Intravenous iron therapy improves the hypercapnic ventilatory response and sleep disordered breathing in chronic heart failure

Abstract

Aims: Intravenous iron therapy can improve symptoms in patients with heart failure, anaemia and iron deficiency. The mechanisms underlying such an improvement might involve chemoreflex sensing and nocturnal breathing patterns.

Methods and results: Patients with heart failure, reduced left ventricular ejection fraction, anaemia (haemoglobin <13 g/dl in men; <12 g/dl in women) and iron deficiency (ferritin <100 or 100-299 μg/L with transferrin saturation <20%) were 2:1 randomized to patient-tailored intravenous ferric carboxymaltose dose or placebo. Chemoreflex sensitivity cardiorespiratory sleep study, symptom assessment and cardiopulmonary exercise test were performed before and 2 weeks after the last treatment dose. Fifty-eight patients (38 active arm/20 placebo arm) completed the study. Intravenous iron was associated with less severe symptoms, higher haemoglobin (12.5 ± 1.4 vs. 11.7 ± 1.0 mg/dl, p < 0.05) and improved haematinic parameters. Ferric carboxymaltose improved the central hypercapnic ventilatory response (-25.8%, p < 0.05 vs. placebo), without changes in peripheral chemosensitivity. In particular, the central hypercapnic ventilatory responses passed from 4.6 ± 6.5 to 2.9 ± 2.9 L/min/mmHg after ferric carboxymaltose and from 4.4 ± 4.6 to 4.6 ± 3.9 L/min/mmHg after placebo (p_{treatment*condition} = 0.046). In patients presenting with sleep-related breathing disorder, apnoea-hypopnoea index was reduced with active treatment as compared to placebo (12 ± 11 vs. 19 ± 13 events/h, p < 0.05). After ferric carboxymaltose, but not after placebo, both peak oxygen uptake (VO₂ ) increased (Δ1.1 ± 2.0 ml/kg/min, p < 0.05) and VO₂ /workload slope was steeper (Δ0.67 ± 1.7 L/min/W, p < 0.01).

Conclusions: Intravenous ferric carboxymaltose improves the hypercapnic ventilatory response and sleep-related breathing disorders in patients with heart failure, anaemia and iron deficiency. These newly described findings, along with improved oxygen delivery to exercising muscles, likely contribute to the favourable effects of ferric carboxymaltose in anaemic patients with heart failure.

Keywords: Anaemia; Chemoreflex; Exercise; Heart failure; Iron; Sleep.

Figure 1

Patients' flow. CV, cardiovascular.

Figure 2

Baseline chemoreflex sensitivity in the two study groups. There were no differences in chemoreflex sensitivity between the two study groups at baseline. Values are expressed as median and median absolute deviation. PetCO₂, partial end‐tidal pressure for carbon dioxide; SpO₂, peripheral oxygen saturation; VE, minute ventilation. *p < 0.05.

Figure 3

Percent variations in chemoreflex sensitivity after treatment in the two study groups. Peripheral chemoreflex sensitivity, both to oxygen and to carbon dioxide did not change in either group as a result of treatment. The central ventilatory response to carbon dioxide was improved (reduced) only in patients treated with intravenous iron. Values are expressed as median and median absolute deviation. PetCO₂, partial end‐tidal pressure for carbon dioxide; SpO₂, peripheral oxygen saturation; VE, minute ventilation. *p < 0.05.

Figure 4

Burden of sleep disordered breathing before and after treatment in the two study groups. The distribution of central, obstructive, mixed apnoeas as well as hypopnoeic events is shown. CSA, central sleep apnoea; i.v., intravenous; mixed, mixed sleep apnoea; OSA, obstructive sleep apnoea. *p < 0.05.