Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Systemic vascular distensibility relates to exercise capacity in connective tissue disease.

OBJECTIVE: Exercise intolerance is a common clinical manifestation of CTD. Frequently, CTD patients have associated cardio-pulmonary disease, including pulmonary hypertension or heart failure that impairs aerobic exercise capacity (pVO2). The contribution of the systemic micro-vasculature to reduced exercise capacity in CTD patients without cardiopulmonary disease has not been fully described. In this study, we sought to examine the role of systemic vascular distensibility, α in reducing exercise capacity (i.e. pVO2) in CTD patients. METHODS: Systemic and pulmonary vascular distensibility, α (%/mmHg) was determined from multipoint systemic pressure-flow plots during invasive cardiopulmonary exercise testing with pulmonary and radial arterial catheters in place in 42 CTD patients without cardiopulmonary disease and compared with 24 age and gender matched normal controls. RESULTS: During exercise, systemic vascular distensibility, α was reduced in CTD patients compared with controls (0.20 ± 0.12%/mmHg vs 0.30 ± 0.13%/mmHg, P =0.01). The reduced systemic vascular distensibility α, was associated with impaired stroke volume augmentation. On multivariate analysis, systemic vascular distensibility, α was associated with a decreased exercise capacity (pVO2) and decreased systemic oxygen extraction. CONCLUSION: Systemic vascular distensibility, α is associated with impaired systemic oxygen extraction and decreased aerobic capacity in patients with CTD without cardiopulmonary disease.

Network Analysis to Risk Stratify Patients With Exercise Intolerance.

RATIONALE: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. OBJECTIVE: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. METHODS AND RESULTS: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P<9.5e-46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo2) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (P<0.01). Compared with a probabilistic model, including 23 independent predictors of pVo2 and pVo2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (P<0.0001; 95% CI, 2.2-8.1) and 2.8-fold (P=0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo2-adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. CONCLUSIONS: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo2 that predict hospitalization in patients with exercise intolerance.

Unexplained exertional intolerance associated with impaired systemic oxygen extraction.

PURPOSE: The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE). METHODS: We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6]. RESULTS: Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001). CONCLUSIONS: We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.

Pulmonary Vascular Resistance During Exercise Predicts Long-Term Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: In heart failure with preserved ejection fraction (HFpEF), the prognostic value of pulmonary vascular dysfunction (PV-dysfunction), identified by elevated pulmonary vascular resistance (PVR) at peak exercise, is not completely understood. We evaluated the long-term prognostic implications of PV-dysfunction in HFpEF during exercise in consecutive patients undergoing invasive cardiopulmonary exercise testing for unexplained dyspnea. METHODS: Patients with HFpEF were classified into 2 main groups: resting HFpEF (n = 104, 62% female, age 61 years) with a pulmonary arterial wedge pressure (PAWP) >15 mmHg at rest; and exercise HFpEF (eHFpEF; n = 81) with a PAWP <15 mmHg at rest, but >20 mmHg during exercise. The eHFpEF group was further subdivided into eHFpEF + PV-dysfunction (peak PVR ≥80 dynes/s/cm-5; n = 55, 60% female, age 64) group and eHFpEF - PV-dysfunction (peak PVR <80 dynes/s/cm-5; n = 26, 42% female, age 54 years) group. Outcomes were analyzed for the first 9 years of follow-up and included any cause mortality and heart failure (HF)-related hospitalizations. The mean follow-up time was 6.7 ± 2.6 years (0.5-9.0). RESULTS: Mortality rate did not differ among the groups. However, survival free of HF-related hospitalization was lower for the eHFpEF + PV-dysfunction group compared with eHFpEF - PV-dysfunction (P = .01). These findings were similar between eHFpEF + PV-dysfunction and the resting HFpEF group (P = .774). By Cox analysis, peak PVR ≥80 dynes/s/cm-5 was a predictor of HF-related hospitalization for eHFpEF (hazard ratio 5.73, 95% confidence interval 1.05-31.22, P = .01). In conclusion, the present study provides insight into the impact of PV-dysfunction on outcomes of patients with exercise-induced HFpEF. An elevated peak PVR is associated with a high risk of HF-related hospitalization.

Right ventriculo-arterial uncoupling and impaired contractile reserve in obese patients with unexplained exercise intolerance.

BACKGROUND: Right 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). METHODS: RV-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. RESULTS: Both 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). CONCLUSIONS: Exercise 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.

Pulmonary haemodynamics during recovery from maximum incremental cycling exercise.

Assessment of cardiac function during exercise can be technically demanding, making the recovery period a potentially attractive diagnostic window. However, the validity of this approach for exercise pulmonary haemodynamics has not been validated.The present study, therefore, evaluated directly measured pulmonary haemodynamics during 2-min recovery after maximum invasive cardiopulmonary exercise testing in patients evaluated for unexplained exertional intolerance. Based on peak exercise criteria, patients with exercise pulmonary hypertension (ePH; n=36), exercise pulmonary venous hypertension (ePVH; n=28) and age-matched controls (n=31) were analysed.By 2-min recovery, 83% (n=30) of ePH patients had a mean pulmonary artery pressure (mPAP) <30 mmHg and 96% (n=27) of ePVH patients had a pulmonary arterial wedge pressure (PAWP) <20 mmHg. Sensitivity of pulmonary hypertension-related haemodynamic measurements during recovery for ePH and ePVH diagnosis was ≤25%. In ePVH, pulmonary vascular compliance (PVC) returned to its resting value by 1-min recovery, while in ePH, elevated pulmonary vascular resistance (PVR) and decreased PVC persisted throughout recovery.In conclusion, we observed that mPAP and PAWP decay quickly during recovery in ePH and ePVH, compromising the sensitivity of recovery haemodynamic measurements in diagnosing pulmonary hypertension. ePH and ePVH had different PVR and PVC recovery patterns, suggesting differences in the underlying pulmonary hypertension pathophysiology.

Age-related upper limits of normal for maximum upright exercise pulmonary haemodynamics.

The exercise definition of pulmonary hypertension was eliminated from the pulmonary hypertension guidelines in part due to uncertainty of the upper limits of normal (ULNs) for exercise haemodynamics in subjects >50 years old.The present study, therefore, evaluated the pulmonary haemodynamic responses to maximum upright incremental cycling exercise in consecutive subjects who underwent an invasive cardiopulmonary exercise testing for unexplained exertional intolerance, deemed normal based on preserved exercise capacity and normal resting supine haemodynamics. Subjects aged >50 years old (n=41) were compared with subjects ≤50 years old (n=25). ULNs were calculated as mean + 2 sdPeak exercise mean pulmonary arterial pressure was not different for subjects >50 and ≤50 years old (23 ± 5 versus 22 ± 4 mmHg, p=0.22), with ULN of 33 and 30 mmHg, respectively. Peak cardiac output was lower in older subjects (median (interquartile range): 12.1 (9.4-14.2)versus16.2 (13.8-19.2) L·min(-1), p<0.001). Peak pulmonary vascular resistance was higher in older subjects compared with younger subjects (mean ± sd: 1.20 ± 0.45 versus 0.82 ± 0.26 Wood units, p<0.001), with ULN of 2.10 and 1.34 Wood units, respectively.We observed that subjects >50 and ≤ 50 years old have different pulmonary vascular responses to exercise. Older subjects have higher pulmonary vascular resistance at peak exercise, resulting in different exercise haemodynamics ULNs compared with the younger population.

Measuring central pulmonary pressures during exercise in COPD: how to cope with respiratory effects.

Respiratory influences are major confounders when evaluating central haemodynamics during exercise. We studied four different methods to assess mean pulmonary artery pressure (mPAP) and pulmonary capillary wedge pressure (PCWP) in cases of respiratory swings. Central haemodynamics were measured simultaneously with oesophageal pressure during exercise in 30 chronic obstructive pulmonary disease (COPD) patients. mPAP and PCWP were assessed at the end of expiration, averaged over the respiratory cycle and corrected for the right atrial pressure (RAP) waveform estimated intrathoracic pressure, and compared with the transmural pressures. Bland-Altman analyses showed the best agreement of mPAP averaged over the respiratory cycle (bias (limits of agreement) 2.5 (-6.0-11.8) mmHg) and when corrected with the nadir of RAP (-3.6 (-11.2-3.9) mmHg). Measuring mPAP at the end of expiration (10.3 (0.5-20.3) mmHg) and mPAP corrected for the RAP swing (-9.3 (-19.8-2.1) mmHg) resulted in lower levels of agreement. The respiratory swings in mPAP and PCWP were similar (r(2)=0.82, slope ± se 0.95 ± 0.1). Central haemodynamics measured at the end of expiration leads to an overestimation of intravascular pressures in exercising COPD patients. Good measurement can be acquired even when oesopghageal pressure is omitted, by averaging pressures over the respiratory cycle or using the RAP waveform to correct for intrathoracic pressure. Assessment of the pulmonary gradient is unaffected by respiratory swings.

SPECTRA Phase 2b Study: Impact of Sotatercept on Exercise Tolerance and Right Ventricular Function in Pulmonary Arterial Hypertension.

BACKGROUND: This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension. METHODS: SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function. RESULTS: Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P=0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function. CONCLUSIONS: The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150.

Mismatch between subjective and objective dysautonomia.

Autonomic symptom questionnaires are frequently used to assess dysautonomia. It is unknown whether subjective dysautonomia obtained from autonomic questionnaires correlates with objective dysautonomia measured by quantitative autonomic testing. The objective of our study was to determine correlations between subjective and objective measures of dysautonomia. This was a retrospective cross-sectional study conducted at Brigham and Women's Faulkner Hospital Autonomic Laboratory between 2017 and 2023 evaluating the patients who completed autonomic testing. Analyses included validated autonomic questionnaires [Survey of Autonomic Symptoms (SAS), Composite Autonomic Symptom Score 31 (Compass-31)] and standardized autonomic tests (Valsalva maneuver, deep breathing, sudomotor, and tilt test). The autonomic testing results were graded by a Quantitative scale for grading of cardiovascular reflexes, sudomotor tests and skin biopsies (QASAT), and Composite Autonomic Severity Score (CASS). Autonomic testing, QASAT, CASS, and SAS were obtained in 2627 patients, and Compass-31 in 564 patients. The correlation was strong between subjective instruments (SAS vs. Compass-31, r = 0.74, p < 0.001) and between objective instruments (QASAT vs. CASS, r = 0.81, p < 0.001). There were no correlations between SAS and QASAT nor between Compass-31 and CASS. There continued to be no correlations between subjective and objective instruments for selected diagnoses (post-acute sequelae of COVID-19, n = 61; postural tachycardia syndrome, 211; peripheral autonomic neuropathy, 463; myalgic encephalomyelitis/chronic fatigue syndrome, 95; preload failure, 120; post-treatment Lyme disease syndrome, 163; hypermobile Ehlers-Danlos syndrome, 213; neurogenic orthostatic hypotension, 86; diabetes type II, 71, mast cell activation syndrome, 172; hereditary alpha tryptasemia, 45). The lack of correlation between subjective and objective instruments highlights the limitations of the commonly used questionnaires with some patients overestimating and some underestimating true autonomic deficit. The diagnosis-independent subjective-objective mismatch further signifies the unmet need for reliable screening surveys. Patients who overestimate the symptom burden may represent a population with idiosyncratic autonomic-like symptomatology, which needs further study. At this time, the use of autonomic questionnaires as a replacement of autonomic testing cannot be recommended.

Deep learned representations of the resting 12-lead electrocardiogram to predict at peak exercise.

AIMS: To leverage deep learning on the resting 12-lead electrocardiogram (ECG) to estimate peak oxygen consumption (V˙O2peak) without cardiopulmonary exercise testing (CPET). METHODS AND RESULTS: V ˙ O 2 peak estimation models were developed in 1891 individuals undergoing CPET at Massachusetts General Hospital (age 45 ± 19 years, 38% female) and validated in a separate test set (MGH Test, n = 448) and external sample (BWH Test, n = 1076). Three penalized linear models were compared: (i) age, sex, and body mass index ('Basic'), (ii) Basic plus standard ECG measurements ('Basic + ECG Parameters'), and (iii) basic plus 320 deep learning-derived ECG variables instead of ECG measurements ('Deep ECG-V˙O2'). Associations between estimated V˙O2peak and incident disease were assessed using proportional hazards models within 84 718 primary care patients without CPET. Inference ECGs preceded CPET by 7 days (median, interquartile range 27-0 days). Among models, Deep ECG-V˙O2 was most accurate in MGH Test [r = 0.845, 95% confidence interval (CI) 0.817-0.870; mean absolute error (MAE) 5.84, 95% CI 5.39-6.29] and BWH Test (r = 0.552, 95% CI 0.509-0.592, MAE 6.49, 95% CI 6.21-6.67). Deep ECG-V˙O2 also outperformed the Wasserman, Jones, and FRIEND reference equations (P < 0.01 for comparisons of correlation). Performance was higher in BWH Test when individuals with heart failure (HF) were excluded (r = 0.628, 95% CI 0.567-0.682; MAE 5.97, 95% CI 5.57-6.37). Deep ECG-V˙O2 estimated V˙O2peak <14 mL/kg/min was associated with increased risks of incident atrial fibrillation [hazard ratio 1.36 (95% CI 1.21-1.54)], myocardial infarction [1.21 (1.02-1.45)], HF [1.67 (1.49-1.88)], and death [1.84 (1.68-2.03)]. CONCLUSION: Deep learning-enabled analysis of the resting 12-lead ECG can estimate exercise capacity (V˙O2peak) at scale to enable efficient cardiovascular risk stratification.

Researchers here present data describing a method of estimating exercise capacity from the resting electrocardiogram. Electrocardiogram estimation of exercise capacity was accurate and was found to predict the onset of the wide range of cardiovascular diseases including heart attacks, heart failure, arrhythmia, and death.This approach offers the ability to estimate exercise capacity without dedicated exercise testing and may enable efficient risk stratification of cardiac patients at scale.

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Postacute Sequelae of SARS-CoV-2: More in Common Than Not?

TOPIC IMPORTANCE: Postacute sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from COVID-19. Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood. REVIEW FINDINGS: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms. SUMMARY: This review illustrates exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Common Data Element item content analysis.

INTRODUCTION: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem chronic disease estimated to affect 836,000-2.5 million individuals in the United States. Persons with ME/CFS have a substantial reduction in their ability to engage in pre-illness levels of activity. Multiple symptoms include profound fatigue, post-exertional malaise, unrefreshing sleep, cognitive impairment, orthostatic intolerance, pain, and other symptoms persisting for more than 6 months. Diagnosis is challenging due to fluctuating and complex symptoms. ME/CFS Common Data Elements (CDEs) were identified in the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) Common Data Element Repository. This study reviewed ME/CFS CDEs item content. METHODS: Inclusion criteria for CDEs (measures recommended for ME/CFS) analysis: 1) assesses symptoms; 2) developed for adults; 3) appropriate for patient reported outcome measure (PROM); 4) does not use visual or pictographic responses. Team members independently reviewed CDEs item content using the World Health Organization International Classification of Functioning, Disability and Health (ICF) framework to link meaningful concepts. RESULTS: 119 ME/CFS CDEs (measures) were reviewed and 38 met inclusion criteria, yielding 944 items linked to 1503 ICF meaningful concepts. Most concepts linked to ICF Body Functions component (b-codes; n = 1107, 73.65%) as follows: Fatiguability (n = 220, 14.64%), Energy Level (n = 166, 11.04%), Sleep Functions (n = 137, 9.12%), Emotional Functions (n = 131, 8.72%) and Pain (n = 120, 7.98%). Activities and Participation concepts (d codes) accounted for a smaller percentage of codes (n = 385, 25.62%). Most d codes were linked to the Mobility category (n = 69, 4.59%) and few items linked to Environmental Factors (e codes; n = 11, 0.73%). DISCUSSION: Relatively few items assess the impact of ME/CFS symptoms on Activities and Participation. Findings support development of ME/CFS-specific PROMs, including items that assess activity limitations and participation restrictions. Development of psychometrically-sound, symptom-based item banks administered as computerized adaptive tests can provide robust assessments to assist primary care providers in the diagnosis and care of patients with ME/CFS.

Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise.

BACKGROUND: Exercise oscillatory ventilation (EOV) is a noninvasive parameter that potently predicts outcomes in systolic heart failure (HF). However, mechanistic insights into EOV have been limited by the absence of studies relating EOV to invasive hemodynamic measurements and blood gases performed during exercise. METHODS AND RESULTS: Fifty-six patients with systolic HF (mean±SEM age, 59±2 years; left ventricular ejection fraction, 30±1%) and 19 age-matched control subjects were studied with incremental cardiopulmonary exercise testing. Fick cardiac outputs, filling pressures, and arterial blood gases were measured at 1-minute intervals during exercise. We detected EOV in 45% of HF (HF+EOV) patients and in none of the control subjects. The HF+EOV group did not differ from the HF patients without EOV (HF-EOV) in age, sex, body mass index, left ventricular ejection fraction, or origin of HF. Univariate predictors of the presence of EOV in HF, among measurements performed during exercise, included higher right atrial pressure and pulmonary capillary wedge pressure and lower cardiac index (CI) but not Paco2 or Pao2. Multivariate logistic regression identified that low exercise CI is the strongest predictor of EOV (odds ratio, 1.39 for each 1.0-L · min(-1) · m(-2) decrement in CI; 95% confidence interval, 1.14-1.70; P=0.001). Among HF patients with EOV, exercise CI was inversely related to EOV cycle length (R=-0.71) and amplitude (R=-0.60; both P<0.001). In 11 HF+EOV subjects treated with 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to increases in CI. CONCLUSION: Exercise oscillatory ventilation is closely related to reduced CI and elevated filling pressures during exercise and may be an important surrogate for exercise-induced hemodynamic impairment in HF patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Persistent Exertional Intolerance After COVID-19: Insights From Invasive Cardiopulmonary Exercise Testing.

BACKGROUND: Some patients with COVID-19 who have recovered from the acute infection after experiencing only mild symptoms continue to exhibit persistent exertional limitation that often is unexplained by conventional investigative studies. RESEARCH QUESTION: What is the pathophysiologic mechanism of exercise intolerance that underlies the post-COVID-19 long-haul syndrome in patients without cardiopulmonary disease? STUDY DESIGN AND METHODS: This study examined the systemic and pulmonary hemodynamics, ventilation, and gas exchange in 10 patients who recovered from COVID-19 and were without cardiopulmonary disease during invasive cardiopulmonary exercise testing (iCPET) and compared the results with those from 10 age- and sex-matched control participants. These data then were used to define potential reasons for exertional limitation in the cohort of patients who had recovered from COVID-19. RESULTS: The patients who had recovered from COVID-19 exhibited markedly reduced peak exercise aerobic capacity (oxygen consumption [VO2]) compared with control participants (70 ± 11% predicted vs 131 ± 45% predicted; P < .0001). This reduction in peak VO2 was associated with impaired systemic oxygen extraction (ie, narrow arterial-mixed venous oxygen content difference to arterial oxygen content ratio) compared with control participants (0.49 ± 0.1 vs 0.78 ± 0.1; P < .0001), despite a preserved peak cardiac index (7.8 ± 3.1 L/min vs 8.4±2.3 L/min; P > .05). Additionally, patients who had recovered from COVID-19 demonstrated greater ventilatory inefficiency (ie, abnormal ventilatory efficiency [VE/VCO2] slope: 35 ± 5 vs 27 ± 5; P = .01) compared with control participants without an increase in dead space ventilation. INTERPRETATION: Patients who have recovered from COVID-19 without cardiopulmonary disease demonstrate a marked reduction in peak VO2 from a peripheral rather than a central cardiac limit, along with an exaggerated hyperventilatory response during exercise.

Neurovascular Dysregulation and Acute Exercise Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Placebo-Controlled Trial of Pyridostigmine.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, postexertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS. RESEARCH QUESTION: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS, and can its treatment improve exercise capacity? STUDY DESIGN AND METHODS: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60-mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 min later. The primary end point was the difference in peak exercise oxygen uptake (Vo2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange. RESULTS: Twenty-three subjects were assigned to receive pyridostigmine and 22 to receive placebo. The peak Vo2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs -40.2 ± 21.3 mL/min; P < .05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak vs rest Vo2 (25.9 ± 15.3 mL/min vs -60.8 ± 25.6 mL/min; P < .01), cardiac output (-0.2 ± 0.6 L/min vs -1.9 ± 0.6 L/min; P < .05), and right atrial pressure (1.0 ± 0.5 mm Hg vs -0.6 ± 0.5 mm Hg; P < .05) were greater in the pyridostigmine group compared with placebo. INTERPRETATION: Pyridostigmine improves peak Vo2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise Vo2, cardiac output, and right atrial pressure following placebo may signal the onset of postexertional malaise. We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03674541; URL: www. CLINICALTRIALS: gov.