tbuckley/cabot-search huggingface dataset:
Abstract 4142875: Beyond Static Cold storage: Partial freezing for extending heart preservation and improving recovery
Authors: Gurjit Singh, Rasha Al-attar, Manuela Lopera Higuita, Maya Chen, Tyler Pugeda, Korkut Uygun, Mehmet Toner, Shannon Tessier
Journal: Circulation (2024)

Background: Cardiovascular diseases, the leading cause of mortality with 17.9 million deaths annually (WHO), often necessitate heart transplants for end-stage organ failure. However, donor heart demand far exceeds supply. Traditional organ preservation methods like static cold storage (SCS) offer a limited 4-6 hour window, while machine perfusion (MP) extends this by circulating an oxygen-rich solution but faces challenges with nutrient depletion and metabolic imbalances. Our "partial freezing" method offers a novel approach to organ preservation using cryoprotectants (CPAs), by achieving a stable frozen state while maintaining an unfrozen fraction to limit ice damage and dehydration Hypothesis: Partial freezing (PF) method can effectively extend the storage duration of rodent hearts while maintaining their viability and function. Methods: The PF of the heart entails six major steps: (1) Procuring hearts (N=3) from adult male Lewis rats (2) Preloading of CPAs (DMSO, glycerol, raffinose, mannitol, and proline) during hypothermic Langendorff mode perfusion for 30 min (3) Freezing the hearts at a controlled rate of 0.3°C/min to -6°C (4) Storage at -6°C for 18 hours (5) Gradual thawing and unloading of CPAs (6) Recovery of hearts during NMP (normothermic machine perfusion) with antioxidant-supplemented Tyrode solution, followed by viability assessment using metabolic, hemodynamic, and molecular parameters. Two control groups were also included in the study: (1) Fresh hearts (N=3) functionally recovered in Tyrode solution, and (2) SCS hearts (N=3), perfused with cold University of Wisconsin (UW) solution and stored in the UW solution for 18 hours at 4°C, then recovered in same solution as the PF hearts. Results: NMP assessments revealed promising outcomes for PF hearts, with histology, TTC (Triphenyltetrazolium chloride) and Connexin-43 immunostaining profiles comparable to fresh controls and superior to SCS hearts. Although PF hearts exhibited lower beating rates, they demonstrated comparable metabolic parameters (lactate and oxygen consumption) and tissue edema compared to fresh controls, indicating preserved cardiac performance post-recovery. Conclusion: Our study shows the potential of the PF method to extend storage to 18 hours while maintaining viability and molecular function similar to fresh controls and superior to SCS hearts. This exploratory study suggests PF as a promising method to extend heart preservation times, addressing current limitations.
Abstract 4142958: Obesity Negatively Impacts Left Ventricular Mitochondrial Electron Transport Chain in End-Stage Heart Failure Patients
Authors: Ramana Vaka, Kristin Edwards, Ngoc Hoang, Babbette Lamarca
Journal: Circulation (2024)

Introduction: Obesity is an independent risk factor for heart failure (HF). Metabolic remodeling resulting from myocardial lipid accumulation is implicated in left ventricular (LV) dysfunction in HF patients with obesity. While obesity is shown to be inextricably linked to mitochondrial dysfunction in metabolic disease, its affect on LV mitochondrial function in failing hearts is unknown. Hypothesis: As such, we hypothesized that HF patients with obesity demonstrate reduced LV mitochondrial function in comparison to HF patients without obesity. Methods: In accordance with an approved IRB protocol, LV biopsies were sampled from end-stage HF patients undergoing left ventricular assist device (LVAD) surgery at the University of Mississippi Medical Center. Approximately 20 mg of LV tissue per patient was used to isolate mitochondria using differential centrifugation. The activities of individual electron transport chain (ETC) complexes (I-IV) and citrate synthase (CS; marker of mitochondrial content) were measured using Oxygraph-2K and spectrophotometer. Complex I-IV rates (nmol e - /min) were normalized to CS activity (nmol e - /min). Normality, statistical significance, correlations were tested using the Kolmogorov-Smirnov test, Welch’s t test, and Pearson correlation respectively. The data are presented as mean± standard error where appropriate. A p-value &lt;0.05 was considered statistically significant. Results: The study included 16 HF patients (3 females; age=52±3 years; 58% black, 42% white; 6 obese, BMI=40.9±2.11 kg/m 2 ; 10 non-obese, BMI=25.74±0.71 kg/m 2 ). Obese HF patients showed significant reductions in Complex I (46% lower, n=6-10, p=0.0343), and Complex IV (47% lower, n=5-10, p=0.0162) activities vs. non-obese HF patients. However, Complex II and III activities were unaltered between the groups. Further, CS activity was not different between the groups suggesting that LV mitochondrial mass is preserved in obese HF patients. Further, our correlation analysis revealed that Complex I (R 2 =0.3090, p=0.0254) and Complex IV (R 2 =0.4418, p=0.0069) activities were inversely correlated with BMI of the patients. Conclusions: The ETC complex I and IV activities are reduced by nearly half in obese HF patients highlighting a pronounced impact of obesity on myocardial mitochondrial function in end-stage failing hearts. These preliminary findings encourage further exploration on obesity mediated mitochondrial perturbations in heart failure patients.
Abstract 4142818: Odorgenetics-based noninvasive and precise neuromodulation of cardiac ganglia plexus prevents myocardial ischemia-induced ventricular arrhythmia
Authors: Liping Zhou, Chengzhe Liu, Hong Jiang, Lilei Yu
Journal: Circulation (2024)

Background: Autonomic imbalance exacerbates arrhythmia after myocardial infarction. Previous studies have utilized optogenetics and other techniques to modulate cardiac autonomic rebalance and significantly suppressed arrhythmia. However, electrical or optogenetic modulation requires implantation of device with electrodes or opto-electrodes, which is invasive and has a limited battery life. Research Questions: Odorgenetics technology is based on the binding of volatile odor molecules to specific G-protein coupled olfactory receptors to rapidly activate neurons. This study aimed to utilize odorgenetics to noninvasively and precisely modulate cardiac ganglia plexus (GPs) to prevent myocardial ischemia-induced ventricular arrhythmias (VAs). Methods: Canines were divided into the control group (n=6) and the odorgenetics group (n=6). pAAV-CMV-Or35a-Or83b-EGFP-tWPA was microinjected into GPs to specifically express olfactory receptors Or35a-Or83b in the odorgenetics group. Four weeks after injection, the volatile odorant molecule 2-pentanone was delivered via inhalation to activate Or35a-Or83b for GP modulation. Myocardial ischemia was induced by 1h left anterior descending occlusion followed with 1h reperfusion. GP odorgenetic stimulation was performed for 2h simutaneously. GP function and neural activity, effective refractory period (ERP), and VAs were measured. Results: Neurons in the GPs were transfected EGFP + in the odorgenetics group. Compared to the control group, inhalation of the odorant molecule 2-pentanone significantly activated GP function and neural activity in the odorgenetics group. Moreover, odorgenetic modulation showed a fast on-off effects on GP neural activity, that is, it can rapidly and reversibly modulate GP neural function and activity. In the control group, myocardial ischemia shortened ERP and increased spatial dispersion, which was improved by GP odorgenetic stimulation. In addition, myocardial ischemia induced VAs were significantly decreased by GP odorgenetic modulation (number of VT/VF: 3.5±4.5 vs. 14.8±7.7, P&lt;0.05 vs. control group). Conclusion: Odorgenetics technology enables noninvasive and fast on-off neuromodulation of cardiac GP, and thus prevents myocardial ischemia-induced VAs.
Abstract 4142878: Temporal and Regional Trends of Mortality Related to Heart Failure in Hypertensive Older Adults in the United States from 1999-2020
Authors: Ahmed Raza, Ubaid Khan, Abu Huraira Bin Gulzar, Mirza Ammar Arshad, Rahman Tanveer, Haroon Sohail, Ali Hamza
Journal: Circulation (2024)

Background: Hypertension is a leading cause of cardiovascular diseases (CVD) and is responsible for one-fourth of all cases of heart failure (HF). It affects approximately 75 million adults, or one in three US adults. Studies demonstrate an association between chronic hypertension and heart failure. Chronic hypertension causes pathological changes in the heart, increasing the risk of HF by twofold in men and by threefold in women. Treatment of high blood pressure prevents and reverses myocardial changes in patients at risk of HF. Objective: Our objective is to identify the mortality patterns related to HF due to hypertension in older adults in the United States, stratified by age, sex, region, and area, and to investigate any changes over time. Methods: We used the data from the CDC WONDER database to determine the crude death rates (CR) and age-adjusted mortality rates (AAMRs) per 100,000 individuals. Our study targeted individuals aged 65 and older. We examined the change in AAMR through annual percent change (APC) and the average annual percentage change (AAPC) using the Joinpoint regression. Results: From 1999 to 2020, HF caused 259,079 deaths in the hypertensive patient population in the US, demonstrating an increasing trend (AAPC = 5.5107). Females (28.57) had higher AAMRs than males (25.56). Non-Hispanic (NH) Black or African Americans had the highest AAMRs (43.99), while NH Asian or Pacific Islanders had the lowest (19.42). AAMRs also varied by region (West: 34.57, South: 27.74, Midwest: 26.78, Northeast: 21.44). Massachusetts and Tennessee had the highest percentage change in AAMRs, while the states with the lowest were New Hampshire and Colorado. Most deaths occurred at a hospice/nursing facility (57.9%). Non-metropolitan areas (30.69) had the highest AAMRs. Conclusions: We report concerning trends of heart failure in the hypertensive population in the US, with the highest mortality rates in females, NH Black/African Americans, and in the Western region. Future research should focus on targeted therapy for the vulnerable population and defining an optimal blood pressure target for HF patients, as the evidence is inconsistent and scarce on this topic.
Abstract 4143039: Circulating Follistatin-like 3 and Risk Prediction of Hypertensive Emergency in Patients with Suspected Preeclampsia
Authors: Marly Azzi, Sanela Potchileev, John Dreixler, Ariel Mueller, Sarosh Rana, Sajid Shahul
Journal: Circulation (2024)

Background: Hypertensive emergency in pregnancy, defined as systolic BP ≥160 and/or diastolic BP ≥110, is a serious complication of hypertensive disorders of pregnancy (HDP). Rapid, aggressive treatment of severe HTN decreases severe Maternal morbidity by 50%. However, few clinical indicators or biomarkers predict the development of severe HTN in pregnancy. Follistatin-like 3 (FSTL3), has been implicated in the development of preeclampsia. We hypothesized that elevated levels of FSTL3 in women for suspected preeclampsia evaluation would predict the development of a hypertensive emergency in pregnancy within two weeks. Methods: This cohort study included patients with singleton pregnancies who presented in obstetric triage at the University of Chicago between July 2021 and July 2023 for suspected preeclampsia evaluation. We measured plasma levels of FSTL3 at presentation and examined for an association between FSTL3 and subsequent development of a hypertensive emergency within 2 weeks. We excluded women who presented with severe preeclampsia or HTN emergencies on presentation to triage. Logistic regression models with receiver-operating characteristic (ROC) analysis were used to determine the clinical utility of FSTL3 in predicting HTN emergencies. Results: Our study included 208 patients, of which 79 (37.98%) developed severe preeclampsia. The median age was 30 years old (IQR 25.5, 34.5); the median BMI was 36.47 (IQR 30.79, 42.40), and the majority were African American (72.60%). The median FSTL3 at presentation was significantly elevated in participants who experienced HTN emergency compared with those who did not, respectively (Median, IQR) (46.47ng/ml, IQR (33.51–66.10)] versus 31.59ng/ml IQR, 27.35, 43.35], P&lt;0.0001). This association was significant after adjustment for maternal age, race, smoking, HDP, and BMI (P=0.03). Figure 1 outlines ROC analysis for specificity and sensitivity of FSTL3 in predicting HTN emergency within 2 weeks with the area under the curve =0.83. Conclusion: In women with suspected preeclampsia, circulating FSTL3 predicts a hypertensive emergency occurring within two weeks of triage presentation. This test may be helpful in risk stratification and management in women with HDP.
Abstract 4142919: Chronic administration of EDG-7500, a novel sarcomere modulator, prevents increases in cardiac mass, T1 relaxation time, and left ventricular end diastolic pressure in a Yucatan mini-pig model of genetic non-obstructive hypertrophic cardiomyopathy.
Authors: Craig Emter, Sarah Lehman, Lindsey Lee, Emy DiNatale, Angela Peter, Marcus Henze, David Bluemke, Darla Tharp, Steve Roof, Carlos del Rio, marc Semigran, Alan Russell, Marc Evanchik
Journal: Circulation (2024)

Introduction: Pathologic cardiac remodeling is a hallmark of hypertrophic cardiomyopathy (HCM). EDG-7500 is a novel oral, selective cardiac sarcomere modulator designed to slow the rate of contraction and speed the rate of relaxation without directly inhibiting myosin motor-head function. EDG-7500 is currently in a phase 2 clinical trial in HCM patients. Aims: To determine if EDG-7500 can prevent pathologic cardiac remodeling and disease progression in a mini-pig model of non-obstructive HCM (nHCM) caused by heterozygous MYH7 R403Q mutation. Approach: R403Q pigs were assigned to 2 groups; placebo control (CTRL; n=7-11) and EDG-7500 treated for 5-6 months (n=5-9), with untreated wild-type (WT; n=6-11) as reference. Cardiac magnetic resonance imaging (CMR) and terminal tissue collection occurred at 7-8 months of age. CMR sequences were collected in 12-16 parallel, short-axis views using a 3T scanner for calculation of left ventricular (LV) EF, volumes, T1-time, and LV mass. LV and left atrial (LA) mass also were measured postmortem. LV end diastolic pressure (EDP) and the end diastolic pressure-volume relationship (EDPVR) were measured in vivo via catheter. Myocardial atrial and brain natriuretic peptide (ANP and BNP) mRNA and α and β myosin heavy chain (MYHC) proteins were evaluated. Statistical significance was set at P≤0.05 (*denotes vs. CTRL) using one way ANOVA or linear regression with data reported as mean±SE. Results: EDG-7500 prevented increases in LV mass both in vivo (CMR; *45±3 vs. 61±6 in CTRL; WT, 46±3g) and postmortem without affecting LV end diastolic volume and EF. EDG-7500 attenuated: 1) increased LV EDP (*10±1 vs. 25±3 in CTRL; WT, 8±1mmHg); 2) decreased LV compliance (EDPVR *1.6±0.2 vs. 3.9±0.4 in CTRL; WT, 1.0±0.1mmHg/mL); and 3) increased LA mass (*12±1 vs. 22±2 in CTRL; WT, 7±1g). EDG-7500 also prevented increased T1-time (*971±31 vs. 1107±26 in CTRL; WT, 925±33msec), which was positively correlated to LV EDP (R=0.75). EDG-7500 prevented HCM-mediated increases in LV BNP (*16±6 vs. 46±13 in CTRL; WT, 1±0.2) and LA ANP mRNA (*3±1 vs.15±4 in CTRL; WT, 1±3), while preventing a pathologic isoform shift to more LA β-MYHC protein (*89%α:11%β vs. 75%α:25%β in CTRL; WT, 92%α:8%β). Conclusion: In a mini-pig model of nHCM, chronic EDG-7500 therapy prevents pathologic cardiac remodeling, decreased LV compliance, and disease progression without impairing resting systolic function. These findings support clinical investigation of EDG-7500 in nHCM.
Abstract 4143027: Impact of Variants of Uncertain Significance on Mortality, Heart Failure,&amp;Cardiac Arrest in Patients with Single Ventricle Disease
Authors: Saige Mitchell, Henry Foote, Jennifer Cohen, Sarah Tallent, Brittany Balint, Andrew Landstrom
Journal: Circulation (2024)

Background&amp;Hypothesis: Single ventricle disease (SVD) is a subtype of congenital heart disease that frequently requires early staged surgical intervention for survival. It is well known that syndromic causes of SVD are associated with worse outcomes. However, the overall effect of variants of uncertain significance (VUSs) found on chromosomal microarray (CMA) has not been explored. We hypothesized that VUSs impart no significant effect on clinical outcomes for patients with SVD when compared to normal chromosomal findings while pathogenic variants have a negative impact on mortality and heart failure. Objective: To explore the impact of CMA VUSs on outcomes in patients with SVD. Methods: We conducted a review of consecutive patients with SVD born between 1985-2023 with a CMA and treated at our institution. Primary outcomes included heart failure, heart transplantation, cardiac arrest, and mortality. Secondary outcomes included gastrostomy tube (G-tube) insertion, tracheostomy, and extracorporeal membrane oxygenation (ECMO). We controlled for possible confounding factors such as gestational age, birth weight, and age at diagnosis. Rates of primary and secondary outcomes were compared using Fisher’s exact test. Freedom from event curves were generated using a log-rank test for comparison. Results: The cohort included 322 consecutive single ventricle patients. The CMA results showed 248 (77.02%) patients having normal CMAs, 42 (13.04%) with VUSs, and 32 (9.94%) with abnormal/pathogenic results. Of those with abnormal CMAs, 22 (68.75%) had a chromosomal abnormality associated with a known genetic syndrome. Analysis using Fisher’s exact test showed lower rates of cardiac arrest and G-tube insertion in VUSs compared to abnormal CMAs (p &lt; 0.05). The one-year survival curve showed higher survival in the normal CMA group compared to the abnormal CMA group (p &lt; 0.05). The cardiac arrest freedom from event curve showed lower event rates in the VUS and normal CMA group compared to the abnormal CMA group (p &lt; 0.05). There was no difference in outcomes between VUSs and normal CMAs. Conclusions: Individuals with SVD and a VUS on CMA have survival rates comparable to those with normal CMAs. In contrast, abnormal CMAs are associated with reduced survival. These findings suggest that VUSs and normal CMAs may be less susceptible to cardiac arrest which is a critical complication of SVD.
Abstract 4142820: Vessel-by-Vessel CT Calcium Scoring in Peripheral Artery Disease: Association with Patient-Level Factors
Authors: Eleanor Rimmerman, Kumudha Musini, Ting-Heng Chou, Jenna Trainer, Said Atway, Michael Go, Mitchel Stacy
Journal: Circulation (2024)

Introduction: Peripheral artery disease (PAD) is an atherosclerotic condition that promotes lower extremity arterial calcification, which can decrease skeletal muscle perfusion, limit revascularization options, contribute to worse revascularization outcomes, and increase risk of adverse events. Although vascular calcium scoring via computed tomography (CT) imaging has already gained attention for risk assessment in coronary artery disease (CAD), analytical methods for vessel-by-vessel CT calcium scoring in PAD remain underdeveloped and understudied. We hypothesized that CT imaging would allow for vessel-specific calcium scoring in PAD patients and elucidate the contributions of patient-level factors promoting vascular calcification. Methods: PAD patients (n=90) were prospectively enrolled and underwent non-contrast CT imaging of the legs (CT parameters: slice thickness 3.27 mm, 120 kVp, 85 mA). Five arteries of interest (femoral-popliteal, anterior tibial, tibioperoneal trunk, posterior tibial, peroneal) were manually segmented using axial CT images along the length of the symptomatic limb. Calcium mass was quantified for each arterial segment using a CT image threshold of ≥130 Hounsfield units and mean calcium mass was calculated for each artery. T-tests were used to compare calcium values between patients with (n=62) and without diabetes mellitus (DM) (n=28). Multivariate linear regression was conducted to assess the role of patient-level factors on vessel-specific calcium burden. Results: Image analysis demonstrated that PAD patients with DM had significantly higher calcium burden compared to PAD patients without DM for 4 out of 5 peripheral arteries assessed (femoral-popliteal p=0.01, anterior tibial p=0.002, peroneal p=0.004, posterior tibial p=0.001). After adjusting for age, sex, and body mass index, multivariate analyses revealed that a history of CAD, dialysis dependence, and DM were significantly and positively associated with peripheral artery calcium burden. Conclusions: CT imaging allows for vessel-by-vessel calcium scoring in PAD and provides insight into the patient characteristics that may contribute to calcium burden. Future broader use of calcium scoring in PAD may allow for identification of ideal roadmaps for interventional planning, identify who is most susceptible to technical failure from interventions, and predict limb outcomes by providing quantitative data related to disease characteristics on a vessel- and lesion-specific basis.
Abstract 4143001: Rapid Diuresis Protocol in Decompensated Heart Failure: Improving Guideline-Directed Medical Therapy Titration and Timely Outpatient Follow-up
Authors: Sherilyn Munoz, Mazin Habhab, Matthew Hollowell, Paul Weber, Ryan Crane, Anastasia Bury, Morgan Korn, Nicole Mitchell, matthew gonzalez
Journal: Circulation (2024)

Current guidelines for treating acute decompensated heart failure (ADHF) recommend inpatient intravenous diuresis until congestion relief, as well as the initiation and advancement of guideline-directed medical therapy (GDMT). Our institution has developed a rapid diuresis team (RDT) to expedite decongestion in hospitalized ADHF patients with the goal of safely reducing length of stay. This study examines the RDT’s potential impact on GDMT titration as well as outpatient follow up timing. Does the RDT protocol improve GDMT titration and time to outpatient follow-up after discharge in patients with ADHF? This retrospective single-center study includes patients undergoing inpatient treatment for ADHF from March 2022 to November 2023 at a tertiary referral center. Demographic, clinical, and laboratory data were obtained. Standard parametric and non-parametric analyses were conducted, along with Kaplan-Meier curve analysis, with statistical significance set at p&lt;0.05. The RDT protocol involves early aggressive diuresis with daily monitoring of weight, fluid intake, and urine output. Aggressive diuresis goals (3-4 L/day urine output) were set and included regular assessments by a multidisciplinary team. Discharge criteria focus on resting symptom resolution, adequate oral diuretic response, and an established follow-up within 3-5 days where GDMT can be adjusted as needed. Out of 255 patients, 128 underwent RDT and 127 received standard care. Patients in the RDT protocol had a shorter average time from hospital discharge to cardiology appointment (4 days vs. 5 days; p = 0.044). Additionally, those in the RDT protocol tended to have higher rates of follow-up within 30 days post-discharge (90% vs. 77%; p = 0.052) (Figure 1). GDMT titration prior to discharge was more common in the RDT group (93 vs. 74 patients; p = 0.025). At the follow-up visit, GDMT titration was also more frequent in the RDT group (55 vs. 43 patients; p = 0.207). Compared to standard care, the RDT protocol results in a shorter time to outpatient follow-up and improved inpatient and outpatient GDMT titration for the treatment of heart failure. The implementation of the RDT protocol appears to enhance the management and outcomes of patients with ADHF.