tbuckley/cabot-search huggingface dataset:
Abstract 13902: Using a Proteomics-Based Cardiovascular Risk Test to Identify Systemic Changes in a Clinical Trial of Nonalcoholic Fatty Liver Disease
Authors: Arun Sanyal, Missy Simpson, Michael Hinterberg, Erin Hales, Clare Paterson, Brent Neuschwander-Tetri, Anna Mae Diehl, Srinivasan Dasarathy, Rohit Loomba, Naga Chalasani, Kris Kowdley, Bilal Hameed, David Kleiner, Cynthia Behling, James Tonascia, Katherine Yates, Stephen A Williams
Journal: Circulation (2023)

Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular outcomes. Assessment of the impact of NASH therapy on cardiovascular risk is an important element of NASH drug development but is challenging particularly in early phase trials. Aptamer-based proteomic profiles (Somalogic®) in serum have been used to develop and validate a risk score as a surrogate for cardiovascular (CV) risk. Hypothesis: Improvement in NASH histology will result in improved proteomic cardiovascular risk scores. Methods: A post-hoc analysis of proteomic profiles of serum samples, using the Somalogic® platform, from the Pioglitazone vs. Vitamin E vs. Placebo for Treatment of Nonalcoholic Fatty Liver Disease (PIVENS) trial was conducted. PIVENS was a 96-week trial of nondiabetic participants with (NASH). We applied the proteomic CV risk scores to samples from baseline, on therapy and end of treatment visits (n=7) visits and received liver histology results at baseline and 96 weeks on N = 209 (84.6%) study participants. Generalized linear and mixed models were used to assess the association between CV risk score, treatment arm and change in liver biopsy results. Results: Baseline scores were similar across groups (mean 0.19, SD 0.14). There was no association between treatment arms and changes in scores during therapy and end of treatment. However, improvement in histological markers of activity (lobular inflammation and NAFLD activity score) and fibrosis were associated with improved cv risk scores (Figure) (p&lt; 0.05 for all). Conclusions: Improvement in hepatic inflammation, NAFLD activity score and fibrosis were associated with improved proteomic CV risk scores regardless of treatment provided. Additional prospective validation of these findings is warranted. Proteomic profiling can potentially be used to track changes in cardiovascular risk profile changes in response to therapy in the short term NASH treatment trials.
Abstract 13977: Insulin-Like Growth Factor Binding Protein 7 is Associated With Development of Cell Senescence and Progression of Coronary Atherosclerosis
Authors: Sergiy Sukhanov, Yusuke Higashi, Svitlana Danchuk, Patricia Snarski, Patrice Delafontaine
Journal: Circulation (2023)

Introduction: Cellular senescence, an irreversible cell cycle arrest, has been associated with atherosclerosis. Senescent cells (SC) secrete proinflammatory molecules contributing to disease progression. Insulin-like growth factor binding protein 7 (IGFBP7) binds IGF-1 and also interacts with IGF-1 receptor, suppressing intracellular IGF-1 signaling. IGFBP7 has been linked to heart failure-associated cell senescence. Hypothesis: We hypothesize that SC secrete IGFBP7, and IGFBP7 contributes to atherogenesis. Methods: Premature cell senescence was induced by treatment of smooth muscle cells (SMC) with H2O2. IGFBP7 levels were measured by immunoblotting of cell lysates and conditioned media (CM) and by immunohistochemistry in Apoe-null mice and in Rapacz hypercholesterolemic pigs. Binding of IGFBP7 with IGF-1 receptor was quantified by proximity ligation assay. Results: H2O2-treated SMC have marked increase in expression of the senescence markers beta-galactosidase (SA-βGal) and γH2A.X, and 3-fold (P&lt;0.05) increase in IGFBP7 in cell CM. Abundant senescent SMC (αSMA + /SA-βGal + ) were detected in fibrous cap’s plaque in murine innominate artery and these cells had increased IGFBP7 compared to SMC in the vascular media. Increased IGFBP7 levels (1.8-fold increase, P&lt;0.05) were also detected in porcine coronary plaque and IGFBP7 upregulation correlated with elevated IGFBP7/IGF-1 receptor binding. These data suggest a mechanistic link between senescence, IGFBP7 upregulation and atherogenesis. SMC were incubated with CM from senescent SMC (or non-senescent controls) to determine if SC-secreted IGFBP7 inhibits IGF-1 signaling. Preincubation with CM from SC inhibited IGF-1-induced Akt phosphorylation, however co-incubation with anti-IGFBP7 antibody reversed this effect, indicating that IGFBP7 in the CM mediates the inhibitory effect on IGF-1 signaling. Conclusions: We have shown that SMC senescence induced IGFBP7 and that high IGFBP7 levels were associated with senescent SMC in the atherosclerotic plaque. IGFBP7 inhibits IGF-1 signaling in vitro and binds IGF-1 receptor in plaque SMC. Our results suggest a novel role of IGFBP7 in senescence and in atherogenesis and identify IGFBP7 as a potential target for anti-atherogenic therapy.
Abstract 139: Targeted Blood Pressure, Oxygenation, and Duration of Device-Based Fever Prevention After Out-of-Hospital Cardiac Arrest - Effects on 1 Year Survival
Authors: Martin A Meyer, Christian Hassager, Henrik Schmidt, Jacob Moller, Jesper Kjaergaard
Journal: Circulation (2023)

Background: In the post-resuscitation phase after cardiac arrest various treatment modalities have been proposed for improving outcomes. The “Blood Pressure and Oxygenation Targets in Post Resuscitation Care” (BOX) trial investigated whether, a higher versus lower blood pressure target, a liberal versus restrictive oxygenation target, and a longer versus shorter duration of device-based fever prevention in comatose patients could improve outcomes. No differences in rates of discharge from hospital with severe disability or dying from all causes at 90 days were found for neither of the 3 interventions However, the long-term effects of these interventions are unknown. Objective: To investigate the effects of each of the 3 interventions of the BOX-trial on 1-year mortality rates. Methods: In the BOX trial (NCT03141099), comatose resuscitated out-of-hospital cardiac arrest patients were randomly assigned to the following interventions at hospital admission: 1. A blood pressure target of either 63 mmHg or 77 mmHg (blinded); 2. An arterial oxygenation target of 68 to 75 mmHg or 98 to 105 mmHg; 3. Device-based fever prevention administered as an initial 24 hours at 36°C and then either 12 or 48 hours at 37°C a total of 36 or 72 hours. Patients were followed for 1 year for the occurrence of death from all causes, and mortality rates are reported separately for each of the 3 interventions. Results: For all three interventions 789 patients were included in the analyses. For the interventions of higher compared to lower blood pressure targets, the 1-year mortality rates were 36% (143 of 393) and 35% (138 of 396), respectively (log-rank p=0.47). For the interventions of liberal compared to restrictive oxygenation targets the 1-year mortality rates were 37% (146 of 395) and 34% (135 of 394), respectively (p=0.46). For the interventions of device-based fever prevention for a total of 72 hours compared to 36 hours the 1-year mortality rates were 36% (142 of 396) and 35% (139 of 393) respectively (p=0.89). Conclusions: There were no indications of differentiated rates of mortality at 1 year for neither a higher compared to lower targeted blood pressure, a liberal compared to restrictive oxygenation target, nor a longer compared to shorter duration of device-based fever prevention.
Abstract 13710: Cardiac Platypnea-Orthodeoxia Syndrome: How the Stars Aligned
Authors: Steven A Hamilton, Diana L Tobler, Kevin Bobrowsky, Ivy A Ku, Alicia Romero
Journal: Circulation (2023)

Case description: A 79-year-old man with recurrent falls, dyslipidemia and recent exercise intolerance presented after a fall. He was putting on shoes, lost his balance and fell. There was no pre-syncope, syncope, dyspnea, chest pain, palpitations or dizziness. On admission, vital signs were normal except oxygen saturation (O2 sat) 79% on room air (and no improvement with supplemental O2). An arterial blood gas (ABG) revealed partial pressure of oxygen 42 mmHg with oxygen saturation 80%. He had lower thoracic spine tenderness, normal respiratory and cardiac exam. CT head showed no acute intracranial abnormalities. CTA chest had no pulmonary embolism, arterio-venous malformations or parenchymal lung disease. There was a thoracic aorta aneurysm (4.5cm at aortic root and 5.1cm at posterior arch). Subsequently, O2 sat was 92% supine and 79% standing. He also had a compression fracture of T12 and spinal asymmetry. A transesophageal echocardiogram (TEE) showed an aneurysmal, hypermobile interatrial septum with early right to left shunt with agitated saline due to a large patent foramen ovale (PFO). Right heart catheterization revealed no pulmonary hypertension and confirmed a step down from the pulmonary vein to left atrium (delta O2 sat 6%). A 30mm Gore Cardioform occluder was used to close the defect and immediately supplemental oxygen was removed, and O2 sat on room air was 95%. Follow up echocardiogram showed no residual shunt and exercise intolerance resolved. Discussion: Unexplained positional hypoxemia raised our suspicion for cardiac POS. Hypoxemia is caused by right to left shunting via the PFO, exacerbated by the thoracic aortic aneurysm and spinal changes such as the T12 fracture and spinal asymmetry. Going from being recumbent to erect there is stretching of the atria causing his PFO to enlarge, increasing the shunt. Additionally, the dilated thoracic aorta exerts mechanical pressure on the right atrium (RA) and interatrial septum, increasing PFO patency and augmenting flow from the inferior vena cava through the PFO. The spinal abnormality may cause more aortic distortion and exert forces on the RA, exacerbating shunting. Percutaneous PFO closure is the treatment of choice with closure immediately leading to significant improvement of hypoxemia.
Abstract 13801: Gender Disparity in Clinical and Management Outcomes in Patients With Pulmonary Embolism: A Systematic Review and Meta-Analysis
Authors: Ubaid Khan, Mohamed T Abuelazm, Ahmed Halem, ahmed badawy, abdallah Saeed, Majd M. AlBarakat, Zaid Hatamleh, Muhammad Moiz Nasir, Shafaqat Ali, Basel Abdelazeem
Journal: Circulation (2023)

Introduction: Gender is a unique characteristic that may contribute significant variation in prognostic aspects and outcomes to various clinical conditions. We aim to compile all evidence from original studies relevant to sex-based disparities in pulmonary embolism (PE) associated clinical outcomes. Methods: We conducted a systematic review and meta-analysis synthesizing observational comparative studies, which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through April 12 th , 2023. We reported dichotomous outcomes using risk ratio (RR) along with the corresponding 95% confidence interval (CI). Results: We included 18 studies with a total of 1,339,937 patients. There was no difference between men and women regarding all-cause mortality (RR: 0.99 with 95% CI [0.89, 1.10], P = 0.81), in-hospital mortality (RR: 0.94 with 95% CI [0.88, 1.02], P = 0.13), PE-related mortality (RR: 0.86 with 95% CI [0.68, 1.09], P = 0.21), and recurrence (RR: 1.00 with 95% CI [0.82, 1.22], P = 0.99). However, the major bleeding rate was significantly higher among women (RR: 0.69 with 95% CI [0.48, 0.98], P= 0.04). Also, there was no difference between men and women regarding catheter thrombolysis (RR: 0.96 with 95% CI [0.81, 1.14], P= 0.66) and heparin infusion (RR: 1.00 with 95% CI [0.95, 1.04], P= 0.90). Conclusion: There was no difference between men and women regarding clinical and management of PE outcomes, with a trend towards worse outcomes and decreased interventions among women, with a significant increase in major bleeding. Further policy measures are required to investigate the reasons behind this trend and if it has any clinically significant impact on patients' management and prognosis.
Abstract 12370: Atrial Fibrillation and Atrial Remodeling Deteriorates Right Heart Function With Preserved LV Function in LKB1 <sup>f/f</sup> /ANF <sup>Cre+</sup> Mice
Authors: Nobuaki Fukuma, Christos Tzimas, Ilaria Russo, Wen Dun, Emily J Tsai
Journal: Circulation (2023)

Introduction: Atrial fibrillation (AF) and right ventricular dysfunction(RVD) are each highly prevalent in heart failure (HF) patients; their co-existence represents a severe HF phenotype. AF and RVD in HF are respectively attributed to left atrial remodeling and pulmonary hypertension due to left heart disease. Yet clinical studies have found that AF, not pulmonary pressure, is independently associated with RVD in HF. These findings suggest the possibility that AF can cause RV dysfunction. Hypothesis: Atrial fibrillation can cause progressive RV dysfunction even in the absence of pulmonary hypertension. Methods: We created an atrial-specific LKB1 knockdown (atrial-LKB1 KD) by injecting AAV9-ANF-Cre retro-orbitally into adult male LKB1 fl/fl mice (age 8 wks). Echocardiography and telemetry were performed at 4- and 12- weeks post AAV9-ANF-Cre. At 12-weeks post-AAV injection, both right ventricular and left ventricular pressure- volume loop recordings were performed. Histological and molecular analyses were also performed at study endpoint. LKB1 fl/fl mice (Cre-) were used as controls (CTL). Results: At 12 wks post-injection, the incidence of AF with atrial remodeling was 100% in atrial-LKB1 KD. Echocardiography revealed RV systolic dysfunction by RV FAC (50.72% vs. 60.45%, p&lt;0.05) and TAPSE (0.89mm vs. 1.15mm, p&lt;0.05) in atrial-LKB1 KD vs. CTL. In contrast, LV FS were comparable between atrial-LKB1 KD and CTL. (40.4% vs. 42%, p=0.38). Atrial-LKB1 KD demonstrated abnormal RV-pulmonary arterial coupling, increased RV systolic pressure, and preserved LV function following atrial remodeling. Expression of genes related to remodeling and inflammation were upregulated in the RV of atrial-LKB1 KD. Compared to that of CTL, RV expression level of Nppb was 3.4-fold higher (p&lt;0.05) and IL1β was 7.1 fold higher (p&lt;0.05) in atrial-LKB1 KD. Conclusions: Our findings strongly suggest that atrial fibrillation alone can cause RV dysfunction with concomitant preserved LV function. Remodeling and inflammation of the RV but not LV in the atrial-LKB1 KD also suggests that the right heart is more vulnerable than the left heart to AF-induced dysfunction.
Abstract 12295: The Timing of Appearance of Untimely Dissociated Potentials After Pulmonary Vein Isolation for Atrial Fibrillation is Related to the Respiratory Phase
Authors: Takanao Mine, Miho Sugitani, Takehiro Kogame, Eiji Fukuhara, Masaharu Ishihara
Journal: Circulation (2023)

Introduction: Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). However, the mechanism and timing of Ectopic beat occurrence remain unclear. Hypothesis: The dissociated potentials (DPs) after pulmonary vein isolation (PVI) for AF are related to the respiratory phase and left atrial pressure (LAP). Methods: 93 patients underwent AF ablation under deep sedation and BiPAP ventilation. [Study1] Respiratory waveforms of 20 patients were recorded simultaneously with LAP. [Study2] In 73 patients, DPs after PVI or left atrial posterior wall (LAPW) isolation were recorded simultaneously with respiratory waveforms for 3 min, and the preceding coupling intervals (CI) of all DPs were measured. Sites with DPs frequencies &lt;10/min were defined as rare DPs sites. In sites with DPs frequencies ≧10/min, sites where the number of DPs with CI shorter than the mean - SD of CI was greater than the number of DPs with CI longer than the mean + SD of CI were defined as short-coupling DPs sites, and long-coupling DPs sites were defined in the opposite cases. Results: [Study1] Respiratory waveforms showed fluctuations similar to LAP, and LAP increased within the respiratory interval in all patients (Fig.1). [Study2] The incidence of DPs on the left PV was lower than that on the right PV and LAPW (28 of 61 left PV 46%, 41 of 66 62%, 3 of 3 100%, P=0.0306). Additionally, the CI of DPs on the left PV was longer (3.1±5.4sec, 2.0±2.8, and 1.6±0.5, P&lt;0.0001). The timing of appearance of DPs was not related to the respiratory phase in all DPs assessments (2126 beats during the respiratory interval and 2155 beats during the rest interval). However, inopportune DPs appeared during the specific respiratory phases: the respiratory interval for short-coupling DPs, and the rest interval for long-coupling DPs and rare DPs sites (P=0.016, Fig.2). Conclusions: The timing of appearance of untimely DPs is related to the respiratory phase and may be associated with an increase in LAP.
Abstract 11344: Targeted Deletion of Arrdc4 Mitigates Cardiac Injury in Insulin-Deficient Diabetes
Authors: Yoshinobu Nakayama, Jun Yoshioka
Journal: Circulation (2023)

Introduction: Diabetic cardiomyopathy is an important contributor to mortality in the diabetic population. However, the pathogenesis of diabetic cardiomyopathy is unclear. Hypothesis: We recently reported that the interaction between glucose transporter 1 (GLUT1) and its adaptor protein Arrdc4 mediates metabolic stress in the ischemic heart. Here, we tested whether this mechanism plays a role in diabetic cardiomyopathy. Methods: To determine glucose responsiveness, mouse neonatal cardiomyocytes were treated with high glucose (25 mM). To investigate cardiac phenotype in vivo, we engineered Arrdc4-knockout (KO) mice by CRISPR/Cas9 technology and created an insulin-deficient diabetic model by intraperitoneal injection of streptozotocin. Results: Arrdc4 expression was robustly stimulated by D-glucose (324±10%, p&lt;0.01) in cardiomyocytes. The glucose responsiveness was mediated by MondoA, a nutrient-sensing transcriptional factor, through a cytoplasmic-nuclear shuttling mechanism. Confocal live imaging showed that Arrdc4 triggered endocytic trafficking of GLUT1 into lysosomes. In the animal model, levels of insulin depletion were comparable between the genotypes. Nevertheless, Arrdc4-KO diabetic mice had enhanced glucose uptake in multiple organs including the heart (139±13%, p&lt;0.01) compared to wild-type (WT) diabetic mice. Arrdc4-KO diabetic hearts had lower induction of oxidative stress, ER stress, and autophagy by hyperglycemia, leading to better mitochondrial function and less cardiomyocyte apoptosis (70±5%, p&lt;0.01) than WT diabetic hearts. Although resting echocardiography could not detect early signs of left ventricular dysfunction, stress hemodynamic analysis uncovered the masked mechanical dysfunction by diabetes and found that Arrdc4-KO diabetic mice retained a greater cardiac response to beta-adrenergic stimulation than wild-type mice (149±5%, p&lt;0.01). Conclusion: The metabolic rearrangements by Arrdc4 deletion improve glucose transport due to the absence of its inhibition towards GLUT1 function, protecting the heart against diabetic damage. These results provide a novel link between GLUT1 and Arrdc4 as a fundamental mechanism of the regulation of glucose homeostasis in diabetic cardiomyopathy.
Abstract 13973: Amyloidosis and Heart Failure is a Deadly Combination: A Retrospective Study From 2015-2019 Using the National Inpatient Sample
Authors: Shreyas Singireddy, Raghav Chawla, Jaime Gonzalez Cardona, Dipal Patel, Haripriya Andanamala
Journal: Circulation (2023)

Introduction: Heart failure (HF) is a common cause of hospitalization in the United States. Amyloidosis has become a more accepted cause of HF in the US however contemporary data on amyloidosis affecting the heart is relatively lacking even in the setting of increased mortality and morbidity rates. This study is aimed to define the prevalence of HF in amyloidosis along with looking at inpatient mortality, length of stay and other relevant factors. Methods: For the current study, the National Inpatient Sample (NIS) was queried for the years 2015 Q4-2019. Our cohort of interest included patients with amyloidosis. We further identified patients with heart failure using the ICD-10 diagnosis codes algorithm for Elixshauser comorbidity scoring. Results: A total of 23,586 patients were identified with amyloidosis between 2015 Q4 and 2019. Interestingly, 49% of those patients (11,560 people) were identified with a diagnosis of HF, reflecting its increased prevalence in patients with amyloidosis. The mean age of the cohort was 71.9 years (SD=12.3), Patients with heart failure were overall more likely to be males (63.7% vs 50.2%, p&lt;0.001), and were more likely to be African American (30.4% vs 16.2%, overall p&lt;0.001), compared to patients without heart failure. When compared to amyloidosis subjects without HF, those with HF experienced an increased rate of mortality (7.2% vs 5.5%, p&lt;0.001), a longer length of stay (LOS) with a mean difference of 0.7 days (7.9 days vs 7.2 days, p&lt;0.001), and a more costly overall hospitalization with a mean difference of $10,906.1 ($90159.3 vs $79253.2, p&lt;0.001). Upon multivariable logistic regression analysis, the presence of HF (OR 1.24, 95%CI 1.11-1.401, p&lt;0.001) was associated with higher odds of in-hospital mortality. Conclusions: Our study shows that HF is a dominant comorbidity in patients with amyloidosis with almost every other patient being affected. Additionally, when compared to those without HF, patients with HF were more likely to be African American, have a longer length of stay, have more costly admissions, and overall had a higher rate of in-patient mortality.
Abstract 12378: Association of Hypertensive Disorders of Pregnancy With Coronary Microvascular Dysfunction 8-10 Years After Delivery
Authors: Malamo Countouris, Janet M Catov, Jianhui Zhu, Nikki de Jong, Judith Brands, Xucai Chen, W. Tony Parks, Kathryn Berlacher, Robin Gandley, Adam C Straub, Flordeliza S Villanueva
Journal: Circulation (2023)

Introduction: Hypertensive disorders of pregnancy ( HDP ) are associated with subsequent adverse cardiac remodeling and cardiovascular disease ( CVD ). The pathophysiologic mechanisms linking HDP to CVD, including the role of myocardial microvascular disease, are understudied. Hypothesis: Individuals with HDP history will have abnormal microvascular coronary flow reserve ( CFR ) 8-10 years after delivery and abnormal CFR will correlate with left ventricular ( LV ) remodeling. Methods: Individuals with pregnancies delivered 2008-2010 underwent burst-replenishment myocardial contrast echocardiography (2017-2020) to quantify myocardial perfusion at rest and during dobutamine stress. Video intensity vs. time data were used to derive β, the rate of rise of video intensity, a correlate for myocardial blood flow. CFR was calculated as the ratio of β at peak stress to β at rest, averaged across LV myocardial regions of interest. Results: We studied 91 individuals (age 38±6, 9.1±0.9 years post-delivery), 19 with a history of HDP). Individuals with abnormal CFR (β ratio &lt;2.0, n=13) had higher pre-pregnancy BMI, baseline heart rate, hemoglobin A1c, and a history of HDP (46.2% vs 16.7%; p =0.026). Association of CFR and HDP was attenuated after adjusting for pre-pregnancy BMI and hemoglobin A1c ( p =0.114). In exploratory subgroup analyses, individuals with both LV remodeling (relative wall thickness&gt;0.42) and HDP had the highest proportion of microvascular dysfunction (41.7% vs. +HDP-LV remodeling 14.3%, -HDP+LV remodeling 7.7%; p =0.0498). Conclusions: Individuals with HDP history may be more likely to have coronary microvascular dysfunction one decade after delivery. Larger studies are needed to determine if microvascular dysfunction may be a mechanism for development of CVD among individuals with HDP.