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.

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.

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.

Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis.

BACKGROUND: Delayed postexercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. The usefulness of HRR to predict exercise impairment and mortality in patients with pulmonary arterial hypertension (PAH), however, remains largely unexplored. METHODS: Seventy-two patients with PAH of varied etiology (New York Heart Association classes I-IV) and 21 age- and gender-matched controls underwent a maximal incremental cardiopulmonary exercise test (CPET), with heart rate being recorded up to the fifth minute of recovery. RESULTS: Heart rate recovery was consistently lower in the patients compared with the controls (P < .05). The best cutoff for HRR in 1 minute (HRR(1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR(1 min) ≤ 18 (n = 40), those with HRR(1 min) >18 (n = 32) had better New York Heart Association scores, resting hemodynamics and 6-minute walking distance. In fact, HRR(1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < .05). The single independent predictor of HRR(1 min) ≤ 18 was the 6-minute walking distance (odds ratio [95% CI] 0.99 [0.98-1.00], P < .05). On a multiple regression analysis that considered only CPET-independent variables, HRR(1 min) ≤ 18 was the single predictor of mortality (hazard ratio [95% CI] 1.19 [1.03-1.37], P < .05). CONCLUSIONS: Preserved HRR(1 min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PAH. Conversely, a delayed HRR(1 min) response has negative prognostic implications, a finding likely to be clinically useful when more sophisticated (and costlier) analyses provided by a full CPET are not available.

Skeletal muscle reoxygenation after high-intensity exercise in mitochondrial myopathy.

This study addressed whether O(2) delivery during recovery from high-intensity, supra-gas exchange threshold exercise would be matched to O(2) utilization at the microvascular level in patients with mitochondrial myopathy (MM). Off-exercise kinetics of (1) pulmonary O(2) uptake VO(2P) (2) an index of fractional O(2) extraction by near-infrared spectroscopy (Δ[deoxy-Hb + Mb]) in the vastus lateralis and (3) cardiac output (Q'(T)) by impedance cardiography were assessed in 12 patients with biopsy-proven MM (chronic progressive external ophthalmoplegia) and 12 age- and gender-matched controls. Kinetics of VO(2P) were significantly slower in patients than controls (τ = 53.8 ± 16.5 vs. 38.8 ± 7.6 s, respectively; p < 0.05). Q'(T), however, declined at similar rates (τ = 64.7 ± 18.8 vs. 73.0 ± 21.6 s; p > 0.05) being typically slower than [Formula: see text] in both groups. Importantly, Δ[deoxy-Hb + Mb] dynamics (MRT) were equal to, or faster than, τVO(2P) in patients and controls, respectively. In fact, there were no between-group differences in τVO(2P)MRTΔ[deoxy-Hb + Mb] (1.1 ± 0.4 vs. 1.0 ± 0.2, p > 0.05) thereby indicating similar rates of microvascular O(2) delivery. These data indicate that the slower rate of recovery of muscle metabolism after high-intensity exercise is not related to impaired microvascular O(2) delivery in patients with MM. This phenomenon, therefore, seems to reflect the intra-myocyte abnormalities that characterize 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.

Impact of right ventricular work and pulmonary arterial compliance on peak exercise oxygen uptake in idiopathic pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, RV dysfunction and decreased peak oxygen uptake (pVO2). However, the pulmonary hemodynamic mechanisms measured by exercise right heart catheterization (RHC) that contribute to reduced pVO2 in idiopathic PAH (IPAH) are not completely characterized. Therefore, we sought to evaluate the exercise RHC determinants of pVO2 in patients with IPAH. METHODS: 519 consecutive patients with suspected and/or confirmed pulmonary hypertension were prospectively screened to identify 20 patients with IPAH. All IPAH patients were prospectively evaluated with resting and exercise RHC and cardiopulmonary exercise testing. RESULTS: 85% of the patients were female; the median age was 34[29-42] years old. At peak exercise, mean pulmonary arterial (PA) pressure was 76 ± 17 mmHg, PA wedge pressure was 14 ± 5 mmHg, cardiac output (CO) was 5.7 ± 1.9 L/min, pulmonary vascular resistance was 959 ± 401 dynes/s/cm5 and PA compliance was 0.9[0.6-1.2] ml/mmHg. On univariate analysis, pVO2 positively correlated to peak CO, peak cardiac index, peak stroke volume index, peak RV stroke work index (RVSWI) and peak oxygen saturation. There was a negative correlation between pVO2 and Δ (rest to peak change) PA compliance. In age-adjusted multivariate model, peak RVSWI (Coefficient = 0.15, Beta = 0.63, 95% CI [0.07-0.22], p < 0.01) and ΔPA compliance (Coefficient = -2.51, Beta = -0.43, 95% CI [-4.34-(-0.68)], p = 0.01) had the best performance predicting pVO2 (R2 = 0.66). CONCLUSIONS: In conclusion, a load dependent measurement of RV function (RVSWI) and the pulsatile component of RV afterload (ΔPA compliance) significantly influence pVO2 in IPAH, further highlighting the pivotal role of hemodynamic coupling to IPAH exercise capacity.

Intercostal and vastus lateralis microcirculatory response to a sympathoexcitatory manoeuvre in patients with chronic obstructive pulmonary disease.

Patients with COPD present with systemic vascular malfunctioning and their microcirculation is possibly more fragile to overcome an increase in the sympathetic vasoconstrictor outflow during sympathoexcitatory situations. To test the skeletal muscle microvascular responsiveness to sympathoexcitation, we asked patients with COPD and age- and sex-matched controls to immerse a hand in iced water [Cold Pressor Test (CPT)]. Near-infrared spectroscopy detection of the indocyanine green dye in the intercostal and vastus lateralis microcirculation provided a blood flow index (BFI). BFI divided by mean blood pressure (MBP) provided an index of microvascular conductance (BFI/MBP). The CPT decreased BFI and BFI/MBP in the intercostal (P = 0.01 and < 0.01, respectively) and vastus lateralis (P = 0.08 and 0.03, respectively) only in the COPD group, and the per cent BFI and BFI/MBP decrease was similar between muscles (P = 0.78 and 0.85, respectively). Thus, our findings support that sympathoexcitation similarly impairs intercostal and vastus lateralis microvascular regulation in patients with COPD.

Prognostic value of six-minute walk distance at a South American pulmonary hypertension referral center.

Six-minute walk distance (6MWD) assessment is recommended for pulmonary arterial hypertension multidimensional risk stratification. However, current 6MWD cut-off values were mainly derived from North American and European pulmonary arterial hypertension registries. Therefore, it is unknown if such cut-off values broadly apply to other geographical populations. In this study, we aimed to identify 6MWD cut-off values for Brazilian pulmonary arterial hypertension patients and to contrast our findings to current international Pulmonary Hypertension guidelines recommendations. One-hundred four consecutive pulmonary arterial hypertension patients were allocated in groups according to their 6MWD, considering 50 m as a clinically relevant 6MWD difference. Next, patients were categorized into different 6MWD ranges based on similar survival rates in each group: < 250 m, 250-400 m, and >400 m. The study outcome was all-cause mortality and transplantation according to the 6MWD range. Survival was truncated at five years. Median follow-up period was 4.35 years (0.48-5.00). Survival rates at 1, 2, 3, and 5 years were 96%, 89%, 81%, and 73%, respectively. Cox analyses adjusted for age, sex, and pulmonary arterial hypertension etiology showed that 6MWD < 250 m and >400 m were associated with higher and lower risk of all-cause mortality and transplantation. According to Harrell's c-statistic, the prognostic discrimination of the 6MWD cut-off value identified by the current study was 0.70 while international Pulmonary Hypertension guidelines 6MWD cut-offs value was 0.61. In conclusion, our findings suggest that 6MWD geographical variations should be considered when assessing risk stratification in pulmonary arterial hypertension.

Inspiratory muscle weakness contributes to exertional dyspnea in chronic thromboembolic pulmonary hypertension.

Determination of potentially-reversible factors contributing to exertional dyspnea remains an unmet clinical need in chronic thromboembolic pulmonary hypertension (CTEPH). Therefore, we aimed to evaluate the influence of inspiratory muscle weakness (IMW) on exercise capacity and dyspnea during effort in patients with CTEPH. We performed a prospective cross-sectional study that included thirty-nine consecutive patients with CTEPH (48 ± 15 yrs, 61% female) confirmed by right heart catheterization that underwent an incremental cardiopulmonary exercise test, 6-minute walk test and maximum inspiratory pressure (MIP) measurement. MIP < 70%pred was found in 46% of patients. On a multiple linear regression analysis, MIP was independently associated with 6MWD and [Formula: see text]. Patients with MIP < 70% presented greater [Formula: see text] than those with MIP ≥ 70%. Additionally, they also presented stronger sensations of dyspnea throughout exercise, even when adjusted for ventilation. At rest and at different levels of exercise, mean inspiratory flow (VT/TI) was significantly higher in patients with MIP < 70%. In conclusion, IMW is associated with a rapid increase of dyspnea, higher inspiratory load and poor exercise capacity in patients with CTEPH.

Optimizing the evaluation of excess exercise ventilation for prognosis assessment in pulmonary arterial hypertension.

BACKGROUND: Increased ventilatory (.VE) response to carbon dioxide output (.VCO2) is a key finding of incremental cardiopulmonary exercise testing in both heart failure and pulmonary arterial hypertension (PAH). As with heart failure, measures of excessive exercise ventilation considering high-to-peak exercise .VE-VCO2 might have higher prognostic relevance than those restrained to sub-maximal exercise in PAH. DESIGN: Cross-sectional and observational study on a tertiary center. METHODS: Eighty-four patients (36 idiopathic and 48 with associated conditions) were followed up for up to five years. Excessive exercise ventilation was calculated as a slope (Δ .VE/Δ .VCO2 to the respiratory compensation point (RCP) and to exercise cessation (PEAK)) and as a ratio (.VE-VCO2 at the anaerobic threshold (AT) and at PEAK). RESULTS: Thirteen patients died and three had atrial septostomy. Multivariable regression analyses revealed that Δ .VE/Δ .VCO2(PEAK) <55 and .VE/.VCO2(PEAK) <57 were better related to prognosis than Δ .VE/Δ .VCO2(RCP) and .VE/.VCO2(AT) (p < 0.01). Δ oxygen uptake (.VO2)/Δ work rate >5.5 ml/min per W was the only other independent prognostic index. According to a Kaplan-Meier survival analysis, 96.9% (90.8% to 100%) of patients showing Δ .VE/Δ .VCO2(PEAK) <55 and Δ .VO2/Δ work rate >5.5 ml/min per W were free from a PAH-related event. In contrast, 74.7% (70.1% to 78.2%) with both parameters outside these ranges had a negative outcome. CONCLUSION: Measurements of excessive exercise ventilation which consider all data points maximize the usefulness of incremental cardiopulmonary exercise testing in the prognosis evaluation of PAH.