Increased Expression of Proinflammatory Genes in Peripheral Blood Cells Is Associated with Cardiac Cachexia in Patients with Heart Failure with Reduced Ejection Fraction.

Background: Cardiac cachexia (CC) in chronic heart failure with reduced ejection fraction (HFrEF) is characterized by catabolism and inflammation predicting poor prognosis. Levels of responsible transcription factors like signal transducer and activator of transcription (STAT)1, STAT3, suppressor of cytokine signaling (SOCS)1 and SOCS3 in peripheral blood cells (PBC) are underinvestigated in CC. Expression of mediators was related to patients' functional status, body composition (BC) and metabolic gene expression in skeletal muscle (SM). Methods: Gene expression was quantified by qRT-PCR in three cohorts: non-cachectic patients (ncCHF, n = 19, LVEF 31 ± 7%, BMI 30.2 ± 5.0 kg/m2), cachectic patients (cCHF; n = 18, LVEF 27 ± 7%, BMI 24.3 ± 2.5 kg/m2) and controls (n = 17, LVEF 70 ± 7%, BMI 27.6 ± 4.6 kg/m2). BC was assessed by dual-energy X-ray absorptiometry. Blood inflammatory markers were measured. We quantified solute carrier family 2 member 4 (SLC2A4) and protein degradation by expressions of proteasome 20S subunit beta 2 and calpain-1 catalytic subunit in SM biopsies. Results: TNF and IL-10 expression was higher in cCHF than in ncCHF and controls (all p < 0.004). cCHF had a lower fat mass index (FMI) and lower fat-free mass index (FFMI) compared to ncCHF and controls (p < 0.05). STAT1 and STAT3 expression was higher in cCHF vs. ncCHF or controls (1.1 [1.6] vs. 0.8 [0.9] vs. 0.9 [1.1] RU and 4.6 [5.5] vs. 2.5 [4.8] vs. 3.0 [4.2] RU, all ANOVA-p < 0.05). The same applied for SOCS1 and SOCS3 expression (1.1 [1.5] vs. 0.4 [0.4] vs. 0.4 [0.5] and 0.9 [3.3] vs. 0.4 [1.1] vs. 0.8 [0.9] RU, all ANOVA-p < 0.04). In cCHF, higher TNF and STAT1 expression was associated with lower FMI (r = 0.5, p = 0.053 and p < 0.05) but not with lower FFMI (p > 0.4). In ncCHF, neither cytokine nor STAT/SOCS expression was associated with BC (all p > 0.3). SLC2A4 was upregulated in SM of cCHF vs. ncCHF (p < 0.03). Conclusions: Increased STAT1, STAT3, SOCS1 and SOCS3 expression suggests their involvement in CC. In cCHF, higher TNF and STAT-1 expression in PBC were associated with lower FMI. Increased SLC2A4 in cachectic SM biopsies indicates altered glucose metabolism.

Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke: results of the prospective HEBRAS study.

BACKGROUND: Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital. METHODS: Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care. RESULTS: Among 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p<0.001). Consequently, fewer patients were classified as cryptogenic after enhanced diagnostic workup (38.5% vs 45.5%, p<0.001). Routine care included echocardiography in 228 (64.0%) patients. CMR was successfully performed in 292 (82.0%) patients and revealed more often a prespecified pathological finding compared with routine echocardiography (16.1% vs 5.3%). Furthermore, study-related ECG monitoring (median duration 162 hours (IQR 98-210)) detected AF in 16 (4.5%) patients, while routine monitoring (median duration 51 hours (IQR 34-74)) detected AF in seven (2.0%) patients. CONCLUSIONS: Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke. TRIAL REGISTRATION NUMBER: NCT02142413.

Magnetic resonance imaging of organ iron before and after correction of iron deficiency in patients with heart failure.

AIMS: Intravenous iron therapy (IVIT) is known to improve functional status in chronic heart failure (CHF) patients. The exact mechanism is not completely understood. We correlated magnetic resonance imaging (MRI) patterns of T2* iron signal in various organs to systemic iron and exercise capacity (EC) in CHF before and after IVIT. METHODS AND RESULTS: We prospectively analysed 24 patients with systolic CHF for T2* MRI pattern of the left ventricle (LV), small and large intestines, spleen, liver, skeletal muscle, and brain for iron. In 12 patients with iron deficiency (ID), we restored iron deficit by IVIT using ferric carboxymaltose. The effects after 3 months were analysed by spiroergometry and MRI. Patients with vs. without ID showed lower blood ferritin, haemoglobin (76 ± 63 vs. 196 ± 82 µg/L and 12.3 ± 1.1 vs. 14.2 ± 1.1 g/dL, all P < 0.002), and in trend a lower transferrin saturation (TSAT) (19.1 [13.1; 28.2] vs. 25.1 [21.3; 29.1] %, P = 0.05). Spleen and liver iron was lower as expressed by higher T2* value (71.8 [66.4; 93.1] vs. 36.9 [32.9; 51.7] ms, P < 0.002 and 33.5 ± 5.9 vs. 28.8 ± 3.9 ms, and P < 0.03). There was a strong trend for a lower cardiac septal iron content in ID (40.6 [33.0; 57.3] vs. 33.7 [31.3; 40.2] ms, P = 0.07). After IVIT, ferritin, TSAT, and haemoglobin increased (54 [30; 104] vs. 235 [185; 339] µg/L, 19.1 [13.1; 28.2] vs. 25.0 [21.0; 33.7] %, 12.3 ± 1.1 vs. 13.3 ± 1.3 g/L, all P < 0.04). Peak VO2 improved (18.2 ± 4.2 vs. 20.9 ± 3.8 mL/min/kg-1 , P = 0.05). Higher peak VO2 at anaerobic threshold was associated with higher blood ferritin, reflecting higher metabolic exercise capacity after therapy (r = 0.9, P = 0.0009). Increase in EC was associated with haemoglobin increase (r = 0.7, P = 0.034). LV iron increased by 25.4% (48.5 [36.2; 64.8] vs. 36.2 [32.9; 41.9] ms, P < 0.04). Spleen and liver iron increased by 46.4 and 18.2%, respectively (71.8 [66.4; 93.1] vs. 38.5 [22.4; 76.9] ms, P < 0.04 and 33.5 ± 5.9 vs. 27.4 ± 8.6 ms, P < 0.007). Iron in skeletal muscle, brain, intestine, and bone marrow remained unchanged (29.6 [28.6; 31.2] vs. 30.4 [29.7; 30.7] ms, P = 0.7, 81.0 ± 6.3 vs. 82.9 ± 9.9 ms, P = 0.6, 34.3 ± 21.4 vs. 25.3 ± 14.1 ms, P = 0.2, 9.4 [7.5; 21.8] vs. 10.3 [6.7; 15.7] ms, P = 0.5 and 9.8 ± 1.5 vs. 13.7 ± 8.9 ms, P = 0.1). CONCLUSIONS: CHF patients with ID showed lower spleen, liver, and in trend lower cardiac septal iron. After IVIT, iron signal of the left ventricle as well as spleen and liver increased. Improvement in EC was associated with increase in haemoglobin after IVIT. In ID, liver, spleen, and brain but not heart iron were associated with markers of systemic ID.

Plasma bioactive adrenomedullin predicts outcome after acute stroke in early rehabilitation.

An early and reliable prediction of outcomes after stroke is important for early effective stroke management and the adequate optimal planning of post-stroke rehabilitation and long-term care. Bioactive adrenomedullin (bio-ADM) is a 52-amino acid peptide that is an important peptide hormone in nervous system diseases. The aim of this study was to investigate the prognostic value of bio-ADM on outcomes after rehabilitation in patients with stroke. A total of 557 consecutive patients with a primary diagnosis of ischemic or hemorrhagic stroke (age 69.6-12.9 years, male 51.3%, ischemic stroke 72.5%), who were admitted to an in-patient early rehabilitation center directly after discharge from acute stroke hospital care, were enrolled in this prospective observational study. Plasma concentrations of bio-ADM were determined by using a chemiluminescence immunoassay (functional assay sensitivity 8 pg/ml). The early rehabilitation barthel index (ERBI) was used for the neurological assessment of the patients. The plasma bio-ADM level was analyzed in association with 6-month all-cause mortality as well as a composite outcome of all-cause mortality, unscheduled re-hospitalization, or transfer to a long-term care facility in a vegetative or minimally conscious state. Bio-ADM levels significantly increased in patients with ischemic stroke who died compared to surviving patients (40.4 pg/ml vs. 23.8 pg/ml, p < 0.001) or in those with composite outcomes compared to those with no events (36.9 pg/ml vs. 23.5 pg/ml, p < 0.001). Six-month all-cause mortality was higher in all patients with bio-ADM levels > 70 pg/ml (HR 4.83 [CI 2.28-10.2]). Patients with bio-ADM levels > 70 pg/ml also had higher rates of 6-month composite outcomes (HR 3.82 [CI 2.08-7.01]). Bio-ADM was an independent predictor of all-cause mortality and 6-month composite outcomes after adjusting for age, gender, and ERBI (adjusted OR 1.5; 95% CI 1.0-2.1; p = 0.047 and adjusted OR 1.48; 95% CI 1.1-2.0; p = 0.01, respectively). Bio-ADM may be a suitable novel biomarker to assess the outcomes of patients in rehabilitation after acute stroke. Elevated bio-ADM concentrations may have prognostic value for fatal and nonfatal events in patients with ischemic stroke during early rehabilitation.

Glucose-Induced Hemodynamic and Metabolic Response of Skeletal Muscle in Heart Failure Patients with Reduced vs. Preserved Ejection Fraction-A Pilot Study.

(1) Background: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) Methods: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) Results: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both p < 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls (p < 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL (p = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL (p = 0.0016); (4) Conclusion: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF.