Response to interleukin-1 blockade with anakinra in women and men with ST-segment elevation myocardial infarction.

BACKGROUND: Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra. METHODS: We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials. RESULTS: We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05). CONCLUSIONS: Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

Interleukin-1 blockers for the treatment of recurrent pericarditis: pathophysiology, patient reported outcomes and perspectives.

ABSTRACT: Recurrent pericarditis (RP) is the most troublesome complication of acute pericarditis reflecting an unresolving inflammation of the pericardial sac around the heart and associated with significant morbidity. Recent studies have shown interleukin-1 (IL-1) signaling to be central to the pathophysiology of cases of RP with evidence of activation of systemic inflammation. We herein review the literature and clinical trials discussing the utility of IL-1 blockade for RP. The early experience of IL-1 blockade with anakinra (Kineret) and its favorable safety profile paved the way for the clinical development of rilonacept (Arcalyst) and subsequent approval by the US FDA for RP. In patients with RP who have become colchicine-resistant and glucocorticoid-dependent, IL-1 blockade with rilonacept or anakinra effectively treats recurrences and prevents future flares, and significantly improves quality of life.

Change in Eosinophil Count in Patients with Heart Failure Treated with Anakinra.

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.

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.

Safety, Tolerability, and Effects of a Single Subcutaneous Administration of SP16 - a SERPIN-like, Small Peptide Agonist of the Low-Density Lipoprotein-like Receptor 1- on the Acute Inflammatory Response in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Modulation of the inflammatory response is a promising therapeutic strategy in acute myocardial infarction. The novel approach is based on the anti-inflammatory and cytoprotective properties mediated by the engagement of the low-density lipoprotein‒related protein 1 (LRP1) receptor. SERPIN peptide 16 (SP16) is a synthetic, selective LRP1 agonist. We herein present the results of a study with a single subcutaneous administration of SP16 in 10 patients with STEMI, to appraise its safety and tolerability and explore the effects on the acute inflammatory response, infarct size, and cardiac function. METHODS: Ten patients with ST-segment elevation myocardial infarction (STEMI) were enrolled within 12 hours of symptoms onset and 6 hours of percutaneous coronary intervention in a single-center, single-arm, open-label study of a single subcutaneous administration of SP16 (0.2 mg/kg). Serial clinical biomarkers and echocardiography data were collected up to 12 months. The data are presented separately for the treatment group and compared with historical controls from a placebo-treated arm in a recently completed clinical trial (N = 28) with similar enrollment criteria. RESULTS: All ten patients with STEMI received subcutaneous administration of SP16, 381 [272-478] minutes after percutaneous coronary intervention, without any treatment-related adverse events. The area under the curve for C-reactive protein was 133 [46-528] mg·d/L in the SP16-treated group versus 286 [141-581] mg·d/L in the historical placebo-treated group ( P = 0.161). The area under the curve for creatine kinase-myocardial band was 1432 [675-3089] ng·d/mL in the SP16-treated group versus 2367 [830-4750] ng·d/mL in the historical placebo-treated patients ( P = 0.428). Left ventricular ejection fraction was 46% [39-54] at baseline and 51% [46-58] at 1 year follow-up in SP16-treated patients (interval change 5% [-0.3% to +9%] P = 0.05) and 44% [38%-56%] at baseline and 53% [43%-59%] at 1 year follow-up in historical placebo-treated patients (interval change 3% [-5% to 10%], P = 0.305). CONCLUSION: A single subcutaneous administration of SP16, a synthetic targeted LRP1 agonist, was safe and well-tolerated in patients with STEMI. A trend toward reduction in the inflammatory response and infarct size with SP16 was noted; however, the sample size for this study was not based on formal statistical criteria. More extensive studies are planned to determine the clinical efficacy of SP16 in STEMI.NCT: NCT04225533.

Arrhythmic Recurrence and Outcomes in Patients Hospitalized With First Episode of Electrical Storm.

Electrical storm (ES) is a life-threatening condition that may lead to recurrent arrhythmias, need for ventricular mechanical support, and death. The study aimed to assess the burden of arrhythmia recurrence and in-hospital outcomes of patients admitted for ES in a large urban hospital. We performed a retrospective analysis of patients admitted with ventricular arrhythmias from January 2018 to June 2021 and identified 61 patients with ES, defined as 3 or more episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF) within 24 hours. We reviewed the in-hospital outcomes and compared outcomes between patients who had no recurrence of VT/VF after the first 24 hours (34 [56%]), those with recurrence of 1 or 2 episodes of VT/VF within a 24-hour period (15 [24%]), and patients with 3 or more recurrent VT/VF events consistent with recurrent ES after the first 24 hours (12 [20%]). Patients with recurrent ES had significantly higher in-hospital mortality as compared with those with recurrent VT/VF not meeting criteria for ES or no recurrences of VT/VF (3 [25%] vs 0 [0%] vs 0 [0%]; p = 0.002). Moreover, patients with recurrent ES also had higher rates of the combined end points of ventricular mechanical support and death (7 [58%] vs 1 [6%] vs 1 [3%], p <0.001), invasive mechanical ventilation and death (10 [83%] vs 2 [13%] vs 2 [6%], p <0.001), catheter ablation or death (12 [100%] vs 7 [47%] vs 12 [35%], p <0.001) and heart transplantation and death (3 [25%] vs 2 [13%] vs 0 [0%], p = 0.018). In conclusion, patients admitted with ES have a high risk of in-hospital recurrence, associated with extremely poor outcomes.

Pericarditis Recurrence After Initial Uncomplicated Clinical Course.

Acute pericarditis is an inflammatory disease associated with a non-negligible risk of acute complications and future recurrence. However, the exact incidence of pericarditis recurrence in patients with a first uncomplicated clinical course is unknown. We sought to evaluate the incidence and clinical predictors of recurrence after a first episode of acute uncomplicated pericarditis in a large urban hospital in the United States. We conducted a retrospective review, through electronic health records, to complete a database that includes patients admitted with a first episode of acute pericarditis and selected only those with an uncomplicated course (without in-hospital death, large pericardial effusion [>20 mm] or tamponade, constriction, or incessant pericarditis) at the VCU Medical Center (Richmond, Virginia) from 2009 to 2018. A total of 240 patients met acute pericarditis criteria: of the 240 patients, 164 patients (68%) had an uncomplicated course (median age [interquartile range] in years: 50 [32 to 62], 43% females). The median follow-up time was 186 (19 to 467) days. Pericarditis was idiopathic in 84 patients (51%). Fifteen patients (9%) had at least 1 episode of recurrent pericarditis. Compared with those without recurrence, patients with recurrent pericarditis were younger (37 [25 to 59] vs 51 [34 to 62] years, p = 0.034), had a higher prevalence of subacute/delayed presentation (2 [13%] vs 1 [1%], p = 0.023), and less frequently received colchicine (6 [40%] vs 100 [67%], p = 0.036). At multivariate logistic regression analysis, subacute presentation and younger age remained predictors of recurrence at follow-up. In conclusion, 9% of patients with acute pericarditis experienced a recurrence over a 6-month median follow-up despite an initial uncomplicated course. Younger age and subacute presentation were associated with a significantly increased risk of recurrence.

Diastolic Dysfunction Contributes to Impaired Cardiorespiratory Fitness in Patients with Lung Cancer and Reduced Lung Function Following Chest Radiation.

Cardiorespiratory fitness (CRF) is a robust and independent predictor of cardiovascular health and overall mortality. Patients with lung cancer often have chronic lung disease, contributing to impaired CRF. Radiation to the heart during lung cancer treatment may further reduce CRF. The determinants of CRF in this population are not well understood. We prospectively evaluated 12 patients with lung cancer without known cardiovascular disease with reduced lung function receiving curative intent thoracic radiotherapy to determine whether cardiac diastolic function, as assessed by Doppler echocardiography and N-terminal pro-brain natriuretic peptide (NTproBNP) levels, correlate with CRF measured by peak oxygen consumption (VO2). Doppler-derived measures of diastolic function and serum NTproBNP levels inversely correlated with peak VO2. In a multivariate regression model, NTproBNP was the strongest independent variable associated with peak VO2. These results suggest that diastolic dysfunction further contributes to reduced CRF in patients with lung cancer who have received radiotherapy.

Increased C-reactive protein is associated with the severity of thoracic radiotherapy-induced cardiomyopathy.

BACKGROUND: Irradiation of the heart during cancer radiotherapy is associated with a dose-dependent risk of heart failure. Animal studies have demonstrated that irradiation leads to an inflammatory response within the heart as well as a reduction in cardiac reserve. In the current study we aimed to evaluate whether inflammatory biomarkers correlated with changes in cardiac function and reserve after radiotherapy for breast or lung cancer. METHODS AND RESULTS: We studied 25 subjects with a history of breast or lung cancer without a prior diagnosis of cardiovascular disease or heart failure, 1.8 years [0.4-3.6] post-radiotherapy involving at least 5 Gray (Gy) to at least 10% of the heart. High-sensitivity C-reactive protein (CRP) was abnormal (≥2 mg/L) in 16 (64%) subjects. Cardiac function and reserve was measured with Doppler echocardiography before and after exercise and defined as left-ventricular ejection fraction (LVEF), early diastolic mitral annulus velocity (e'), and increase in LV outflow tract velocity time integral cardiac output (cardiac reserve) with exercise. Subjects with abnormal CRP had significantly lower LVEF (51 [44-59] % vs 61 [52-64] %, P = 0.039), lower e' (7.4 [6.6-7.9] cm/sec vs 9.9 [8.3-12.0] cm/sec, P = 0.010), and smaller cardiac reserve (+ 1.5 [1.2-1.7] L/min vs + 1.9 [1.7-2.2] L/min, P = 0.024). CONCLUSION: Elevated systemic inflammation is associated with impaired left-ventricular systolic and diastolic function both at rest and during exercise in subjects who have received radiotherapy with significant incidental heart dose for the treatment of cancer.

SHIRAZ: an automated histology image annotation system for zebrafish phenomics.

Histological characterization is used in clinical and research contexts as a highly sensitive method for detecting the morphological features of disease and abnormal gene function. Histology has recently been accepted as a phenotyping method for the forthcoming Zebrafish Phenome Project, a large-scale community effort to characterize the morphological, physiological, and behavioral phenotypes resulting from the mutations in all known genes in the zebrafish genome. In support of this project, we present a novel content-based image retrieval system for the automated annotation of images containing histological abnormalities in the developing eye of the larval zebrafish.