BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in approximately 50% of POTS and fibromyalgia patients.RESEARCH QUESTION: Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN? STUDY DESIGN AND METHODS: We analyzed 1,516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mm Hg, results from 160 patients meeting ME/CFS criteria who had skin biopsy test results were compared with 36 control subjects. Restto-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 AE 2 vs 8.3 AE 1.5; P < .0001) and peak VO 2 (80% AE 21% vs 101.4% AE 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% AE 19% vs 99.5% AE 23.8% vs 99.9% AE 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low-and normal-flow participants (0.74% AE 0.1% vs 0.88 AE 0.11 vs 0.86 AE 0.1; P < .0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% were consistent with SFN (epidermal innervation #5.0% of predicted; P < .0001). Denervation severity did not correlate with exertional measures.

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13–16, 17–20, and 21–24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13–16, 17–20, and 21–24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.

BackgroundRight ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV–arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH).MethodsRV–arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese−ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure < 15 mmHg but ≥ 20 mmHg on exercise. Exercise haemodynamics were further evaluated in 18 controls, 20 Obese−ePVH and 17 Obese+ePVH patients.ResultsBoth Obese−ePVH and Obese+ePVH groups developed exercise RV–arterial uncoupling (peak Ees/Ea = 1.45 ± 0.26 vs 0.67 ± 0.18 vs 0.56 ± 0.11, p < 0.001, controls vs Obese−ePVH vs Obese+ePVH respectively) with higher peak afterload (peak Ea = 0.31 ± 0.07 vs 0.75 ± 0.32 vs 0.88 ± 0.62 mL/mmHg, p = 0.043) and similar peak contractility (peak Ees = 0.50 ± 0.16 vs 0.45 ± 0.22 vs 0.48 ± 0.17 mL/mmHg, p = 0.89). RV contractile reserve was highest in controls (ΔEes = 224 ± 80 vs 154 ± 39 vs 141 ± 34% of baseline respectively, p < 0.001). Peak Ees/Ea correlated with peak pulmonary vascular compliance (PVC, r = 0.53, p = 0.02) but not peak pulmonary vascular resistance (PVR, r = − 0.20, p = 0.46). In the larger cohort, Obese+ePVH patients on exercise demonstrated higher right atrial pressure, lower cardiac output and steeper pressure-flow responses. BMI correlated with peak PVC (r = − 0.35, p = 0.04) but not with peak PVR (r = 0.24, p = 0.25).ConclusionsExercise RV–arterial uncoupling and reduced RV contractile reserve further characterise obesity-related exercise intolerance. RV dysfunction in obesity may develop independent of exercise LV filling pressures.