Acute, but not chronic, aerobic exercise alters the impact of ex vivo LDL and fatty acid stimulation on monocytes and macrophages from healthy, young adults.

BACKGROUND: Elevated low-density lipoprotein (LDL) and triglyceride concentrations are associated with future cardiovascular risk in young adults. Conversely, chronic physical activity is generally accepted to reduce CVD risk. Atherosclerosis is a major underlying cause of CVD, and atherogenesis is mediated by peripheral monocytes and monocyte-derived macrophages. The study aimed to determine if an individual's physical activity level impacts the phenotype of monocytes and monocyte-derived macrophages when stimulated with LDL and fatty acid ex vivo. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from healthy, young adults of differing physical activity levels before and after a single bout of moderate intensity exercise (25 min at 60% of VO2peak). PBMCs were stimulated with LDL and palmitate ex vivo prior to differentiation into macrophages. Monocyte subset percentages and monocyte-derived macrophage expression of phenotypic (CD86, CD206) and functional (CCR2, ERK 1/2) markers were evaluated by flow cytometry. RESULTS: Compared to baseline, ex vivo LDL and palmitate stimulation decreased (p = 0.038) non-classical monocyte percentage from 24.7 ± 3.2 to 21.5 ± 2.6% in all participants. When ex vivo lipid stimulation was preceded by acute exercise, non-classical monocyte percentage was similar to baseline levels (p = 0.670, 25.8 ± 2.15%). Macrophage CD86/CD206 was increased from 1.30 ± 0.14 to 1.68 ± 0.19 when preceded by acute exercise in all participants. No differences were observed between participants of differing physical activity levels. CONCLUSIONS: Findings suggest that acute exercise modulates monocyte phenotype after LDL and palmitate stimulation in a protective manner, however, chronic physical activity does not alter monocyte/macrophage responses to any experimental condition in this population.

Abnormal left ventricular subendocardial perfusion and diastolic function in women with obesity and heart failure and preserved ejection fraction.

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.

Contribution of hemoglobin concentration to cardiorespiratory fitness in black African American patients with recently decompensated heart failure and reduced ejection fraction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Anemia is prevalent among B-AA patients with recently decompensated HFrEF and appears to be a significant contributor to reductions in peak VO2.

Sarcopenic Obesity Is Associated With Reduced Cardiorespiratory Fitness Compared With Nonsarcopenic Obesity in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In patients with HFrEF and obesity, sarcopenia, defined as low SMMI, is associated with a clinically significant reduction in CRF, independent of adiposity.

LPS differentially affects expression of CD14 and CCR2 in monocyte subsets of Post-STEMI patients with hyperglycemia.

AIMS: Following ST-segment elevation myocardial infarction (STEMI), recruitment and activation of monocytes [classical (CD14++CD16-CCR2++), intermediate (CD14++CD16+CCR2+), non-classical (CD14LowCD16++CCR2Low)] are needed for myocardial wound healing. Monocyte surface receptor CC chemokine receptor type 2 (CCR2) is responsible for monocyte chemotaxis to sites of inflammation and the lipopolysaccharide (LPS)-binding protein co-receptor, CD14, is involved in pro-inflammatory monocyte activation. The purpose of this investigation was to determine the effects of ex-vivo LPS activation on monocyte subset CD14 and CCR2 expression in post-STEMI individuals with normal and elevated random blood glucose. METHODS: Post-STEMI subjects were identified as normal random glucose (NG, <98 mg/dL, n = 13) or impaired random glucose (IG, ≥98 mg/dL, n = 26) and monocytes were analyzed for non-activated and LPS-activated (1 µg/mL for 4 h) CCR2 and CD14 expression. RESULTS: Non-activated intermediate monocytes from IG showed decreased CD14 expression when compared to NG, which was maintained following LPS-activation. The NG group showed a larger absolute reduction in classical CCR2 expression, leading to a significant difference between NG and IG following LPS-activation. CONCLUSION: Results suggest a heightened response to pro-inflammatory activation in IG following STEMI, which may impair or delay post-STEMI myocardial healing, and thus increase the incidence of chronic heart failure. NIH 1R34HL121402.

Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study.

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.

Sex differences in monocyte CCR2 expression and macrophage polarization following acute exercise.

Monocyte chemokine receptor 2 (CCR2) and phosphorylated extra-cellular regulated kinase 1 & 2 (ERK1/2) impact macrophage differentiation and progression of atherosclerosis. Whereas aerobic exercise favorably modulates the immune system and reduces atherosclerotic risk, it is unknown whether sex differences exist in the monocyte/macrophage response to acute aerobic exercise. AIMS: To determine the impact of an acute bout of moderate intensity aerobic exercise on monocyte and macrophage CCR2 expression, ERK1/2 phosphorylation, and macrophage polarization in pre-menopausal women and men. MATERIALS AND METHODS: Blood samples were collected in 24 people (Women/Men; n = 12) prior to (PRE), immediately after a bout of moderate intensity cycle ergometry (POST), and 2 h (2H) following exercise. Monocyte and macrophage CCR2 and phosphorylated ERK1/2 as well as macrophage CD86 and CD206 were analyzed by flow cytometry. KEY FINDINGS: PRE classical monocyte CCR2 expression was greater in women compared to men (Women: 20546.2 ± 2306.4 vs. Men: 14437.6 ± 1201.9 AUF; p = 0.028) and was reduced in women at 2H (PRE: 20546.2 ± 2306.4 vs. 2H: 15856.9 ± 1314.4 AUF; p = 0.027). POST classical monocyte CCR2 expression was inversely associated (r = -0.697, p = 0.012) with POST classical monocyte ERK1/2 phosphorylation in women only. The percentage of CCR2+ macrophages was lower in women at POST (Women: 62.0 ± 8.9 vs. Men: 83.6 ± 3.1; p = 0.031) and at 2H (Women: 60.3 ± 8.4 vs. Men: 83.5 ± 3.0%; p = 0.016). SIGNIFICANCE: These data suggest that a single bout of moderate intensity aerobic exercise differentially impacts monocyte CCR2 expression and macrophage polarization in women compared to men.

Patient Perceptions of Exertion and Dyspnea With Interleukin-1 Blockade in Patients With Recently Decompensated Systolic Heart Failure.

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; ß = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; ß = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF.

Heart failure clinical trial enrollment at a rural satellite hospital.

INTRODUCTION: Heart failure is a clinical condition that notably affects the lives of patients in rural areas. Partnering of a rural satellite hospital with an urban academic medical center may provide geographically underrepresented populations with heart failure an opportunity to access to controlled clinical trials (CCTs). METHODS: 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 and assigned to treatment with an anti-inflammatory drug for heart failure or placebo. We used the electronic health record and remote guidance and oversight from the VCU-MCV resources using a close-loop communication network to work with local resources at the facility to perform screening, consenting and enrollment. RESULTS: One hundred subjects with recently decompensated heart failure 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. CONCLUSION: 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 heart failure to underrepresented individuals from rural areas. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797001.

Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART).

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.

Preservation of Cardiac Reserve and Cardiorespiratory Fitness in Patients With Acute De Novo Versus Acute on Chronic Heart Failure With Reduced Ejection Fraction.

There is limited understanding on the potential differences in the pathophysiology between de novo heart failure with reduced ejection fraction (HFrEF) and acute on chronic HFrEF. The aim of this study was to assess differences in cardiorespiratory fitness (CRF) parameters between de novo heart failure and acute on chronic HFrEF using cardiopulmonary exercise testing (CPX). We retrospectively analyzed CPX data measured within 2 weeks of discharge following acute hospitalization for HFrEF. Data are reported as median and interquartile range or frequency and percentage (%). We included 102 patients: 32 (31%) women, 81 (79%) black, 57 (51 to 64) years of age, BMI of 34 (29 to 39) Kg/m2. Of these, 26 (25%) had de novo HFrEF and 76 (75%) had acute on chronic HFrEF. When compared with acute on chronic, patients with de novo HFrEF had a significantly higher peak oxygen consumption (VO2) (16.5 [12.2 to 19.4] vs 12.8 [10.1 to 15.3] ml·kg-1·min-1, p <0.001), %-predicted peak VO2 (58% [51 to 75] vs 49% [42 to 59]) p = 0.012), peak heart rate (134 [117 to 147] vs 117 [104 to 136] beats/min, p = 0.004), peak oxygen pulse (12.2 [10.5 to 15.5] vs 9.9 [8.0 to 13.1] ml/beat, p = 0.022) and circulatory power (2,823 [1,973 to 3,299] vs 1,902 [1,372 to 2,512] mm Hg·ml·kg-1·min-1, p = 0.002). No significant difference in resting left ventricular ejection fraction was found between groups. In conclusion, patients with de novo HFrEF have better CRF parameters than those with acute on chronic HFrEF. These differences are not explained by resting left ventricular systolic function but may be related to greater preservation in cardiac reserve during exercise in de novo HFrEF patients.

Clinical trial enrollment at a rural satellite hospital during COVID-19 pandemic.

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.

Cardiopulmonary exercise testing during the COVID-19 pandemic.

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has presented a global public health emergency. Although predominantly a pandemic of acute respiratory disease, corona virus infectious disease-19 (COVID-19) results in multi-organ damage that impairs cardiopulmonary (CP) function and reduces cardiorespiratory fitness. Superimposed on the CP consequences of COVID-19 is a marked reduction in physical activity that exacerbates CP disease (CPD) risk. CP exercise testing (CPET) is routinely used in clinical practice to diagnose CPD and assess prognosis; assess cardiovascular safety for rehabilitation; and delineate the physiological contributors to exercise intolerance and exertional fatigue. As such, CPET plays an important role in clinical assessments of convalescent COVID-19 patients as well as research aimed at understanding the long-term health effects of SARS-CoV-2 infection. However, due to the ventilatory expired gas analysis involved with CPET, the procedure is considered an aerosol generating procedure. Therefore, extra precautions should be taken by health care providers and exercise physiologists performing these tests. This paper provides recommendations for CPET testing during the COVID-19 pandemic. These recommendations include indications for CPET; pre-screening assessments; precautions required for testing; and suggested decontamination protocols. These safety recommendations are aimed at preventing SARS-CoV-2 transmission during CPET.

A phase 1 clinical trial of SP16, a first-in-class anti-inflammatory LRP1 agonist, in healthy volunteers.

BACKGROUND: Endogenous 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. METHODS: A 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). RESULTS: Treatment 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. CONCLUSION: A one-time treatment with SP16 for doses up to 0.2 mg/kg or 12 mg was safe in healthy volunteers.

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

ABSTRACT: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Impact of physical activity on monocyte subset CCR2 expression and macrophage polarization following moderate intensity exercise.

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. Purpose: To determine the impact of physical activity status on monocyte subset CCR2 surface expression and macrophage polarization in response to an acute bout of moderate intensity cycle ergometry. Methods: 24 healthy women and men (12 high physically active [HIACT]: ≥1500 METmin/wk MVPA & 12 low physically active [LOACT]: <600 METmin/wk MVPA) underwent an acute moderate intensity (60% VO2peak) bout of cycle ergometry for 30 â€‹min. Blood samples were collected prior to (PRE), immediately (POST), 1 â€‹h (1H), and 2 â€‹h (2H) following exercise. Monocyte CCR2 and macrophage CD86 (M1) and CD206 (M2) were analyzed by flow cytometry. Results: Intermediate monocyte CCR2 decreased in response to exercise in the HIACT group (PRE: 11409.0 â€‹± â€‹1084.0 vs. POST: 9524.3 â€‹± â€‹1062.4; p â€‹= â€‹0.034). Macrophage CD206 was lower in the LOACT compared to the HIACT group at 1H (HIACT: 67.2 â€‹± â€‹5.6 vs. LOACT: 50.1 â€‹± â€‹5.2%; p â€‹= â€‹0.040). Macrophage CD206 at 1H was associated with both PRE (r â€‹= â€‹0.446, p â€‹= â€‹0.043) and POST (r â€‹= â€‹0.464, p â€‹= â€‹0.034) non-classical monocyte CCR2. Conclusion: These data suggest that regular moderate to vigorous physical activity positively impacts both monocytes and macrophages following acute moderate intensity exercise and that this impact may contribute to the prevention of coronary artery disease.