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Abstract Background Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF. Method We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes. Discussion The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF. Trial registration: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.

Abstract Background Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. Methods Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. Discussion The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Background: Interleukin-1 blockade with anakinra leads to a transient increase in eosinophil blood count (eosinophils) in patients with acute myocardial infarction. We aimed to investigate the effect of anakinra on changes in eosinophils in patients with heart failure (HF) and their correlation with cardiorespiratory fitness (CRF). Methods: We measured eosinophils in 64 patients with HF (50% females), 55 (51–63) years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF, measuring peak oxygen consumption (VO2) with a treadmill test. Results: Treatment with anakinra significantly and transiently increased eosinophils, from 0.2 [0.1–0.3] to 0.3 [0.1–0.4] × 103 cells/µL (p < 0.001) and from 0.3 [0.2–0.5] to 0.2 [0.1–0.3] × 103 cells/µL, with suspension (p < 0.001). Changes in eosinophils correlated with the changes in peak VO2 (Spearman’s Rho = +0.228, p = 0.020). Eosinophils were higher in patients with injection site reactions (ISR) (n = 8, 13%; 0.5 [0.4–0.6] vs. 0.2 [0.1–0.4] × 103 cells/µL, p = 0.023), who also showed a greater increase in peak VO2 (3.0 [0.9–4.3] vs. 0.3 [−0.6–1.8] mLO2·kg−1·min−1, p = 0.015). Conclusion: Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and a greater improvement in peak VO2.

ContextThe pharmacokinetics of liothyronine causes concerns for cardiovascular toxicity. While the effects of sustained increase in serum T3 concentrations are well described, little is known on the effects of acute changes in T3 concentrations due to rapid action of thyroid hormone.ObjectiveTo assess the clinical relevance of transient increase of T3 levels on cardiovascular system and energy metabolism.SettingDouble-blind, three arms, placebo controlled, cross-over study (ClinicalTrials.gov Identifier: NCT03098433).Study ParticipantsTwelve volunteers (3 females, 9 males), age 27.7 ± 5.1 years.InterventionOral administration of liothyronine 0.7 mcg/kg, equimolar dose of levothyroxine (0.86 mcg/kg), or placebo in three identical study visits. Blood samples for total T3, free T4 were collected at times 0’, 60’ 120’ 180’ 240’. Continuous recording of heart rate, blood pressure, and hemodynamic data was performed using the volume clamp method. Resting energy expenditure was measured by indirect calorimetry. An echocardiogram was performed on each study visit at baseline and after the last blood sampling.Main Outcome MeasuresChanges in cardiovascular function and energy expenditure.ResultsFollowing the administration of liothyronine, serum T3 reached a Cmax of 421 ± 57 ng/dL with an estimated Tmax of 120 ± 26 minutes. No differences between study arms were observed in heart rate, blood pressure, hemodynamics parameters, energy expenditure, and in echocardiogram parameters.ConclusionsThe absence of measurable rapid effects on the cardiovascular system following a high dose of liothyronine supports the rationale to perform long-term studies to assess its safety and effectiveness in patients affected by hypothyroidism.

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined.Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions.Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of “feel irritable,” “feel hungry,” and “I am craving.” For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine.Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine.Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.

Abstract Introduction: Controlled clinical trials (CCTs) have traditionally been limited to urban academic clinical centers. Implementation of CCTs in rural setting is challenged by lack of resources, the inexperience of patient care team members in CCT conductance and workflow interruption, and global inexperience with remote data monitoring. Methods: We report our experience during the coronavirus disease 2019 (COVID-19) pandemic in activating through remote monitoring a multicenter clinical trial (the Study of Efficacy and Safety of Canakinumab Treatment for cytokine release syndrome (CRS) in Participants with COVID-19-induced Pneumonia [CAN-COVID] trial, ClinicalTrials.gov Identifier: NCT04362813) at a rural satellite hospital, the VCU Health Community Memorial Hospital (VCU-CMH) in South Hill, VA, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospital (VCU-MCV), Richmond, VA. We used the local resources at the facility and remote guidance and oversight from the VCU-MCV resources using a closed-loop communication network. Investigational pharmacy, pathology, and nursing were essential to operate the work in coordination with the lead institution. Results: Fifty-one patients with COVID-19 were enrolled from May to August 2020, 35 (69%) at VCU-MCV, and 16 (31%) at VCU-CMH. Among the patients enrolled at VCU-CMH, 37.5% were female, 62.5% Black, and had a median age of 60 (interquartile range 56–68) years. Conclusion: Local decentralization of this trial in our experience gave rural patients access to a novel treatment and also accelerated enrollment and more diverse participants’ representative of the target population.

BackgroundEndogenous serine protease inhibitors are associated with anti-inflammatory and pro-survival signaling mediated via Low-density lipoprotein receptor-related protein 1 (LRP1) signaling. SP16 is a short polypeptide that mimics the LRP1 binding portion of alpha-1 antitrypsin.MethodsA pilot phase I, first-in-man, randomized, double blind, placebo-controlled safety study was conducted to evaluate a subcutaneous injection at three dose levels of SP16 (0.0125, 0.05, and 0.2 mg/kg [up to 12 mg]) or matching placebo in 3:1 ratio in healthy individuals. Safety monitoring included vital signs, laboratory examinations (including hematology, coagulation, platelet function, chemistry, myocardial toxicity) and electrocardiography (to measure effect on PR, QRS, and QTc).ResultsTreatment with SP16 was not associated with treatment related serious adverse events. SP16 was associated with mild-moderate pain at the time of injection that was significantly higher than placebo on a 0-10 pain scale (6.0+/-1.4 [0.2 mg/kg] versus 1.5+/-2.1 [placebo], P = 0.0088). No differences in vital signs, laboratory examinations and electrocardiography were found in those treated with SP16 versus placebo.ConclusionA one-time treatment with SP16 for doses up to 0.2 mg/kg or 12 mg was safe in healthy volunteers.

OBJECTIVES/GOALS: Heart failure (HF) is a clinical condition that notably affects the lives of patients in rural areas. The partnering of a rural satellite hospital with an urban academic medical center may provide geographically underrepresented populations with HF an opportunity to access controlled clinical trials (CCTs). METHODS/STUDY POPULATION: We report our experience in screening, consenting and enrolling subjects at the VCU Health Community Memorial Hospital (VCU-CMH) in rural South Hill, Virginia, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospitals (VCU-MCV), Richmond, VA. Subjects were enrolled in a clinical trial sponsored by the National Institutes of Health (ClinicalTrials.gov: NCT03797001) and assigned to treatment with an anti-inflammatory drug for HF or placebo. We used the electronic health record and remote guidance and oversight from the VCU-MCV resources using a closed-loop communication network to work with local resources at the facility to perform screening, consenting and enrollment. RESULTS/ANTICIPATED RESULTS: One hundred subjects with recently decompensated HF were screened between January 2019 and August 2021, of these 61 are enrolled to date: 52 (85 %) at VCU-MCV and 9 (15%) at VCU-CMH. Of the subjects enrolled at VCU-CMH, 33% were female, 77% Black, with a mean age of 5210 years. DISCUSSION/SIGNIFICANCE: The use of a combination of virtual/remote monitoring and guidance of local resources in this trial provides an opportunity for decentralization and access of CCTs for potential novel treatment of HF to underrepresented individuals from rural areas.

Hemodialysis (HD) and peritoneal dialysis (PD) are the primary means of managing end stage renal disease (ESRD). However, these treatment modalities are associated with the onset of coagulation abnormalities. Effective management of coagulation risk among these patients requires the identification of surrogate markers that provide an early indication of the coagulation abnormalities. The role of sphingolipids in the manifestation and prediction of coagulation abnormalities among dialysis patients have never been investigated. Herein, we report the first instance of an in depth investigation into the sphingolipid changes among ESRD patients undergoing HD and PD. The results reveal distinct differences in terms of perturbations to specific sphingolipid biosynthetic pathways that are highly dependent on the treatment modality. Our studies also demonstrated strong correlation between specific sphingolipids and coagulation parameters, such as HexCer(d18:1/26:0) and maximal amplitude (MA), SM(d18:1/24:1) and tissue factor pathway inhibitor, and sphingosine 1-phosphate d18:1 and FX (Spearman ρ of 0.93, 0.89, and −0.89, respectively). Furthermore, our study revealed the potential for using HexCer(d18:1/22:0), HexCer(d18:1/24:0), and HexCer(d18:1/26:0) (r2 = 0.71, 0.82, and 0.63, respectively) and coagulation parameter MA (r2 = 0.7) for successful diagnosis of differential coagulopathies among ESRD patients undergoing HD, providing an opportunity toward personalized disease management.

Background: Impaired cardiorespiratory fitness (CRF) is a hallmark of heart failure (HF). Serum levels of C-reactive protein (CRP), a systemic inflammatory marker, and of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of myocardial strain, independently predict adverse outcomes in HF patients. Whether CRP and/or NT-proBNP also predict the degree of CRF impairment in HF patients across a wide range of ejection fraction is not yet established.Methods: Using retrospective analysis, 200 patients with symptomatic HF who completed one or more treadmill cardiopulmonary exercise tests (CPX) using a symptom-limited ramp protocol and had paired measurements of serum high-sensitivity CRP and NT-proBNP on the same day were evaluated. Univariate and multivariate correlations were evaluated with linear regression after logarithmic transformation of CRP (log10) and NT-proBNP (logN).Results: Mean age of patients was 57 ± 10 years and 55% were male. Median CRP levels were 3.7 [1.5–9.0] mg/L, and NT-proBNP levels were 377 [106–1,464] pg/ml, respectively. Mean peak oxygen consumption (peak VO2) was 16 ± 4 mlO2•kg−1•min−1. CRP levels significantly correlated with peakVO2 in all patients (R = −0.350, p < 0.001) and also separately in the subgroup of patients with reduced left ventricular ejection fraction (LVEF) (HFrEF, N = 109) (R = −0.282, p < 0.001) and in those with preserved EF (HFpEF, N = 57) (R = −0.459, p < 0.001). NT-proBNP levels also significantly correlated with peak VO2 in all patients (R = −0.330, p < 0.001) and separately in patients with HFrEF (R = −0.342, p < 0.001) and HFpEF (R = −0.275, p = 0.032). CRP and NT-proBNP did not correlate with each other (R = 0.05, p = 0.426), but independently predicted peak VO2 (R = 0.421, p < 0.001 and p < 0.001, respectively).Conclusions: Biomarkers of inflammation and myocardial strain independently predict peak VO2 in HF patients. Anti-inflammatory therapies and therapies alleviating myocardial strain may independently improve CRF in HF patients across a large spectrum of LVEF.

OBJECTIVES/SPECIFIC AIMS: Cardiac radiation exposure following anti-cancer (CA) thoracic radiotherapy (RT) treatment increases risk of heart failure in a dose-dependent manner with a predominantly restrictive cardiomyopathy phenotype and is characterized by a diffuse fibrosis within the myocardium. The peak oxygen pulse (O2Pulse) determined at cardiopulmonary exercise testing (CPET) is the quotient of oxygen consumption (VO2) divided by the heart rate (HR) at peak exercise. Through deduction of the Fick equation (VO2 = cardiac output (CO) x arteriovenous oxygen difference) it provides a noninvasive estimate of the stroke volume response to exercise. Knowledge of the relationship between cardiac radiation dose and O2Pulse may provide mechanistic insight into the cardiac reserve of the CA survivor following thoracic RT. METHODS/STUDY POPULATION: Patients without a history of cardiovascular disease with a history of thoracic RT for CA treatment with significant incidental heart exposure (≥5 Gray (Gy) to ≥10% of the heart volume) underwent treadmill CPET to determine cardiorespiratory fitness and cardiac magnetic resonance (CMR) imaging to quantify central hemodynamics and for myocardial tissue characterization. The mean cardiac radiation dose (MCRD) and %volume of heart dose was determined from dose-volume histograms reflective of the dose contributions from all RT treatments for each patient. The oxygen pulse (milliliters (mL) of O2 per heart beat) was determined by dividing the absolute VO2 by the HR (beats per minute, bpm) at peak exercise and reported as %-predicted values to account for age and gender differences. Data are reported as number (%) or median (interquartile range). A stepwise multivariate linear regression model was created from significant univariate RT and CMR variables to determine independent predictors of %O2Pulse. RESULTS/ANTICIPATED RESULTS: Thirty patients (age = 63 [57-67] years, 18 [60%] female, 2.0 [0.1-28.7] years since completion of RT) underwent study procedures. The peak VO2=1376 mL·min-1 (62% of predicted) and peak HR = 150 (122-164) bpm resulted in a peak O2Pulse of 9.2 mL/beat (82% of predicted). The MCRD = 5.6 [3.7-17.8] Gy was inversely associated with %O2Pulse at univariate analysis (R = −0.514, p < .01), but was not retained at multivariate analysis. The CMR-derived CO ([4.9 (4.09-5.90) Liters/minute], β = +.374, p < .01), CMR-extracellular volume ([ECV, 26.9 (24.8-29.2)%], β = −.536, p < .01), and volume of the heart exposed to ≥30 Gy ([2.5 (0-15.0)Gy], (β = −.345, p = .01) were retained in the model (R2 = .709, F(3,19) = 15.438, p < .001) and were independent predictors of the %O2Pulse. DISCUSSION/SIGNIFICANCE OF IMPACT: In patients with significant heart exposure following RT, %O2Pulse (a surrogate of stroke volume response to exercise) is inversely associated with cardiac radiation dose and is related to central hemodynamics (CO) and markers of diffuse fibrosis (ECV).

OBJECTIVES/SPECIFIC AIMS: Cocaine use is a significant health problem in the United States and associated with increased risk of adverse cardiovascular outcomes. Our goal was to evaluate the effects of rapid cocaine infusions on cardiovascular hemodynamics among patients with cocaine abuse disorder. METHODS/STUDY POPULATION: Patients with a history of cocaine abuse but no overt cardiovascular disease received 4 consecutive intravenous infusions of cocaine (0, 10, 20, 40 mg) given in randomized, double-blinded order. The infusion procedure was repeated on 2 consecutive days (4 infusions each day). Following each dose, patients underwent continuous monitoring via fingertip plethysmography for 30 minutes, followed by an additional 30 minutes washout procedure. Patients were surveyed throughout this timeline to record symptoms of cocaine response. Finger tracings were then used to calculate arterial pressure curves and parameters of heart rate, blood pressure, cardiac output, stroke volume, and systemic vascular resistance according to device-specific algorithms. Mean values were calculated over the entire 30 minutes follow-up and peak values were defined as the maximum value sustained over any 60-second interval during the follow-up period. RESULTS/ANTICIPATED RESULTS: Seven patients were enrolled and received cocaine infusions of 2 consecutive days. Cocaine dose was positively associated with mean cardiac output (R=0.489, p

OBJECTIVES/SPECIFIC AIMS: Nonalcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and can exist in 2 histological subtypes: simple hepatic steatosis (SHS) and nonalcoholic steatohepatitis (NASH), a clinically aggressive variant. Fatigue is the most common complaint in patients with NAFLD but the etiology of fatigue is unknown. Thus, the goal of this study was to objectively evaluate fatigue via maximal cardiopulmonary exercise testing and identify determinants of exercise intolerance in NAFLD. METHODS/STUDY POPULATION: In total, 14 subjects with histologically confirmed NAFLD were prospectively enrolled. Subjects with cirrhosis or those with known history of heart failure (systolic or diastolic) were excluded. Fatigue was quantified via the Duke Activity Status Index (DASI) questionnaire. A symptom-limited treadmill cardiopulmonary exercise test was performed in all subjects to measure exercise time (ET) and peak oxygen consumption (peak VO2). Doppler-echocardiography was performed to measure systolic and diastolic function. RESULTS/ANTICIPATED RESULTS: The DASI score and ET was significantly reduced in patients with NASH (n=10) when compared to those with SHS [40.2 (IQR=24.2–50.7) vs. 58.2 (IQR=50.7–58.2), p=0.04]; [9.1 (IQR=6.4–12.2) vs. 13.1 (IQR=12.5–13.1) min, p=0.02, respectively] reflecting moderate fatigue and impaired overall exercise capacity. The ET was directly linked to peak VO2 (R=+0.79, p

OBJECTIVES/SPECIFIC AIMS: Our goal was to compare the ventriculo-arterial coupling and left ventricular mechanical work of patients with systolic and diastolic heart failure (SHF and DHF). METHODS/STUDY POPULATION: Patients with New York Heart Association Functional Class II-III HF symptoms were included. SHF was defined as left ventricular (LV) ejection fraction50%. Analysis of the fingertip arterial blood pressure tracing captured with a finger plethysmography cuff according to device-specific algorithms provided brachial artery blood pressure and stroke volume. LV end-systolic volume was measured separately via transthoracic echocardiography. Arterial elastance (Ea), a measure of pulsatile and nonpulsatile LV afterload, was calculated as LV end-systolic pressure (ESP)/end-diastolic volume. End-systolic elastance (Ees), a measure of load-independent LV contractility, was calculated as LV ESP/end-systolic volume. Ventriculo-arterial coupling (VAC) ratio was defined as Ea/Ees. Stroke work (SWI) was calculated as stroke volume index×LV end-systolic pressure×0.0136 and potential energy index (PEI) as 1/2×(LV end-systolic volume×LV end-systolic pressure×0.0136). Total work index (TWI) was the sum of SWI+PEI. RESULTS/ANTICIPATED RESULTS: Patients with SHF (n=52) and DHF (n=29) were evaluated. Median (IQR) age was 57 (51–64) years. There were 48 (58%) and 59 (71%) patients were male and African American, respectively. Cardiac index was 2.8 (2.2–3.2) L/minute and 3.0 (2.8–3.3) L/minute in SHF and DHF, respectively (p=0.12). Self-reported activity levels (Duke Activity Status Index, p=0.48) and heart failure symptoms (Minnesota Living with Heart Failure Questionnaire, p=0.55) were not different between SHF and DHF. Ea was significantly lower in DHF compared with SHF patients [1.3 (1.2–1.6) vs. 1.7 (1.4–2.0) mmHg; p