITY VERSUS WISHFUL THINKING?
Authors: Matthew Smith-Cohn, Nicholas Burley, Stuart Grossman
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Drug delivery to treat neurologic disease and cancers of the central nervous system (CNS) is severely limited by the blood-brain barrier (BBB). Vasoactive peptides (VAPs) such as regadenoson, adenosine, and labradimil have been shown in animal studies to transiently open the BBB, and regadenoson is currently under investigation in humans to determine if it might improve CNS drug delivery. There is currently limited information regarding the potential for other VAPs to open the BBB transiently. METHODS We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the BBB, we devised a four-tier classification system to organize data available in the literature which factors in alterations in BBB integrity and effects on normal brain vasculature and systemic blood vessels. This data was further sorted based on whether it comes from humans, animals, or in vitro systems. RESULTS We identified 38 VAPs with potential BBB permeability-altering properties. To date, none of these has been shown to open the BBB in humans. Thirteen VAPs increased BBB permeability in rodents. The remaining 25 had favorable physiologic effects on blood vessels but lack specific information on permeability changes to the BBB. We ranked VAPs in a four-tier ranking system related to their known physiologic actions. CONCLUSION Rodent studies document that analogs of bradykinin and adenosine transiently disrupt the BBB leading to higher chemotherapy concentrations in the CNS. VAPs remain an understudied class of drugs with the potential to increase drug delivery to the CNS. Dozens of VAPs have yet to be formally evaluated for this important clinical effect. This retrospective review summarizes the available data on VAPs highlighting agents that deserve further in vitro and in vivo investigations.
Abstract 12870: Transesophageal Echocardiography to Guide Correct Implantation Site of the Leadless Pacemaker
Authors: Bashaer Gheyath, Roshni V Khatiwala, Pankaj Malhotra, Dali Fan
Journal: Circulation (2021)

Introduction: MICRA™ (Medtronic USA) leadless pacemakers are used to avoid complications common to conventional pacemakers, but there is still a 4% risk of complications (e.g., cardiac perforation, tamponade, and embolization). Septal device implantation may decrease risk, but helpful cardiac landmarks (e.g., tricuspid valve, pulmonary valve (PV)) are not seen under fluoroscopy. There is little guidance regarding alternative intra-procedural (IP) imaging. We studied the spatial relationship of the MICRA™ to cardiac landmarks via transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE). Methods: Our prospective observational study included 23 patients undergoing MICRA™ implantation with TEE ( Table 1) . Interventricular septal placement was confirmed by fluoroscopy, electrocardiography (ECG) and TEE. Distances between the device and cardiac landmarks were measured by TTE and TEE and analyzed with ECG parameters during pacing ( Fig 1A, Fig 1B ). Results: Septal positioning of the device was achieved in all patients. TEE transgastric (0-20/90-110°) and lower mid-esophageal (40-60/130-150° with biplane) views best visualized device position. The aortic valve (AV) in the TTE apical 5 chamber view was used as a surrogate for RV apex to PV distance. With appropriate septal deployment, QRS morphology showed earlier R wave transition and 44% increased QRS width ( Table 1 ). Conclusions: TEE can guide appropriate leadless pacemaker septal implantation, and correlates with QRS pacing morphology. Further studies are required to establish reference ranges of distances from the device to cardiac landmarks to prove optimal device deployment.
Methionine supplementation: potential for improving alveolar macrophage function through reverse cholesterol transport?
Authors: Marissa O'Callaghan, Feargal Helly, Elizabeth Tarling, Michael P. Keane, Cormac McCarthy
Journal: European Respiratory Journal (2021)

We read with great interest the article "Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis" by Hadchouel et al [1]. The MARS1 (methionine tRNA synthetase) gene encodes the cytosolic methionine tRNA synthetase (MetRS), which plays a critical role in protein biosynthesis by charging tRNAs with methionine, leading to the formation of methionyl-tRNA. Pulmonary alveolar proteinosis (PAP) associated with a mutation in this gene causes severe disease and carries a high mortality rate. The authors found that methionine supplementation led to an improvement in respiratory status with clearance of extracellular lipoproteinaceous material, and normalisation of reactive oxygen species (ROS) production by peripheral blood monocytes. The authors hypothesised that this shift in ROS production following methionine treatment reflects resolution of macrophage dysfunction caused by the MARS1 mutation [1], and thus clinical improvement. While ROS plays an important and versatile role in macrophage mediated immunity, we believe this may be only one of the functional improvements in alveolar macrophages as a result of methionine therapy. We commend the authors on presenting these interesting findings and propose that methionine may also play a pivotal role in alveolar macrophage lipid catabolism and reverse cholesterol transport, thus affecting global macrophage function. Methionine may directly influence alveolar macrophage function through direct effect on reverse cholesterol transport <https://bit.ly/2ZJlomg>
Abstract 9859: Secondhand Smoke Exposure is Associated with Abnormal P-Wave Axis
Authors: Travis M Skipina, Nikhil Patel, Bharathi Upadhya, Elsayed Z Soliman
Journal: Circulation (2021)

Introduction: Secondhand smoke exposure (SHSE) is associated with increased risk of cerebrovascular accident (CVA). Abnormal p-wave axis (aPWA) is a marker for atrial disease that is also associated with CVA risk. Hypothesis: SHSE is independently associated with aPWA. Methods: This analysis included 5,986 nonsmokers (age 61.7±13.8, 45.8% men, 77.4% whites) from the Third National Health and Nutrition Examination Survey. SHSE was defined as serum cotinine ≥1ng/mL. Serum cotinine cut-points of ≥3ng/mL and ≥6ng/mL were used to assess dose-response. Multivariable logistic regression was used to examine the association between SHSE and aPWA. The consistency of this association was tested among subgroups stratified by demographics and comorbidities. Results: About 18.5% (n=1109) of the participants had SHSE. After adjusting for demographic and comorbid covariates, SHSE was associated with a 28% increased odds of aPWA (p-value=0.003). Serum cotinine cut-points of ≥3ng/mL and ≥6ng/mL were associated with 35% increased odds of aPWA (p-value=0.002) and 38% increased odds of aPWA (p-value=0.002), respectively. This association was stronger among those of white ethnicity [Odds Ratio (95% Confidence Interval): 1.36 (1.12-1.66), interaction p-value=0.04]. Conclusions: SHSE is associated with aPWA with possible effect modification by ethnicity. This is a novel finding that further underscores the harmful effects of SHSE on cardiovascular health and merits a personalized risk assessment when counseling patients on SHSE. Further prohibition of smoking in public areas should be emphasized, especially in regions with less-stringent public health policies.
Abstract 13084: Occurrence of Infective Endocarditis After Transcatheter versus Surgical Pulmonary Valve Implantation: Results of a Nationwide Administrative Database
Authors: Alicia Jeanette J Fischer, Dominic Enders, Helmut Baumgartner, Gerhard P Diller, Gerrit Kaleschke
Journal: Circulation (2021)

Background: It is unclear if the risk of infective endocarditis (IE) differs between transcatheter (TPVI) and surgical (SPVR) pulmonary valve implantation. We sought to address this question using administrative data including a large nationwide patient population. Methods: All congenital heart disease (CHD) patients ≥4 years of age who underwent isolated pulmonary valve implantation were identified in the BARMER Health Insurance Company database (≈9 million members, representative of the German population). Data from 01/2005 to 12/2018 were analyzed with regard to overall survival and complications particularly focusing on IE. Results: Overall, 461 pulmonary valve implantations were performed in 413 patients (59.4% male, median age 18.6 years (IQR 12.8-31.3)). Of those, 38.4% (n=177) underwent TPVI, while 61.6% (n=284) were treated with SPVR. Overall, IE was diagnosed in 8.0% (n=37) of cases after a median of 1.3 years (IQR 0.2-3.7). In the TPVI cohort, IE occurred in 10.2% (n=18) of cases, while IE was diagnosed in 6.7% (n=19) of cases with SPVR ( p =0.217). Furthermore, 5.0% (n=23) of all patients died during follow-up (of those n=4 within 90 days after diagnosis of IE). On multivariable Cox-regression analysis, previous diagnosis of IE was associated with a higher risk of re-IE ( p =0.025), but no association between IE and age ( p =0.17), sex ( p =0.34) or type of CHD was found ( p =0.71). While the overall rate of IE was not dependent on the treatment modality, there were significant time-dependent differences: Within the first year of follow-up, freedom from IE or death was significantly higher in the TPVI cohort (HR 5.26 [95% CI 1.59-16.67], p =0.006) compared to SPVR), but within the 3-10 year period the probability reversed in favor of the SPVR cohort (HR 10.07 [95% CI 3.41-29.76], p &lt;0.001) compared to TPVI). Conclusion: In a cohort of 413 patients undergoing pulmonary valve implantation, infective endocarditis occurred in 8.0% of cases. The overall rate of infective endocarditis was not significantly different between surgical and interventional pulmonary valve procedures. However, while early endocarditis was more often related to surgical procedures, the mid-term IE risk was significantly lower in surgically treated patients.
Abstract 10569: Risk Factors for Adverse Outcome in Prenatally Diagnosed Heterotaxy Syndrome in the Current Era
Authors: Jill J Savla, Jack Rychik, Karl Degenhardt, Christine Falkensammer, Jill Combs, Anita Szwast
Journal: Circulation (2021)

Introduction: Fetuses with heterotaxy syndrome (HS) and congenital heart disease continue to have worse outcomes compared to other lesions. We sought to explore differences between asplenia and polysplenia subtypes and to identify risk factors for poor outcome in the current era. Methods: All cases of fetal HS seen at our center between 1/2005 and 3/2018 were included in this study. Prenatal echocardiographic parameters and clinical outcomes were recorded. Findings were compared between the asplenia and polysplenia subtypes via Chi-square or Fisher’s exact analysis. Univariate logistic regression was utilized to identify prenatal variables predictive of fetal demise. Postnatal survival was examined with Kaplan-Meier curves and univariate Cox proportional hazards models. Results: The cohort consisted of 155 subjects: 86 with asplenia and 69 with polysplenia. There were 36 with biventricular (2V) and 119 with univentricular (1V) physiology. Asplenia subjects were more likely to have 1V physiology, common atrioventricular canal (CAVC), conotruncal anomaly, and pulmonary venous obstruction (all p&lt;0.001). Polysplenia subjects were more likely to have systemic venous anomalies (p&lt;0.001), complete heart block (CHB, p&lt;0.001), ventricular dysfunction (p=.005), and hydrops (p=0.03). There were 105 subjects born alive, 7 fetal demises, 40 terminations, and 3 lost to follow-up prior to birth. Postnatal follow-up data were available for 96/105 (91%) subjects with median follow-up of 5.5 years (IQR 1.2-10.5). Estimated 5-year survival was 72% (95% CI 62-80) for the entire cohort and there was no difference in overall postnatal survival between polysplenia and asplenia subtypes (p=0.24). CHB and ventricular dysfunction were significant risk factors for both fetal demise and postnatal death. Pulmonary venous obstruction and CAVC were additional risk factors for postnatal death. Conclusions: Fetuses with HS continue to have high rates of postnatal mortality, particularly if CHB, ventricular dysfunction, or pulmonary venous obstruction are identified. CHB and ventricular dysfunction are also significant risk factors for fetal demise. Further research is needed to improve management of CHB and pulmonary venous obstruction in this high-risk group.
T-Cell Telomere Length As a Biomarker to Predict Outcome in Patients Receiving CAR-T Immunotherapy
Authors: Enzo Tedone, Mohammed Sayed, Tsung-Po Lai, Aishwarya Sannareddy, Dheepthi P. Ramasamy, Larry D. Anderson, Farrukh T. Awan, Gurbakhash Kaur, Stephen Chung, Yazan F. Madanat, Prapti Patel, Syed M Rizvi, Praveen Ramakrishnan, Madhuri Vusirikala, Robert H. Collins, John Sweetenham, Jerry Shay, Ankit Kansagra
Journal: Blood (2021)
Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS‐Induced Signals
Authors: Yu‐Wei Zhou, Yu Wu
Journal: Advanced Healthcare Materials (2021)

Macrophages settle in heterogeneous microenvironments rendered by other cells and extracellular matrices. It is well known that chemical stimuli direct macrophage behavior; however, the contributions of viscosity, which increases in inflammatory tissues but not in tumors, are ignored in immune responses including effective activation and timely attenuation. This paper demonstrates that transient lipopolysaccharide (LPS)-treated macrophages benefit from elastic substrates, whereas viscoelastic substrates with similar storage moduli support the inflammatory responses of macrophages under persistent stimulations and consequently amplify the distinctions between the transient and persistent LPS-induced transcriptional programs. Actin filaments (F-actin) fluctuate in line with transcriptional profiles and can be mathematically predicted by a clutch-like model. Moreover, viscosity modifies immune responses through transcription factors NF-κB and C/EBPδ, which act as switches discriminating transient and persistent infections. Interestingly, enhanced immune responses, consistent with the lower activated states, are attenuated promptly by the actin nucleation-related translocation of ATF3 to nuclei. These findings suggest that the substrate viscoelasticity induces more intense inflammation only in the case of persistent infection and promotes more sensitively perceiving the duration of infection through the F-actin correlated transcription factors. In addition, it may facilitate the cognition of immune response in inflammatory and cancerous microenvironments and have a wide range of applications in inflammatory regulations.
Abstract 12813: Left Main Disease—Not as Straightforward as It Seems
Authors: Tiffany Dong, Nabil Sabbak, Saberio Lo Presti, Richard A Grimm, Venugopal Menon
Journal: Circulation (2021)

A 51 year-old female with a past medical history of hypertension presents with chest pain that began 12 hours earlier. EKG showed biphasic T waves in the anterior leads and ST depressions in the lateral leads with a dynamic trend in troponins. LHC showed severe LM stenosis extending into the proximal LAD and LCx. An IABP was placed due to persistent angina despite being on a nitroglycerin drip. Given the minimal involvement the other coronary arteries, a coronary CT angiogram was pursued to evaluate for other non-atherosclerotic etiologies. The CT showed a periaortic soft tissue mass that encased the left main and the right pulmonary artery. The differential for conditions causing compression of the coronaries includes aortic or pulmonary artery aneurysms, abscesses, thymoma, lymphoma, teratoma and bronchogenic cysts. A PET scan showed metabolic activity of a supraclavicular lymph node, the mediastinal mass and a pericardial effusion. Her lymph node biopsy and mediastinal mass biopsy were consistent with a thymic carcinoma. Although thymomas are the most common anterior mediastinal tumor in adults, thymic carcinoma are rarer, more aggressive and thus spread outside the thymus. For thymic carcinomas, the ideal treatment is complete surgical resection while non-surgical candidates should undergo chemotherapy and radiation. Due to the proximity of the carcinoma the aorta and pulmonary artery, our patient was deemed not a surgical candidate and underwent radiation. This unique case highlights that non-athlerosclerotic etiologies should be entertained in cases of isolated left main disease and the importance of utilizing multimodality imaging to identify such causes.
Molecular Features and Clinical Outcomes of Extramedullary Plasmacytomas
Authors: Rie Nakamoto-Matsubara, Valentina Nardi, Cristina Panaroni, Keertik Fulzele, Tomoaki Mori, Rakesh Verma, Andrew J. Yee, Andrew R. Branagan, Elizabeth O'Donnell, Noopur S. Raje
Journal: Blood (2021)