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.
C-C chemokine receptor 2 (CCR2) is required for monocyte chemotaxis to inflamed areas. Monocytes undergo diapedesis and differentiate into inflammatory M1 or anti- inflammatory M2 macrophages. Skewing of M1/M2 balance toward M1 may lead to sustained inflammation and disease development, including cardiovascular disease (CVD). CCR2 activation increases phosphorylation of extra-cellular regulated kinase 1 and 2 (pERK) which is necessary for M2 polarization but not M1. PURPOSE: To evaluate the differences and time course of CCR2 and pERK in fit (FIT) and unfit (UF) males following acute exercise. METHODS: 5 FIT (VO2peak ≥45ml O2/kg/min) and 5 UF (VO2peak <40ml O2/kg/min) males performed 30 minutes of cycling. Intensity was adjusted to maintain an average blood lactate concentration of 8mM/L. Blood samples were taken pre-exercise, immediately (POST), 1 hour (1H), and 2 hours (2H) post. Cells were fixed and stained using antibodies against CD14, CD16, CCR2, and pERK. Monocytes were defined by CD14 and CD16 using flow cytometry. RESULTS: A main effect for pERK (p=0.017) suggested a difference between groups. pERK increased POST in FIT (3113 [PRE] vs. 4116 [POST], p = 0.031). CCR2 was not significantly altered within groups. However, CCR2 was significantly different between groups at POST (12316 [FIT] vs. 3253 [UNFIT], p=0.001) and CCR2 was positively correlated with pERK at POST (R=0.77, p<0.02) and at 1H (R=0.94, p<0.001) with all subjects. CONCLUSION: Higher pERK in FIT males may increase monocyte recruitment and differentiation to the M2 macrophage phenotype. This likely helps maintain M1/M2 macrophage balance which may decrease the incidence of CVD.
Coronary artery disease (CAD) is an immune-mediated disease in which CCR2 attracts classical, intermediate, and non-classical monocytes to the arterial intima where they differentiate to macrophages. Balance between pro-inflammatory M1 and anti-inflammatory M2 macrophages contributes to CAD prevention. Moderate to vigorous intensity physical activity (MVPA) elicits an immune response and reduces the incidence of CAD, however, the impact of prior MVPA on monocyte subset CCR2 expression and macrophage polarization following acute exercise is unknown.
Sarcopenia impairs cardiorespiratory fitness (CRF) in patients with heart failure with reduced ejection fraction (HFrEF). Obesity has also been shown to impair CRF; however, the effects of sarcopenia on CRF in patients with obesity and HFrEF are unknown. The aim of this analysis was to examine differences in CRF between patients with sarcopenic obesity (SO) and non-SO (NSO) with HFrEF. We also assessed associations between skeletal muscle mass index (SMMI) and CRF.Forty patients with HFrEF and obesity underwent cardiopulmonary exercise testing to collect measures of CRF including peak oxygen consumption (VO2), circulatory power, oxygen uptake efficiency slope, O2 pulse, and exercise time. Body composition was performed in all patients using bioelectrical impedance analysis to quantify fat mass index and divide patients into SO and NSO based on SMMI cutoffs. Results are presented as mean (SD) or median [interquartile range] as appropriate.Nearly half (43% [n=17]) of patients had SO. Patients with SO had a lower SMMI than those with NSO, and no differences in fat mass index were observed between groups. Those with SO achieved a lower absolute peak VO2 (NSO, 1.62±0.53 L·min-1 versus SO, 1.27±0.44 L·min-1, P=0.035), oxygen uptake efficiency slope (NSO, 1.92±0.59 versus SO, 1.54±0.48, P=0.036), and exercise time (NSO, 549±198 seconds versus SO, 413±140 seconds, P=0.021) compared to those with NSO. On multivariate analysis, SMMI remained a significant predictor of absolute peak VO2 when adjusted for age, sex, adiposity, and HF severity.In patients with HFrEF and obesity, sarcopenia, defined as low SMMI, is associated with a clinically significant reduction in CRF, independent of adiposity.
Previous studies have shown that patients with heart failure with reduced ejection fraction (HFrEF) and anemia have reduced peak oxygen consumption (VO2). Black or African American (B-AA) patients have a higher prevalence of anemia and are underrepresented in clinical studies of HFrEF. The aim of this study was to determine the contribution of hemoglobin to peak VO2 in B-AA patients recently hospitalized for acute decompensated HFrEF.We analyzed cardiopulmonary exercise testing (CPX) data measured within two weeks of discharge for acute decompensated HF in B-AA patients with HFrEF (left ventricular ejection fraction [LVEF] ≤40%) without severe anemia (Hb<8 g/dL). Blood samples were collected prior to CPX. Data are reported as median [interquartile range] and compared between groups with the Mann-Whitney, Chi-Square, and Spearman's rank tests.We included 81 patients; 27 (33%) women, 57 [27-79] years of age, Body Mass Index of 33 [15-55] kg/m2 and LVEF of 30 [23-36] %. Hemoglobin ranged between 9.1 to 18.1 g/dL (median= 13.3 [11.9-14.5] g/dL); 26 (32%) were considered to have anemia based on a Hb concentration of males <13 g/dL and females <12 g/dL. Peak VO2 was lower in patients with anemia (11.8 [10.0-14.2] vs. 14.1 [10.6-17.0] mL·kg-1·min-1; P=0.010) with a significant correlation between peak VO2 and hemoglobin concentration (R=+0.455; P<0.001).Anemia is prevalent among B-AA patients with recently decompensated HFrEF and appears to be a significant contributor to reductions in peak VO2.
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 (VO 2 ) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO 2 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 Purpose – Coronary microvascular dysfunction (CMD) is common in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. Stress cardiovascular magnetic resonance (CMR) has been proposed as a non-invasive tool for detection of CMD. The aim of this study was to determine relationship between CMD and diastolic function in patients with HFpEF using a novel CMR technique. Methods – Patients with obesity and HFpEF without epicardial coronary artery disease (CAD) underwent Doppler echocardiography to measure diastolic function, followed by vasodilator stress CMR, using a single bolus, dual sequence, quantitative myocardial perfusion mapping to measure myocardial blood flow (MBF) at rest and at peak hyperemia. With this, myocardial perfusion reserve (MPR), global stress endocardial-to-epicardial (endo:epi) perfusion ratio, and total ischemic burden (IB, defined as myocardial segments with MBF < 1.94 mL/min/g) were calculated. Results are reported as median and interquartile range. Results – Nineteen subjects were enrolled (100% female, 42% Black). Median age was 64 [56–72] years. Global stress MBF was 2.43 ml/min/g [2.16–2.78] and global myocardial perfusion reserve (MPR) was 2.34 [2.07–2.88]. All had an abnormal subendocardial perfusion with an endo:epi of less than 1 (0.87 [0.81–0.90]). Regional myocardial hypoperfusion was detected in 14 (74%) patients with an IB of 6% [0-34.4]. Endo:epi ratio significantly correlated with IB (R=-0.510, p = 0.026) and measures of diastolic function (R = 0.531, p = 0.019 and R=-0.544, p = 0.014 for e’ and E/e’ respectively). Conclusion – Using a novel quantitative stress CMR myocardial perfusion mapping technique, women with obesity and HFpEF were found to have patterns of abnormal subendocardial perfusion which significantly correlated with measures of diastolic dysfunction.
