Iron deficiency is associated with impaired biventricular reserve and reduced exercise capacity in patients with unexplained dyspnea

BACKGROUND: Iron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear.

METHODS: Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography (CPETecho) in a tertiary care dyspnea clinic. ID was defined as ferritin <300µg/l and transferrin saturation (TSAT)<20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed.

RESULTS: Of 272 CPETecho patients, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6±7.6 vs 17.8±8.8ml/kg/min; p=0.009) and maximal workload (89±50 vs 108±56 watt p=0.047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (p<0.05) and depressed RV function by tricuspid s' (p=0.004), tricuspid annular plane systolic excursion (TAPSE; p=0.034) and RV end-systolic pressure-area ratio (RVESPAR; p=0.038), with more RV-pulmonary artery uncoupling measured by TAPSE/systolic pulmonary arterial pressure ratio (p=0.023). RVESPAR change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09±0.72 vs. 2.58±1.14 mmHg/cm2; p<0.001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; p=0.036). CPETecho resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio above 14, with equal distribution in patients with (28.6%) or without ID (25.4%, p=0.611). None of the aforementioned findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea.

CONCLUSION: In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with reduced exercise capacity, diminished biventricular contractile reserve and reduced peripheral oxygen extraction.