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 and Results: Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 mg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO(2)), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO(2) (14.6 +/- 7.6 mL/kg/minvs 17.8 +/- 8.8 mL/kg/min; P=.009) and maximal workload (89 +/- 50 watt vs 108 +/- 56 watt P=.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 <.05) and depressed RV function by tricuspid s' (P=.004), tricuspid annular plane systolic excursion (P=.034), and RV end-systolic pressure-area ratio (P=.038), with more RV-pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P=.023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 +/- 0.72 mm Hg/cm(2) vs 2.58 +/- 1.14 mm Hg/cm(2); P <.001). ID was associated with impaired peripheral oxygen extraction (peakVO(2)/peak cardiac output; P=.036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P=.611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea. Conclusions: In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.