Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19.

OBJECTIVES: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment. METHODS: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention. RESULTS: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02). DISCUSSION: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence. It is a retrospective cohort study.

AIDS impact special issue 2023: two-way associations between relationship quality and uptake of couples health screening including HIV testing and counselling together: quantitative analysis of a couples cohort in rural South Africa.

In the context of a couples cohort established to evaluate an optimised couples-focused behavioural intervention in rural South Africa, we examined: (1) Is couples' relationship quality (RQ) associated with couples HIV testing and counselling (CHTC) uptake? (2) Does CHTC uptake or the intervention components uptake improve subsequent RQ? Enrolled couples, (n = 218), previously naïve to couples HIV testing, were invited to two group sessions and offered four couples counselling sessions (CS1-CS4), as part of the intervention and administered a questionnaire individually at baseline, four weeks, and four months, which included item-scales to measure RQ: satisfaction, intimacy, dyadic trust, conflict, and mutual constructive communication. Logistic models indicated that no baseline RQ measures were significantly associated with CHTC uptake. Linear regression models showed that CHTC uptake before four weeks assessment significantly improved couples' satisfaction and trust at four weeks, and intimacy at four months. Attending at least one CS was associated with increased satisfaction, intimacy, and decreased conflict within couples at four weeks; the improvement in intimacy was sustained at four months. Consistent with the theoretical interdependence model, our findings suggest that CHTC and CS seemed to strengthen aspects of relationship quality, possibly leading to further collaboration in managing lifestyle changes and treatment adherence.

Differential cardiopulmonary haemodynamic phenotypes in PASC-related exercise intolerance.

Background: Post-acute sequelae of COVID-19 (PASC) affect a significant proportion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom. This study aimed to characterise the invasive haemodynamic abnormalities of PASC-related exertional intolerance using invasive cardiopulmonary exercise testing (iCPET). Study design and intervention: 55 patients were recruited from the Yale Post-COVID-19 Recovery Program, with most experiencing mild acute illness. Supine right heart catheterisation and iCPET were performed on all participants. Main results: The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO2) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group). On average, the PASC alone group exhibited a "normal" peak exercise capacity, V'O2 (89±18% predicted). ∼25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise heart failure with preserved ejection fraction (HFpEF) and two with exercise pulmonary hypertension (PH)). PASC patients with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO2 with well compensated PH (i.e., peak V'O2 and CO >80% respectively) despite aberrant central cardiopulmonary exercise haemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m-2. To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group comprising obese non-PASC group (n=61) derived from a historical iCPET cohort was used. The non-PASC obese patients with preserved peak V'O2 (>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14 versus 25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12 versus 86±10% predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO2 was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19). Conclusions: This study highlights the importance of considering impaired pEO2 in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of the current study also highlight the prevalence of a distinct high output HFpEF phenotype in PASC with a primary peripheral limitation to exercise.

Nicotine flux as a powerful tool for regulating nicotine delivery from e-cigarettes: Protocol of two complimentary randomized crossover clinical trials.

INTRODUCTION: Electronic cigarette (EC) use has increased rapidly in the last decade, especially among youth. Regulating nicotine delivery from ECs could help curb youth uptake and leverage EC use in harm reduction yet is complicated by varying device and liquid variables that affect nicotine delivery. Nicotine flux, the nicotine emission rate, is a parameter that incorporates these variables and focuses on the performance rather than the design of an EC. Nicotine flux therefore could be a powerful regulatory tool if it is shown empirically to predict nicotine delivery and subjective effects related to dependence. METHODS AND ANALYSIS: This project consists of two complementary clinical trials. In Trial I, we will examine the relationship between nicotine flux and the rate and dose of nicotine delivery from ECs, hence, impacting abuse liability. It will also examine the extent to which this relationship is mediated by nicotine form (i.e., freebase versus protonated). At Yale School of Medicine (YSM), study participants will puff EC devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. In Trial II, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut (AUB), participants will use EC devices with varying nicotine fluxes and forms, while dependency measures, such as the urge to use ECs, nicotine craving, and withdrawal symptoms, will be assessed. We will also monitor puffing intensity and real-time exposure to toxicants. ETHICS AND DISSEMINATION: The protocol of Trial I and Trial II was approved by YSM and AUB IRBs, respectively. We will disseminate study results through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: NCT05706701 for Trial I and NCT05430334 for Trial II.

Integrating Right Ventricular Pressure Waveform Analysis With Two-Point Volume Measurement for Quantification of Systolic and Diastolic Function: Experimental Validation and Clinical Application.

OBJECTIVE: To define in an experimental model the variance, accuracy, precision, and concordance of single-beat measures of right ventricular (RV) contractility and diastolic capacitance relative to conventional reference standards, and apply the methods to a clinical data set. DESIGN: A retrospective, observational analysis of recorded pressure waveforms and RV volume measurements. SETTING: At a university laboratory. PARTICIPANTS: Archived data from previous studies of anesthetized swine and awake patients undergoing clinically-indicated right-heart catheterization. INTERVENTIONS: Recording of RV pressure with simultaneous measurement of RV volume by conductance (swine) or 3-dimensional (3D) echocardiography (humans) during changes in contractility and/or loading conditions. MEASUREMENTS AND MAIN RESULTS: Using experimental data, single-beat measures of RV contractility quantified as end-systolic elastance, and diastolic capacitance quantified as the predicted volume at an end-diastolic pressure of 15 mmHg (V15), were compared to multi-beat, preload- variant, reference standards using correlation, Bland-Altman analysis, and 4-quadrant concordance testing. This analysis indicated that the methods were not directly interchangeable with reference standards, but were sufficiently robust to suggest potential clinical utility. Clinical application supported this potential by demonstrating enhanced assessment of the response to inhaled nitric oxide in patients undergoing diagnostic right-heart catheterization. CONCLUSIONS: Study results supported the possibility of integrating automated RV pressure analysis with RV volume measured by 3D echocardiography to create a comprehensive assessment of RV systolic and diastolic function at the bedside.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

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.

Noninvasive determinants of pulmonary hypertension in interstitial lung disease.

Pulmonary hypertension (PH) in interstitial lung disease (ILD) is associated with increased mortality and impaired exertional capacity. Right heart catheterization is the diagnostic standard for PH but is invasive and not readily available. Noninvasive physiologic evaluation may predict PH in ILD. Forty-four patients with PH and ILD (PH-ILD) were compared with 22 with ILD alone (non-PH ILD). Six-min walk distance (6MWD, 223 ± 131 vs. 331 ± 125 m, p = 0.02) and diffusing capacity for carbon monoxide (DLCO, 33 ± 14% vs. 55 ± 21%, p < 0.001) were lower in patients with PH-ILD. PH-ILD patients exhibited a lower gas-exchange derived pulmonary vascular capacitance (GXCAP, 251 ± 132 vs. 465 ± 282 mL × mmHg, p < 0.0001) and extrapolated maximum oxygen uptake (VO2max) (56 ± 32% vs. 84 ± 37%, p = 0.003). Multivariate analysis was performed to determine predictors of VO2 max. GXCAP was the only variable that predicted extrapolated VO2 max among PH-ILD and non-PH ILD patients. Receiver operating characteristic curve analysis assessed the ability of individual noninvasive variables to distinguish between PH-ILD and non-PH ILD patients. GXCAP (area under the curve [AUC] 0.85 ± 0.04, p < 0.0001) and delta ETCO2 (AUC 0.84 ± 0.04, p < 0.0001) were the strongest predictors of PH-ILD. A CART analysis selected GXCAP, estimated right ventricular systolic pressure (eRVSP) by echocardiogram, and FVC/DLCO ratio as predictive variables for PH-ILD. With this analysis, the AUC improved to 0.94 (sensitivity of 0.86 and sensitivity of 0.93). Patients with a GXCAP ≤ 416 mL × mmHg had an 82% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and high FVC/DLCO ratio >1.7 had an 80% probability of PH-ILD. Patients with GXCAP ≤ 416 mL × mmHg and an elevated eRVSP by echocardiogram >43 mmHg had 100% probability of PH-ILD. The incorporation of GXCAP with either eRVSP or FVC/DLCO ratio distinguishes between PH-ILD and non-PH-ILD with high probability and may therefore assist in determining the need to proceed with a diagnostic right heart catheterization and potential initiation of pulmonary arterial hypertension-directed therapy in PH-ILD patients.

Protocol: evaluation of an optimised couples-focused intervention to increase testing for HIV in rural KwaZulu-Natal, South Africa, the Igugu Lethu ('Our treasure') cohort study.

BACKGROUND: Between 2012 and 2015, the Uthando Lwethu (UL) study demonstrated that a theory-based behavioural couples-focused intervention significantly increased participation in couples HIV testing and counselling (CHTC) among South African couples who had never previously tested for HIV together or mutually disclosed their HIV status, 42% compared to 12% of the control group at 9 months follow-up. Although effective, we were nonetheless concerned that in this high prevalence setting the majority (58%) of intervention couples chose not to test together. In response we optimised the UL intervention and in a new study, 'Igugu Lethu', we are evaluating the success of the optimised intervention in promoting CHTC. METHODS: One hundred eighty heterosexual couples, who have been in a relationship together for at least 6 months, are being recruited and offered the optimised couples-focused intervention. In the Igugu Lethu study, we have expanded the health screening visit offered to couples to include other health conditions in addition to CHTC. Enrolled couples who choose to schedule CHTC will also have the opportunity to undertake a random blood glucose test, blood pressure and BMI measurements, and self-sample for STI testing as part of their health screening. Individual surveys are administered at baseline, 4 weeks and 4 months follow-up. The proportion of couples who decide to test together for HIV will be compared to the results of the intervention arm in the UL study (historical controls). To facilitate this comparison, we will use the same recruitment and follow-up strategies in the same community as the previous UL study. DISCUSSION: By strengthening communication and functioning within the relationship, the Igugu Lethu study, like the previous UL study, aims to transform the motivation of individual partners from a focus on their own health to shared health as a couple. The Igugu Lethu study findings will answer whether the optimised couples-focused behavioural intervention and offering CHTC as part of a broader health screening for couples can increase uptake of CHTC by 40%, an outcome that would be highly desirable in populations with high HIV prevalence. TRIAL REGISTRATION: Retrospectively registered. ISRCTN Registry ISRCTN 46162564 Registered on 26th May 2022.

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.

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.

Sex Differences and the Role of Sex Hormones in Pulmonary Hypertension.

Pulmonary arterial hypertension is characterized by progressive pulmonary vascular remodeling and the eventual development of right heart failure. Multiple mechanisms are responsible, including vasoconstriction, metabolic flux, and inflammation. Since the early descriptions of pulmonary hypertension, female sex has been associated with increased prevalence of the disease, with research showing both detrimental and beneficial effects of estrogen and its metabolites. This article aims to describe how the female paradox arises from sex differences in pulmonary hypertension and how this has an impact on pathophysiology and future treatment.

Arterial load and right ventricular-vascular coupling in pulmonary hypertension.

Right ventricular (RV) functional adaptation to afterload determines outcome in pulmonary hypertension (PH). RV afterload is determined by the dynamic interaction between pulmonary vascular resistance (PVR), characteristic impedance (Zc), and wave reflection. Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of RV afterload; however, there is an unmet need for an easier bedside measurement of this complex variable. Although a recent study showed that Zc and wave reflection can be estimated from RV pressure waveform analysis and cardiac output, this has not been validated. Estimations of Zc and wave reflection coefficient (λ) were validated relative to conventional spectral analysis in an animal model. Zc, λ, and the single-beat ratio of end-systolic to arterial elastance (Ees/Ea) to estimate RV-pulmonary arterial (PA) coupling were determined from right heart catheterization (RHC) data. The study included 30 pulmonary artery hypertension (PAH) and 40 heart failure with preserved ejection fraction (HFpEF) patients [20 combined pre- and postcapillary PH (Cpc-PH) and 20 isolated postcapillary PH, (Ipc-PH)]. Also included were 10 age- and sex-matched controls. There was good agreement with minimal bias between estimated and spectral analysis-derived Zc and λ. Zc in PAH and Cpc-PH groups exceeded that in the Ipc-PH group and controls. λ was increased in Ipc-PH (0.84 ± 0.02), Cpc-PH (0.87 ± 0.05), and PAH groups (0.85 ± 0.04) compared with controls (0.79 ± 0.03); all P values were <0.05. λ was the only afterload parameter associated with RV-PA coupling in PAH. In the PH-HFpEF group, RV-PA uncoupling was independent of RV afterload. Our findings indicate that Zc and λ derived from an RV pressure curve can be used to improve estimation of RV afterload. λ is the only afterload measure associated with RV-PA uncoupling in PAH, whereas RV-PA uncoupling in PH-HFpEF appears to be independent of afterload consistent with an inherent abnormality of the RV myocardium.NEW & NOTEWORTHY Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of right ventricle (RV) afterload; however, measurement of this variable is complex. We demonstrate that characteristic impedance (Zc) and a wave reflection coefficient, λ, can be derived from RV pressure waveform analysis. In addition, RV dysfunction in left heart disease is independent of its afterload. The current study provides a platform for future studies to examine the pharmacotherapeutic effects and prognosis of different measures of RV afterload.

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.

The Evolution in Nomenclature, Diagnosis, and Classification of Pulmonary Hypertension.

The current description of pulmonary hypertension is a testament to the physicians and scientists who dedicated their lives to furthering understanding of the pulmonary circulation. This has spanned a millennium, from ancient Egyptian descriptions of human anatomy to the current molecular and hemodynamic phenotyping of pulmonary hypertension. The recent Sixth World Symposium on Pulmonary Hypertension is a direct result of these discoveries and reflects an evolution in a classification scheme that has spanned half a century. This provides a framework for future directions related to therapeutics and mechanisms of disease.

Diagnostic utility of sub-maximum cardiopulmonary exercise testing in the ambulatory setting for heart failure with preserved ejection fraction.

Pulmonary hypertension is commonly associated with heart failure with preserved ejection fraction. In heart failure with preserved ejection fraction, the elevated left-sided filling pressures result in isolated post-capillary pulmonary hypertension or combined pre- and post-capillary pulmonary hypertension. Although right heart catheterization is the gold standard for diagnosis, it is an invasive test with associated risks. The ability of sub-maximum cardiopulmonary exercise test as an adjunct diagnostic tool in pulmonary hypertension-associated heart failure with preserved ejection fraction is not known. Forty-six patients with heart failure with preserved ejection fraction and pulmonary hypertension (27 patients with combined pre- and post-capillary pulmonary hypertension and 19 patients with isolated post-capillary pulmonary hypertension) underwent sub-maximum cardiopulmonary exercise test followed by right heart catheterization. The study also included 18 age- and gender-matched control subjects. Several sub-maximum gas exchange parameters were examined to determine the ability of sub-maximum cardiopulmonary exercise test to distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Conventional echocardiogram measures did not distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Compared to isolated post-capillary pulmonary hypertension, combined pre- and post-capillary pulmonary hypertension had greater ventilatory equivalent for carbon dioxide (VE/VCO2) slope, reduced delta end-tidal CO2 change during exercise, reduced oxygen uptake efficiency slope, and reduced gas exchange determined pulmonary vascular capacitance. The latter was significantly associated with right heart catheterization determined pulmonary artery compliance (r = 0.5; p = 0.0004). On univariate analysis, sub-maximum VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance emerged as independent predictors of the extrapolated maximum oxygen uptake (%predicted) (ß-coefficient values of -7.32, 95% CI: -13.3 - (-1.32), p = 0.01; 8.01, 95% CI: 1.96-14.05, p = 0.01; 8.78, 95% CI: 2.26-15.29, p = 0.01, respectively). Sub-maximum gas exchange parameters obtained during cardiopulmonary exercise test in an ambulatory setting allows for discrimination between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Additionally, sub-maximum cardiopulmonary exercise test derived VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance influences aerobic capacity in heart failure with preserved ejection fraction.