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.

Clinical utility of ventilatory and gas exchange evaluation during low-intensity exercise for risk stratification and prognostication in pulmonary arterial hypertension.

BACKGROUND AND OBJECTIVE: Peak oxygen consumption (pVO2 ), determined from CPET, provides a valuable indication of PAH severity and patient prognosis. However, CPET is often contraindicated in severe PAH and frequently terminated prior to achievement of a sufficient exercise effort. We sought to determine whether in PAH low-intensity [i.e. freewheeling exercise (FW)] exercise reveals abnormal VE /VCO2 and PET CO2 responses that are associated with pVO2 and serve as indices of PAH risk stratification and mortality. METHODS: Retrospective analysis of CPET from 97 PAH patients and 20 age-matched controls was undertaken. FW VE /VCO2 and PET CO2 were correlated with pVO2 % age-predicted. Prognostication analysis was conducted using pVO2 > 65% age-predicted, as known to represent a low mortality risk. Primary outcome was mortality from any cause. RESULTS: FW PET CO2 was correlated with pVO2 (P < 0.0001; r = 0.52), while FW VE /VCO2 was not (P = 0.13; r = -0.16). ROC curve analyses showed that FW PET CO2 (AUC = 0.659), but not FW VE /VCO2 (AUC = 0.587), provided predictive information identifying pVO2 > 65% age-predicted (best cut-off value of 28 mm Hg). By Cox analysis, FW PET CO2 < 28 mm Hg remained a predictor of mortality after adjusting for age and PAH aetiology (HR: 2.360, 95% CI: 1.144-4.866, P = 0.020). CONCLUSION: Low PET CO2 during FW is associated with reduced pVO2 in PAH and provides predictive information for PAH risk stratification and prognostication.

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.

Inhaled Treprostinil in Pulmonary Hypertension Associated with Lung Disease.

PURPOSE: Pulmonary hypertension (PH) in the setting of parenchymal lung disease adversely affects quality of life and survival. However, PH-specific drugs may result in ventilation/perfusion imbalance and currently, there are no approved PH treatments for this patient population. In the present retrospective study, data from 22 patients with PH associated with lung disease treated with inhaled treprostinil (iTre) and followed up clinically for at least 3 months are presented. METHODS: PH was defined by resting right heart catheterization as a mean pulmonary artery pressure (mPAP) ≥ 35 mmHg, or mPAP ≥ 25 mmHg associated with pulmonary vascular resistance ≥ 4 Woods Units. Follow-up evaluation was performed at the discretion of the attending physician. RESULTS: From baseline to follow-up, we observed significant improvement in functional class (n = 22, functional class III-IV 82 vs. 59%, p = 0.041) and 6-min walk distance (n = 11, 243 ± 106 vs. 308 ± 109; p = 0.022), without a deleterious effect on resting peripheral oxygen saturation (n = 22, 92 ± 6 vs. 94 ± 4; p = 0.014). Most of the patients (86%, n = 19/22) were using long-term nasal supplemental oxygen at baseline. During follow-up, only one patient had increased supplemental oxygen requirement. The most common adverse events were cough, headache, and diarrhea. No severe adverse event was reported. CONCLUSIONS: The results suggest that iTre is safe in patients with Group 3 PH and evidence of pulmonary vascular remodeling in terms of functional class, gas exchange, and exercise capacity. Additionally, iTre was well tolerated. The potential role of PH-specific drugs in Group 3 PH should be further assessed in larger prospective studies.

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.

A haemodynamic study of pulmonary hypertension in chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis is a common fibrotic interstitial lung disease. The prevalence of pulmonary hypertension diagnosed by right heart catheterisation and its cardiopulmonary function findings in patients with chronic hypersensitivity pneumonitis are unknown. Consecutive symptomatic patients with chronic hypersensitivity pneumonitis were prospectively evaluated. All patients were submitted to right heart catheterisation, pulmonary function testing, a 6-min walk test, echocardiography, blood gas determination and N-terminal pro-brain natriuretic peptide analyses. Nonhypoxaemic patients also underwent incremental cardiopulmonary exercise testing. 50 patients underwent right heart catheterisation; 25 (50%) of these had pulmonary hypertension and 22 (44%) had a pre-capillary haemodynamic pattern. The patients with pre-capillary pulmonary hypertension had lower forced vital capacity (mean ± sd 50 ± 17% versus 69 ± 22% predicted, p<0.01), carbon monoxide diffusing capacity (37 ± 12% versus 47 ± 14% predicted, p<0.01), arterial oxygen tension (median (interquartile range) 59.0 (47.8-69.3) versus 73.0 (62.2-78.5) mmHg, p<0.01) and saturation after the 6-min walk test (78 ± 8% versus 86 ± 7%, p<0.01). In pre-capillary pulmonary hypertension, oxygen uptake was also lower at the anaerobic threshold (41 ± 11% versus 50 ± 8% predicted, p=0.04) and at peak exercise (12.8 ± 1.6 versus 15.0 ± 2.5 mL · kg(-1) · min(-1), p=0.02). Pre-capillary pulmonary hypertension is common in symptomatic chronic hypersensitivity pneumonitis and is related to interstitial lung disease severity. Additionally, pulmonary hypertension is more prevalent in hypoxaemic patients with impaired lung function and exercise capacity.

CD147 Plasma Levels in Hospitalised Patients with Covid-19 Pneumonia Predict Illness Severity and In-Hospital Mortality.

COVID-19 and infectious diseases have been included in strategic development goals (SDG) of United Nations (UN). The CD147 receptor is one of several receptors for the SARS-CoV-2 spike protein that could mediate Covid-19 viral infection of host cells. It has been recently proposed to regulate viral invasion and dissemination among lymphocytes and progenitor/stem cells. A soluble by-product of CD147 (sCD147) exists in plasma and has been previously identified as a marker of diabetes and platelet activation. We examined plasma sCD147 levels in 161 Covid-19 patients at hospital admission. We demonstrated significantly higher plasma sCD147 levels in Covid-19 patients, which correlated with plasma multiorgan dysfunction biomarkers interleukin-6, creatinine and Troponin I. Importantly, sCD147 admission levels were associated with Covid-19 severity and survival, carrying potential value as a biomarker in hospitalized patients with Covid-19 infection.

Is pulmonary arterial hypertension associated with schistosomiasis distinct from pulmonary arterial hypertension associated with portal hypertension?

Pulmonary arterial hypertension associated with schistosomiasis (SchPAH) and pulmonary arterial hypertension associated with portal hypertension (PoPAH) are lung diseases that develop in the presence of liver diseases. However, mechanistic pathways by which the underlying liver conditions and other drivers contribute to the development and progression of pulmonary arterial hypertension (PAH) are unclear for both etiologies. In turn, these unknowns limit certainty of strategies to prevent, diagnose, and reverse the resultant PAH. Here we consider specific mechanisms that contribute to SchPAH and PoPAH, identifying those that may be shared and those that appear to be unique to each etiology, in the hope that this exploration will both highlight known causal drivers and identify knowledge gaps appropriate for future research. Overall, the key pathophysiologic differences that we identify between SchPAH and PoPAH suggest that they are not variants of a single condition.

Exercise intolerance in post-coronavirus disease 2019 survivors after hospitalisation.

Rationale: Post-coronavirus disease 2019 (COVID-19) survivors frequently have dyspnoea that can lead to exercise intolerance and lower quality of life. Despite recent advances, the pathophysiological mechanisms of exercise intolerance in the post-COVID-19 patients remain incompletely characterised. The objectives of the present study were to clarify the mechanisms of exercise intolerance in post-COVID-19 survivors after hospitalisation. Methods: This prospective study evaluated consecutive patients previously hospitalised due to moderate-to-severe/critical COVID-19. Within mean±sd 90±10 days of onset of acute COVID-19 symptoms, patients underwent a comprehensive cardiopulmonary assessment, including cardiopulmonary exercise testing with earlobe arterialised capillary blood gas analysis. Measurements and main results: 87 patients were evaluated; mean±sd peak oxygen consumption was 19.5±5.0 mL·kg-1·min-1, and the tertiles were ≤17.0, 17.1-22.2 and ≥22.3 mL·kg-1·min-1. Hospitalisation severity was similar among the three groups; however, at the follow-up visit, patients with peak oxygen consumption ≤17.0 mL·kg-1·min-1 reported a greater sensation of dyspnoea, along with indices of impaired pulmonary function, and abnormal ventilatory, gas-exchange and metabolic responses during exercise compared to patients with peak oxygen consumption >17 mL·kg-1·min-1. By multivariate logistic regression analysis (receiver operating characteristic curve analysis) adjusted for age, sex and prior pulmonary embolism, a peak dead space fraction of tidal volume ≥29 and a resting forced vital capacity ≤80% predicted were independent predictors of reduced peak oxygen consumption. Conclusions: Exercise intolerance in the post-COVID-19 survivors was related to a high dead space fraction of tidal volume at peak exercise and a decreased resting forced vital capacity, suggesting that both pulmonary microcirculation injury and ventilatory impairment could influence aerobic capacity in this patient population.

Exercise metabolomics in pulmonary arterial hypertension: Where pulmonary vascular metabolism meets exercise physiology.

Pulmonary arterial hypertension is an incurable disease marked by dysregulated metabolism, both at the cellular level in the pulmonary vasculature, and at the whole-body level characterized by impaired exercise oxygen consumption. Though both altered pulmonary vascular metabolism and abnormal exercise physiology are key markers of disease severity and pulmonary arterial remodeling, their precise interactions are relatively unknown. Herein we review normal pulmonary vascular physiology and the current understanding of pulmonary vascular cell metabolism and cardiopulmonary response to exercise in Pulmonary arterial hypertension. We additionally introduce a newly developed international collaborative effort aimed at quantifying exercise-induced changes in pulmonary vascular metabolism, which will inform about underlying pathophysiology and clinical management. We support our investigative approach by presenting preliminary data and discuss potential future applications of our research platform.

Cardiopulmonary disease as sequelae of long-term COVID-19: Current perspectives and challenges.

COVID-19 infection primarily targets the lungs, which in severe cases progresses to cytokine storm, acute respiratory distress syndrome, multiorgan dysfunction, and shock. Survivors are now presenting evidence of cardiopulmonary sequelae such as persistent right ventricular dysfunction, chronic thrombosis, lung fibrosis, and pulmonary hypertension. This review will summarize the current knowledge on long-term cardiopulmonary sequelae of COVID-19 and provide a framework for approaching the diagnosis and management of these entities. We will also identify research priorities to address areas of uncertainty and improve the quality of care provided to these patients.

Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

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 PGP9.5-immunolabeled 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. Rest-to-peak changes in cardiac output (Qc) were compared with oxygen uptake (Qc/VO2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO2 tertiles. RESULTS: During exercise, the 160 ME/CFS patients averaged lower RAP (1.9 ± 2 vs 8.3 ± 1.5; P < .0001) and peak VO2 (80% ± 21% vs 101.4% ± 17%; P < .0001) than control subjects. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4% ± 19% vs 99.5% ± 23.8% vs 99.9% ± 19.5% predicted; P < .01). In contrast, systemic oxygen extraction was impaired in high-flow vs low- and normal-flow participants (0.74% ± 0.1% vs 0.88 ± 0.11 vs 0.86 ± 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. INTERPRETATION: These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance-depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Sex-Related Differences in Dynamic Right Ventricular-Pulmonary Vascular Coupling in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO2) in HFpEF is not known. RESEARCH QUESTION: The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF. STUDY DESIGN AND METHODS: This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance. RESULTS: Both HFpEF groups experienced decreased peak VO2 (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO2 compared with female patients (58 ± 16% vs 70 ± 15%; P < .05). Male patients with HFpEF had a more pronounced increase in RV afterload, Ea (1.8 ± 0.6 mm Hg/mL/m2 vs 1.3 ± 0.4 mm Hg/mL/m2; P < .05) and failed to increase RV contractility during exercise, resulting in dynamic RV-PA uncoupling (0.9 ± 0.4 vs 1.2 ± 0.4; P < .05) and subsequent reduced stroke volume index augmentation. In contrast, female patients with HFpEF were able to augment RV contractility in the face of increasing afterload, preserving RV-PA coupling during exercise. INTERPRETATION: Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO2 compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO2 compared with male patients with HFpEF.