Effect of ferric carboxymaltose on calculated plasma volume status and clinical congestion: a FAIR‐HF substudy

Iron deficiency worsens symptoms, quality of life, and exercise capacity in chronic heart failure (CHF) and might do so by promoting fluid retention. We assessed whether iron repletion improved congestion in CHF and appraised the prognostic utility of calculated plasma volume status (PVS), a novel index of congestion, in the FAIR‐HF data set. Methods and results In FAIR‐HF, 459 iron deficient CHF patients were randomized to intravenous ferric carboxymaltose (FCM) or saline and assessed at 4, 12, and 24 weeks. Using weight and haematocrit, we calculated PVS in 436 patients. At baseline, PVS and weight were −5.5 ± 7.7% and 76.9 ± 14.3 kg, with peripheral oedema evident in 35% of subjects. Higher PVS values correlated to other congestion surrogates such as lower serum albumin. At 4 weeks, FCM was associated with greater reductions in weight (0.02) and PVS (P −4% at baseline predicted worse outcomes even after adjustment for treatment assignment (hazard ratio 1.88, 95% confidence interval 1.01-3.51, 0.046). Conclusions Intravenous iron therapy with FCM is associated with early reductions in PVS and weight, implying that decongestion might be one mechanism via which iron repletion aids CHF patients. Calculated PVS is of prognostic utility in this cohort

Cardioprotective effect of the mitochondrial unfolded protein response during chronic pressure overload

Background The mitochondrial unfolded protein response (UPRmt) is activated when misfolded proteins accumulate within mitochondria and leads to increased expression of mitochondrial chaperones and proteases to maintain protein quality and mitochondrial function. Cardiac mitochondria are essential for contractile function and regulation of cell viability, while mitochondrial dysfunction characterizes heart failure. The role of the UPRmt in the heart is unclear. Objectives The purpose of this study was to: 1) identify conditions that activate the UPRmt in the heart; and 2) study the relationship among the UPRmt, mitochondrial function, and cardiac contractile function. Methods Cultured cardiac myocytes were subjected to different stresses in vitro. Mice were subjected to chronic pressure overload. Tissues and blood biomarkers were studied in patients with aortic stenosis. Results Diverse neurohumoral or mitochondrial stresses transiently induced the UPRmt in cultured cardiomyocytes. The UPRmt was also induced in the hearts of mice subjected to chronic hemodynamic overload. Boosting the UPRmt with nicotinamide riboside (which augments NAD+ pools) in cardiomyocytes in vitro or hearts in vivo significantly mitigated the reductions in mitochondrial oxygen consumption induced by these stresses. In mice subjected to pressure overload, nicotinamide riboside reduced cardiomyocyte death and contractile dysfunction. Myocardial tissue from patients with aortic stenosis also showed evidence of UPRmt activation, which correlated with reduced tissue cardiomyocyte death and fibrosis and lower plasma levels of biomarkers of cardiac damage (high-sensitivity troponin T) and dysfunction (N-terminal pro–B-type natriuretic peptide). Conclusions These results identify the induction of the UPRmt in the mammalian (including human) heart exposed to pathological stresses. Enhancement of the UPRmt ameliorates mitochondrial and contractile dysfunction, suggesting that it may serve an important protective role in the stressed heart

Effect of ferric carboxymaltose on calculated plasma volume status and clinical congestion: a FAIR-HF substudy

Aims: Iron deficiency worsens symptoms, quality of life, and exercise capacity in chronic heart failure (CHF) and might do so by promoting fluid retention. We assessed whether iron repletion improved congestion in CHF and appraised the prognostic utility of calculated plasma volume status (PVS), a novel index of congestion, in the FAIR-HF data set. Methods and results: In FAIR-HF, 459 iron deficient CHF patients were randomized to intravenous ferric carboxymaltose (FCM) or saline and assessed at 4, 12, and 24 weeks. Using weight and haematocrit, we calculated PVS in 436 patients. At baseline, PVS and weight were -5.5 ± 7.7% and 76.9 ± 14.3 kg, with peripheral oedema evident in 35% of subjects. Higher PVS values correlated to other congestion surrogates such as lower serum albumin. At 4 weeks, FCM was associated with greater reductions in weight (0.02) and PVS (P -4% at baseline predicted worse outcomes even after adjustment for treatment assignment (hazard ratio 1.88, 95% confidence interval 1.01-3.51, 0.046). Conclusions: Intravenous iron therapy with FCM is associated with early reductions in PVS and weight, implying that decongestion might be one mechanism via which iron repletion aids CHF patients. Calculated PVS is of prognostic utility in this cohort

Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial

ObjectivesThis study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.BackgroundAnemia is common in patients with CHF.MethodsIn a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin ≥9.0 to ≤12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 μg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak Vo2(ml/min), exercise duration, and health-related quality of life.ResultsDifferences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (−0.7 to 1.7) for peak Vo2(p = 0.40), 45 ml/min (−35 to 127) for absolute peak Vo2(p = 0.27), and 108 s (−11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient’s Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.ConclusionsIn patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak Vo2was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234)

Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF:a randomized, controlled, observer-blinded trial

Objectives We tested the hypothesis that intravenous iron improves exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure (CHF) and iron deficiency.Background Anemia is common in heart failure. Iron metabolism is disturbed, and administration of iron might improve both symptoms and exercise tolerance.Methods We randomized 35 patients with CHIF (age 64 +/- 13 years, peak oxygen consumption [pVo(2)] 14.0 +/- 2.7 ml/kg/ min) to 16 weeks of intravenous iron (200 mg weekly until ferritin > 500 ng/ml, 200 mg monthly thereafter) or no treatment in a 2:1 ratio. Ferritin was required to be < 100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation < 20%. Patients were stratified according to hemoglobin levels (< 12.5 g/dl [anemic group] vs. 12.5 to 14.5 g/dl [nonanemic group]). The observer-blinded primary end point was the change in absolute PVo(2).Results The difference (95% confidence interval [CI]) in the mean changes from baseline to end of study between the iron and control groups was 273 (151 to 396) ng/ml for ferritin (p < 0.0001), 0.1 (-0.8 to 0.9) g/dl for hemoglobin (p = 0.9), 96 (-12 to 205) ml/min for absolute pVo(2) (P = 0.08), 2.2 (0.5 to 4.0) ml/kg/min for pVo(2)/kg (p = 0.01), 60 (-6 to 126) s for treadmill exercise duration (p = 0.08), -0.6 (-0.9 to -0.2) for New York Heart Association (NYHA) functional class (p = 0.007), and 1.7 (0.7 to 2.6) for patient global assessment (p = 0.002). In anemic patients (n = 18), the difference (95% CI) was 204 (31 to 378) ml/min for absolute PVo(2) (P = 0.02), and 3.9 (1.1 to 6.8) ml/kg/min for pVo(2)/kg (p = 0.01). In nonanemic patients, NYHA functional class improved (p = 0.06). Adverse events were similar.Conclusions Intravenous iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism. Benefits were more evident in anemic patients. (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure; http://www.clinicaltrials.gov/ct/show/NCT00125996; NCT00125996)