Search

Does the peripheral chemoreflex play a role in cardiac baroreflex dysfunction in patients with pulmonary arterial hypertension (PAH)? Here we provide new evidence of cardiac baroreflex dysfunction under spontaneous and, most notably, provoked blood pressure fluctuations in patients with nonhypoxemic PAH. Importantly, impaired cardiac baroreflex effectiveness during provoked blood pressure fluctuations was independently associated with poorer functional capacity. Finally, our results indicated that the peripheral chemoreflex did not mediate cardiac baroreflex dysfunction among those patients.

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 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.

Neuro-endocrinological manifestations rarely are described in cases of SARS- CoV-2. We describe a case of a previously hypertensive patient who presented COVID-19 and developed refractory arterial hypotension. In the investigation, low levels of ACTH and cortisol were observed, suggesting secondary adrenal insufficiency as the cause of refractory hypotension.

Background Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context. Methods 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation–perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation. Results Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA). Conclusions The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO., There are distinct regional differences in the management of CTEPH patients but globally, the proportion of patients managed by PEA remains stable, independently of the new established treatment options of PAH therapies and BPA https://bit.ly/3zEXxkv

Background Pulmonary arterial hypertension (PAH) is a rare and severe complication of systemic lupus erythematosus (SLE). This study aimed to evaluate clinical and laboratory risk factors associated with PAH in SLE patients. Methods This was a retrospective case-control study in which patients with SLE with PAH (SLE-PAH) confirmed by right heart catheterization (RHC) were compared with SLE patients without PAH. Clinical and demographic variables related to SLE and PAH and nailfold capillaroscopy were evaluated by reviewing the medical records of the patients. Results Twenty-one patients with SLE-PAH and 44 patients with SLE without PAH matched for sex and disease duration were included. The scleroderma (SD) pattern on nailfold capillaroscopy was more frequently found in patients with SLE-PAH than in those without PAH (56.3% versus 15.9%, respectively, p = 0.002). By univariate analysis, Raynaud’s phenomenon, history of abortion, and SD pattern on capillaroscopy were associated with PAH. Arthritis was a protective factor for PAH development. Multivariate analysis showed that the SD pattern on capillaroscopy was the only variable associated with a significantly higher risk of PAH, with an odds ratio of 6.393 (95% confidence interval, 1.530–26.716; p = 0.011). Conclusion In this study, SD pattern was associated with a 6.3-fold increased risk for PAH development in SLE patients, suggesting that nailfold capillaroscopy might be useful as a screening method to identify SLE patients with a high risk of developing this severe complication.

SARS coronavirus-2 (SARS-CoV-2) detection in different clinical specimens has raised important insights about its pathogenesis, but some details remain to be understood. In that respect, disrupt viral control seen in solid organ transplant patients on chronic immunosuppression can help unveil pathogenic mechanisms and characterize new coronavirus disease-19 (COVID-19) immunological and clinical aspects, as well as secondary complications. We herein report a case of SARS-CoV-2 detection in ascitic fluid from a kidney transplant patient with decompensated cirrhosis and COVID-19 and then discuss about immune, cellular, and virological aspects of such clinical presentation of the disease, which also included a disseminated infection, demonstrated by viral detection in his blood sample. We subsequently discuss about the fatal outcome caused by a secondary bloodstream infection by Cryptococcus neoformans. This unprecedented case report presents ascitic fluid as a novel specimen in which SARS-CoV-2 can be detected. Immune dysregulation and cumulative risk factors may lead to secondary infections by opportunistic agents, including Cryptococcus neoformans.

Background: Pulmonary arterial hypertension (PAH) treatment guidelines recommend patients achieve/maintain a low-risk profile. Many patients treated with PAH-targeted therapy do not meet this treatment goal. Aim: Compare switching to riociguat (RIO) with continued phosphodiesterase type 5 inhibitors (PDE5i) in intermediate risk patients with PAH. Methods: REPLACE (NCT02891850) was a randomized, open-label, 24-week Phase 4 study. Patients in WHO functional class [FC] III, with 6-minute walking distance [6MWD] 165–440 m were randomized to remain on PDE5i or switch to RIO 2.5 mg tid–max. Endothelin receptor antagonist pretreatment continued in both arms. The blinded, centrally adjudicated composite primary endpoint was defined as no clinical worsening (CW) plus clinical improvement (two of the following: ≥10%/≥30 m increase in 6MWD, WHO FC I/II, or ≥30% reduction in N-terminal pro-brain natriuretic peptide [NT-proBNP]). Secondary endpoints included 6MWD, WHO FC (both blinded assessment), NT-proBNP, and CW (death from any cause, hospitalization for worsening PAH or disease progression). Safety was evaluated throughout. Results: 111 patients were randomized to RIO, 115 to PDE5i. The primary endpoint was met in 45 patients (41%) with RIO and 23 (20%) with PDE5i (OR 2.8; 95% CI 1.5–5.1; p=0.0007). Of those not achieving the endpoint, 1 RIO patient (1%) and 10 PDE5i patients (9%) had CW including 3 PDE5i patients (3%) who died. AEs were similar between arms, with a higher incidence of serious AEs with PDE5i (17%) than RIO (7%). Conclusions: REPLACE demonstrated that patients on PDE5i at intermediate risk are more likely to show clinical improvement without CW upon switching to RIO than those who remain on PDE5i.

SARS Coronavirus-2 detection in different clinical specimens, including serum and stool, has raised important insights about its dynamics and pathogenesis, but some details remain to be understood.In that respect, disrupt viral control seen in immunocompromising conditions can help unveil pathogenetic mechanisms and characterize new Coronavirus Disease-19 immunological and clinical aspects in general.We herein report a case of cirrhosis decompensation with ascites due to COVID-19 and unprecedented detection of SARS-CoV-2 in ascitic fluid, hence a possible acute viral peritonitis, as well as in serum, leading to a fatal disseminated infection.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious and debilitating disease caused by occlusion of the pulmonary arterial bed by hematic emboli and by the resulting fibrous material. Such occlusion increases vascular resistance and, consequently, the pressure in the region of the pulmonary artery, which is the definition of pulmonary hypertension. The increased load imposed on the right ventricle leads to its progressive dysfunction and, finally, to death. However, CTEPH has a highly significant feature that distinguishes it from other forms of pulmonary hypertension: the fact that it can be cured through treatment with pulmonary thromboendarterectomy. Therefore, the primary objective of the management of CTEPH should be the assessment of patient fitness for surgery at a referral center, given that not all patients are good candidates. For the patients who are not good candidates for pulmonary thromboendarterectomy, the viable therapeutic alternatives include pulmonary artery angioplasty and pharmacological treatment. In these recommendations, the pathophysiological bases for the onset of CTEPH, such as acute pulmonary embolism and the clinical condition of the patient, will be discussed, as will the diagnostic algorithm to be followed and the therapeutic alternatives currently available.

Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment. A hipertensão arterial pulmonar (HAP) é uma doença dos vasos sanguíneos pulmonares que resulta em insuficiência cardíaca direita. Acredita-se que a HAP ocorra em cerca de 5% a 10% dos pacientes com esquistossomose hepatoesplênica, particularmente por S. mansoni. A lesão dos vasos sanguíneos pulmonares pode resultar de uma combinação de embolização de ovos por meio de derivações portocava para os pulmões, causando resposta inflamatória tipo 2 localizada e remodelação do vaso, desencadeando patologia autônoma que se torna independente do antígeno e alto débito cardíaco, como visto na hipertensão portopulmonar . A condição provavelmente é subdiagnosticada, pois há pouca triagem sistemática e os fatores de risco para o desenvolvimento de HAP não são conhecidos. A triagem é feita por ecocardiografia, e o diagnóstico formal requer cateterismo cardíaco direito invasivo. Pacientes com HAP associada ao Schistosoma apresentam redução da capacidade funcional e podem ser tratados com vasodilatadores pulmonares, o que melhora os sintomas e pode melhorar a sobrevida. Existem modelos animais desta doença que podem ajudar na compreensão da patogênese da doença e identificar novos alvos para triagem e tratamento. Mecanismos patogênicos incluem imunidade tipo 2 e ativação e sinalização na via de TGF-β. Ainda existem grandes incertezas em relação ao desenvolvimento, curso e tratamento da HAP associada ao Schistosoma.

Several studies of patients with COVID-19 have evaluated biological markers for predicting outcomes, most of them retrospectively and with a wide scope of clinical severity. We followed a prospective cohort of patients admitted in hospital wards with moderate COVID-19 disease, including those with a history of kidney transplantation, and examined the ability of changes in routine hematologic laboratory parameters to predict and mirror the patients’ clinical course regarding the severity of their condition (classified as critical vs. non-critical) and in-hospital mortality or hospital discharge. Among the 68 patients, 20 (29%) were kidney transplanted patients (KT), and they had much higher mortality than non-kidney transplanted patients in this cohort (40% X 8.3%). Lymphocytes, neutrophils and neutrophils/lymphocytes ratio (NLR) at admission and platelets as well as the red blood cells parameters hemoglobin, hematocrit, and RDW by the time of hospital discharge or death clearly differentiated patients progressing to critical disease and those with clinical recovery. Patients with deteriorating clinical courses presented elevated and similar NLRs during the first week of hospitalization. However, they were dramatically different at hospital discharge, with a decrease in the survivors (NLR around 5.5) and sustained elevation in non-survivors (NLR around 21). Platelets also could distinguish survivors from non-survivors among the critical patients. In conclusion, routine hematologic tests are useful to monitor the clinical course of COVID-19 patients admitted with moderate disease. Unexpectedly, changes in hematologic tests, including lymphopenia, were not predictive of complicated outcomes among KT recipients.

Introduction Great ventilation to carbon dioxide output (Δ V ˙ E/Δ V ˙ CO 2 ) and reduced end-tidal partial pressures for CO 2 (PetCO 2 ) during incremental exercise are hallmarks of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (IPAH). However, CTEPH is more likely to involve proximal arteries, which may lead to poorer right ventricle–pulmonary vascular coupling and worse gas exchange abnormalities. Therefore, abnormal PetCO 2 profiles during exercise may be more prominent in patients with CTEPH and could be helpful to indicate disease severity. Methods Seventy patients with CTEPH and 34 with IPAH underwent right heart catheterization and cardiopulmonary exercise testing. According to PetCO 2 pattern during exercise, patients were classified as having an increase or stabilization in PetCO 2 up to the gas exchange threshold (GET), an abrupt decrease in the rest-exercise transition or a progressive and slow decrease throughout exercise. A subgroup of patients with CTEPH underwent a constant work rate exercise test to obtain arterial blood samples during steady-state exercise. Results Multivariate logistic regression analyses showed that progressive decreases in PetCO 2 and SpO 2 were better discriminative parameters than Δ V ˙ E/Δ V ˙ CO 2 to distinguish CTEPH from IPAH. This pattern of PetCO 2 was associated with worse functional impairment and greater reduction in PaCO 2 during exercise. Conclusion Compared to patients with IPAH, patients with CTEPH present more impaired gas exchange during exercise, and PetCO 2 abnormalities may be used to identify more clinically and hemodynamically severe cases.

Hypocapnia and endothelial dysfunction might impair microvascular cerebral blood flow (CBFmicr) and cerebrovascular reactivity to CO2 (CVRCO2). Pulmonary arterial hypertension (PAH) is characteristically associated with chronic alveolar hyperventilation and microvascular endothelial dysfunction. We therefore determined CBFmicr (pre-frontal blood flow index (BFI) by the indocyanine green-near infrared spectroscopy methodology) during hypocapnia and hypercapnia in 25 PAH patients and 10 gender- and age-matched controls. Cerebral BFI was lower in patients than controls at similar transcutaneous PCO2 (PtcCO2) levels in both testing conditions. In fact, while BFI increased from hypocapnia to hypercapnia in all controls, it failed to increase in 17/25 (68%) patients. Thus, BFI increased to a lesser extent from hypo to hypercapnia ("Δ") in patients, i.e., they showed lower Δ BFI/Δ PtcCO2 ratios than controls. In conclusion, CBFmicr and CVRCO2 are lessened in clinically stable, mildly-impaired patients with PAH. These abnormalities might be associated with relevant clinical outcomes (hyperventilation and dyspnea, cognition, cerebrovascular disease) being potentially amenable to pharmacological treatment.

Cardiopulmonary exercise testing (CPET) on a treadmill or cycle ergometer provides an integrated assessment of the cardiorespiratory system during exertion and is widely used in clinical practice. An incremental step test (IST) can be an alternative for eliciting maximal exercise responses. Therefore, 20 patients with pre-capillary PH (65% female, 41 ± 15 yrs) randomly performed a symptom-limited CPET on a cycle ergometer and IST. Metabolic, cardiovascular, ventilatory and gas exchange variables were recorded during both tests. There was a greater desaturation and higher VO2PEAK in IST compared to CPET. The VO2GET, HR PEAK (% pred), ΔVE/ΔVCO2 and ΔHR/ΔVO2 were similar in both IST and CPET. By linear regression analyses, the work performed on IST [W = (mass × 9,8 m/s2 x vertical distance)] was a predictor of peak VO2 independent of the gender and age (r2 = 077, p = 0001). In conclusion, IST elicited higher peak cardiopulmonary responses and has a good agreement with known severity markers in patients with pre-capillary PH.

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: 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 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.

KEY POINTS: Dysfunction of post‐exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases. The afferent mechanisms that regulate the post‐exercise cardiac autonomic control remain unclear. We found that afferent signals from carotid chemoreceptors restrain the post‐exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH). Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults. The results demonstrate that the carotid chemoreceptors contribute to the regulation of post‐exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post‐exercise cardiac autonomic dysfunction in patients with PAH. ABSTRACT: Dysfunction of post‐exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post‐exercise cardiac autonomic control. Twenty non‐hypoxaemic patients with PAH and 13 age‐ and sex‐matched HA pedalled until 90% of peak work rate observed in a symptom‐limited ramp‐incremental exercise test. Recovery consisted of unloaded pedalling for 5 min followed by seated rest for 6 min. During recovery, subjects randomly inhaled either 100% O(2) (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O(2) (normoxia) as control. Post‐exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300 s of recovery, using linear and non‐linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post‐exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120 s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.

Schistosomiasis is a prevalent cause of pulmonary arterial hypertension (PAH) currently classified as Group 1 pulmonary hypertension (PH) [1]. In comparison to other etiologies of PAH such as idiopathic PAH, Schistosomiasis-associated PAH (Sch-PAH) has not been extensively studied. Potential mechanisms of PAH development in schistosomiasis include systemic and localised lung inflammation, involvement of other organs such as the liver and spleen, and direct blockage of precapillary vessels from parasite egg embolisation. Currently, the diagnosis of Sch-PAH relies on hemodynamics assessment using right heart catheterisation. In several etiologies of PH, loss of visualised distal vascular volume has been quantified from pulmonary angiography [2, 3] and computed tomography (CT) of the lungs [4–6]. Additionally, loss of distal vascular volume has been shown to be associated with loss of vascular cross-sectional area histologically [7]. In this pilot study we hypothesised that relative loss of arterial pulmonary vascular volume differentially correlates with hemodynamics in Sch-PAH patients, compared to a group of control subjects. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Conflict of interest: Dr. Rahaghi reports grants from NHLBI/NIH, during the conduct of the study. Conflict of interest: Dr. Hilton has nothing to disclose. Conflict of interest: Dr. Correa has nothing to disclose. Conflict of interest: Dr. Loureiro has nothing to disclose. Conflict of interest: Dr. Ota-Arakaki has nothing to disclose. Conflict of interest: Dr. Verrastro has nothing to disclose. Conflict of interest: Dr. Lee reports other from NANO X IMAGING LTD (NNOX), outside the submitted work. Conflict of interest: Dr. Mickael has nothing to disclose. Conflict of interest: Dr. Nardelli has nothing to disclose. Conflict of interest: Dr. Systrom has nothing to disclose. Conflict of interest: Dr. Waxman has nothing to disclose. Conflict of interest: Dr. Washko reports grants from NIH, grants and other from Boehringer Ingelheim, other from Quantitative Imaging Solutions, other from PulmonX, grants and other from Janssen Pharmaceuticals, other from GlaxoSmithKline, other from Novartis, other from Vertex, other from CSL Behring, outside the submitted work; and Dr. Washko's spouse works for Biogen . Conflict of interest: Dr. San Jose Estepar reports grants from NIH-NHLBI, during the conduct of the study; personal fees from LeukoLabs, grants and personal fees from Boehringer Ingelheim, personal fees from Chiesi, from null, outside the submitted work; and he is also a founder and co-owner of Quantitative Imaging Solutions which is a company that provides image based consulting and develops software to enable data sharing. Conflict of interest: Dr. Graham reports grants from NIH, during the conduct of the study. Conflict of interest: Dr. Oliveira has nothing to disclose.

Background: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have exercise limitation due to hemodynamic and gas exchange abnormalities. Also, a delayed oxygen uptake (VO2) recovery is expected in conditions with impaired O2 delivery and/or utilization as they would prevent a rapid payment of O2 debit. Therefore, we aimed to determine the clinical value of VO2 and O2 pulse off-kinetics during early recovery in predicting disease severity and survival of patients with CTEPH. Methods: Forty-two patients (27 women, 49±15 yrs) with CTEPH were followed for a median of 4.5 years. At baseline, they underwent right heart catheterization, six-minute walk test and incremental cardiopulmonary exercise test. The presence of an abnormal increase of O2 pulse during recovery and the time required for a 50% decline of peak VO2 (T1/2VO2) were recorded. Results: T1/2VO2 was negatively related with cardiac output (r= -0.5, p Conclusion: Increased O2 pulse during recovery as compared to O2 pulse at peak exercise is a marker of disease severity and poor prognosis, due to delayed VO2 recovery in relation to heart rate, in patients with CTEPH.

Indices of pulmonary vascular dysfunction are associated with mortality in chronic hypersensitivity pneumonitis http://ow.ly/1nwG30jwTSm

Increased “wasted” ventilation and heightened neural drive explains excess exercise ventilation in CTEPH http://ow.ly/Z4YBc

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

Background Pulmonary arterial hypertension (PAH) is characterized by a pulmonary capillary wedge pressure (PCWP) of ≤15 mm Hg, given a normal left ventricular filling pressure (LVFP). However, recent studies have shown that, in PAH patients, diagnosis based on PCWP can erroneously classify a significant number of patients compared with diagnosis based on left ventricular end-diastolic pressure (LVEDP). Therefore, we sought to compare the diagnostic accuracy of end-expiratory PCWP and LVEDP measurements in patients suspected of having pulmonary hypertension (PH). Methods We reviewed the hemodynamic data from 122 patients suspected of having PH who underwent simultaneous right- and left-side heart catheterizations at a PH referral center from 2006 to 2011. Results PH was diagnosed in 105 patients, 79% of whom ( n = 83) showed a pre-capillary pattern according to the LVEDP measurement. Ninety percent of patients with PCWP ≤15 mm Hg were correctly classified as having pre-capillary PH. However, 39% of patients with a PCWP >15 mm Hg had LVEDP ≤15 mm Hg and would have been erroneously diagnosed with pulmonary venous hypertension based on their PCWP measurements alone. The sensitivity and specificity was 0.89 and 0.64, respectively. A Bland-Altman analysis of the PCWP and LVEDP measurements revealed a mean bias of 0.3 mm Hg with 95% limits of agreement of −7.2 to 7.8 mm Hg. Conclusions A PCWP ≤15 mm Hg was found to be a reliable indicator of normal LVFP in pre-capillary PH patients. When measured properly and analyzed in the clinical context, PCWP is a valuable tool for accurate diagnosis of PAH.

The prevailing view is that exertional dyspnoea in patients with combined idiopathic pulmonary fibrosis (IPF) and emphysema (CPFE) can be largely explained by severe hypoxaemia. However, there is little evidence to support these assumptions.We prospectively contrasted the sensory and physiological responses to exercise in 42 CPFE and 16 IPF patients matched by the severity of exertional hypoxaemia. Emphysema and pulmonary fibrosis were quantified using computed tomography. Inspiratory constraints were assessed in a constant work rate test: capillary blood gases were obtained in a subset of patients.CPFE patients had lower exercise capacity despite less extensive fibrosis compared to IPF (p=0.004 and 0.02, respectively). Exertional dyspnoea was the key limiting symptom in 24 CPFE patients who showed significantly lower transfer factor, arterial carbon dioxide tension and ventilatory efficiency (higher minute ventilation (V′E)/carbon dioxide output (V′CO2) ratio) compared to those with less dyspnoea. However, there were no between-group differences in the likelihood of pulmonary hypertension by echocardiography (p=0.44). High dead space/tidal volume ratio, low capillary carbon dioxide tension emphysema severity (including admixed emphysema) and traction bronchiectasis were related to a highV′E/V′CO2ratio in the more dyspnoeic group.V′E/V′CO2nadir >50 (OR 9.43, 95% CI 5.28–13.6; p=0.0001) and total emphysema extent >15% (2.25, 1.28–3.54; p=0.01) predicted a high dyspnoea burden associated with severely reduced exercise capacity in CPFEContrary to current understanding, hypoxaemiaper seis not the main determinant of exertional dyspnoea in CPFE. Poor ventilatory efficiency due to increased “wasted” ventilation in emphysematous areas and hyperventilation holds a key mechanistic role that deserves therapeutic attention.

Introduction: Cardiopulmonary exercise testing (CPET) has long been used in the assessment of chronic dyspnoea. The aim of this study was to evaluate the role of CPET in the diagnosis of psychogenic dyspnoea in patients undergoing investigation of unexplained breathlessness. Methods: Patients performed ramp-incremental CPET on cycle-ergometer as workup evaluation of unexplained dyspnoea (UD) between 2010 and 2015. Detailed clinical history, complementary diagnostic tests, and final diagnosis were recorded. Results: Forty-seven patients with UD were identified. Mean age was 46 yo (17–71) and the majority were women (64%), with a mean BMI of 28.7 (16.9–43). CPET suggested central cardiac limitation to exercise in 5 patients, ventilatory limitation was inferred in 3 of them and deconditioning was considered to be the cause of limitation in 6 cases. Erratic breathing or persistent tachypnoea throughout exercise, consistent with Primary Hyperventilation Syndrome, was observed in 14 subjects (29%). In addition, 6 of 19 patients with normal CPET were also ultimately considered to have psychogenic dyspnoea by the referring physician in light of unremarkable physical examination as well as laboratory and radiologic evaluation ruling out organic causes of dyspnoea. The frequency of psychogenic dyspnoea was similar for both genders (41.2% male vs. 43.3% female), but interestingly erratic breathing was more commonly seen among women (11) than men (3). Conclusions: CPET was helpful in the diagnosis of psychogenic dyspnoea in patients with unexplained dyspnoea not only by identifying erratic and uncoupled ventilatory-metabolic responses, but also by excluding cardiorespiratory or metabolic abnormalities.

Introduction: Patients with CTEPH have more proximal and heterogenous obstructive vascular lesions that may lead to more pronounced gas exchange abnormalities during walking compared to patients with IPAH. Objective: To analyze the physiological responses during the 6MWT in patients with CTEPH and IPAH. Methods: 15 patients with IPAH (29.5±19.6 yrs; 53% female; 80% NYHA functional class II and III) and 27 with CTEPH (50.4±16.3 yrs; 60% female; 96% NYHA FC II and III), with similar resting hemodynamics (cardiac index: 2.21±0.43 vs 2.32±0.65 and pulmonary vascular resistance 1132±416 vs 883±352 dynes.s.cm -3 ) were included. Patients underwent the 6MWT using a portable metabolic cart (Oxycon Mobile). Results: There was no difference in the walking distance between the two groups, expressed in absolute or %predicted [419,7±61,7m (79±11%pred) vs 429,2±82,4m (78±14 %pred), p>0.05, VE/VCO 2 53±13 vs 57±11, p>0.05. Despite similar cardiovascular performance at the end of the test (heart rate 68±6 vs 67±17 %pred and O 2 pulse 70±16 vs 64±16%pred, p>0.05), patients with CTEPH presented a higher oxyhemoglobin desaturation by pulse oximetry (SpO 2 89±7 vs 85±4% p=0.03) and greater sensation of dyspnea [Borg score 3(0;6) vs 5(2;8) p=0,04]. Conclusion: Patients with CTEPH present more severe gas exchange abnormalities and greater sensation of dyspnea during 6MWT.

INTRODUCTION: Pulmonary bleeding is a possible complication of the enlarged bronchial arteries commonly found in patients with proximal vascular obstructive lesions. Therefore, we hypothesize that the incidence of haemoptysis in patients with operable CTEPH is higher than in non-operable CTEPH or PAH. METHODS: A cohort of 175 patients with PAH and 96 patients with CTEPH were followed up from 2010 to 2015. RESULTS: During a median follow-up of 2.4 yrs (2.6-3.1), clinically relevant haemoptysis occurred in 3/175 (1.7%) patients with PAH (1 idiopathic and 2 associated with rheumatic disease), in 1/41 (2.4%) patient with non-operable CTEPH and 4/56 (7%) patients with operable CTEPH. The event rate was 0.5, 0.9 and 7.7 per 100 patient-years, respectively (p CONCLUSIONS: Haemoptysis is more frequent in patients with operable than non-operable CTEPH or IPAH. Despite its rarity, it can present with life-threatening respiratory failure. Mechanisms are uncertain, but may involve bronchial and pulmonary arteries aneurysmatic dilatations.

Introduction: Despite therapeutic advances, exercise capacity of patients with CTEPH is often compromised. In addition to central haemodynamic impairment, systemic inflammation and low oxygen delivery may lead to abnormalities in peripheral striated muscles with important repercussion in muscular groups placed under high demand conditions. Since excessive ventilation is a key feature of patients with CTEPH, we hypothesize that inspiratory muscle weakness (IMW) is a frequent finding and may be associated with exercise impairment. Objective: To evaluate the frequency of IMW [maximal inspiratory pressure (Pi MAX ) pred ] in patients with CTEPH and its association with peak VO 2 obtained at cardiopulmonary exercise test (CPET) and distance of 6 minute walk test (6MWT). Methods: 24 patients with CTEPH [54±11 yrs; 38% male; 46% in NYHA functional class (FC) III/IV], confirmed by right-heart catheterization, underwent a CPET, 6MWT and PI MAX measurements. Results: Pi max pred was found in 41% of patients. Despite similar haemodynamics [cardiac index 2.4±0.6 vs 2.2±0.4L/min/m 2 and pulmonary vascular resistance (PVR) 854 ± 317 vs 823 ± 374 dynes.s.cm -3 ], patients with IMW showed lower 6MWD (342 ± 99 vs 442 ± 67m), lower peak VO 2 (50.8 ± 9.4 vs 63.8 ± 17.2% predicted) and increased ΔVE/ΔVCO 2 , compared to patients with Pi MAX >70% pred (p MAX was the only independent predictor of Peak VO 2 (partial r 0.445, p 0.04). Similar results were found for 6MWD as outcome variable. Conclusions: Pi MAX was independently associated with exercise capacity, when adjusted for resting heamodynamics and FC.

Introduction: Oxygen pulse is accepted as a surrogate for stroke volume (SV) and arteriovenous oxygen difference during cardiopulmonary exercise testing (CPET). It is frequently reduced in patients with pulmonary arterial hypertension (PAH) because of their inability to properly increase SV during effort. However, similar alterations can be seen in patients with abnormal oxygen extraction, such as mitochondrial myopathy (MM). We aimed to investigate whether cardiovascular responses during exercise would be able to distinguish PAH from MM. Methods: Comparison of incremental CPET of 16 patients with MM and 21 with PAH, matched for age, gender, and % predicted peak VO2 (39±14 vs 37±14yo, 85% vs 62% female, 58±12 vs 64±12%predVO2, for PAH and MM, respectively, p>0.05). Results: O2pulse at peak of exercise was similarly reduced in both diseases (70±22 vs 71±20%pred, p0.94), but ΔHR/ΔVO2 was higher in PAH (117±42 vs 94±18beats/L, p0.04). A cutoff of 120beats/L best discriminated the groups [Sensitivity 47%; Specificity 93%; Positive likelihood ratio (PLR) 7.6 (95% CI, 1.1-53)]. In addition, 15/21 (71%) PAH patients exhibited plateau or fall of O2pulse during exercise. In contrast, only 4/16 (25%) MM patients presented plateau (p Conclusion: A greater response of heart rate to oxygen consumption (ΔHR/ΔVO2≥120 beats/L) and the presence of an abnormal plateau of O2pulse during exercise are more frequently found in patients with PAH than MM.

BACKGROUND: Incremental cardiopulmonary exercise testing (CPET) is recommended to evaluate severity, prognosis and responses to intervention in patients with pulmonary hypertension (PH). Despite evidences regarding its utility, complication rates in the majority of studies involving CPET in PH are rarely reported. Therefore, we aimed to assess the frequency of side-effects related to CPET in a large adult PH cohort. METHODS: We reviewed all consecutive CPET performed between Jun07 and Dec15. A priori exclusions to perform CPET included: history of exercise-induced syncope or a non-stable clinical condition in the last month and pulse oxymetry RESULTS: From 2485 CPET performed, 1195 (48%) were done in PH patients. The mean age was 46±15yo and 69,7% were female. Regarding severe complications, 01 patient presented with syncope followed by seizure, 01 with somnolence and 05 with pre-syncope with hypotension. In addition, 9 patients presented with EKG abnormalities that led to CPET interruption: 05 supraventricular arrhythmias, 01 ventricular arrhythmia and 03 with angina and EKG signals of myocardial ischemia. In summary, the number of total serious complications that demanded exercise interruption was 16/1195 (1,33%) and all events resolved without sequelae or death. CONCLUSION: Our data, of a large sample of tests, provide evidence that CPET is a safe tool in clinical practice with a low risk of severe complications when performed by an experienced team in previous selected adult patients with PH.

Introduction: Despite controversy, Maximal Voluntary Ventilation (MVV) is still considerate a key physiological variable to assess ventilatory reserve in maximum cardiopulmonary exercise test. It can be measured or calculated using forced expiratory volume in 1 second (FEV1) by equations derived from healthy individuals. Patients with pulmonary hypertension (PH) may have abnormalities in pulmonary function tests that may change the accuracy of measured MVV. Objective: Determine whether calculated MVV is an adequate method in patients with PH. Methods: We evaluated 119 patients with PH (60% of Group 1 and 40% of Group 4 of Nice Classification; 66% female; 47±15yrs). Patients performed three acceptable and reproducible maximal maneuvers (difference of 10% or less between values) and recorded value was the highest. Estimated MVV was defined by an equation validated for Brazilian healthy population (MVV=FEV1x37.5+15.8). Results: The average of measured and estimated MVV was 98.1±21.2 and 100.7±27.2L/min, respectively. The agreement interval between them was wide and there was a great variability between values (mean difference: -2.6L/min; 95% limits of agreement range from −25.7 to 26.7L/min). There was an overestimation of estimated values at lower measured MVV and underestimation at higher values. Conclusion: There is a poor agreement between estimated and measured MVV in patients with PH.

Introduction: Despite advances in pharmacological treatment, mortality in patients with chronic thromboembolic pulmonary hypertension (CTEPH) not deemed to surgery remains high. Therefore, risk stratification is necessary to a better clinical management and to establish prognosis. Since enlarged dead space ventilation and low CO2 set-point are key features of this disease, we hypothesize that an excessive ventilatory response during exercise may indicate a poor outcome. Methods: Forty-two non-operable patients with CTEPH (49±15 yrs; 64% female, 57% NYHA functional class III/IV) were prospectively evaluated from 2010 to 2015. They underwent a right heart catheterization, a 6 minute walk test and an incremental cardiopulmonary exercise test (CPET) at baseline. Results:During a median follow-up of 2 years (95% CI, 2.1-3.4), 11 deaths were recorded. Estimated survival was 85% at 1 year (95% CI, 79-91); 81% at 2 yrs (74-87) and 77% at 3 yrs (70-84). In an univariate analysis, mortality was associated with pulmonary vascular resistance (PVR) ≥ 1000 dynes.s.cm-3 [HR 9.21 (1.17-72.16), p 0.03], 6 minute walk distance ≤ 360m [HR 6.03 (1.27-28.59), p 0.02], Peak oxygen consumption (VO2)≤ 45% pred [HR 3.43 (1.02-11.55), p. 0.04] and ventilatory response to carbon dioxide output (ΔVE/ΔVCO2)≥ 65 [HR 10.00 (2.15-46.57), p 0.003]. A multivariate analysis including PVR, Peak VO2 and ΔVE/ΔVCO2 revealed excessive ventilation to be an independent risk factor for mortality [adjusted HR 5.96 (1.18-30.64), 0.04]. Conclusion: Excessive exercise ventilation during incremental CPET is helpful for the prognostic evaluation of non-operable patients with CTEPH.

Right ventricular (RV) dysfunction harbingers adverse prognosis in pulmonary arterial hypertension (PAH). Although conventional two-dimensional echocardiography (2DE) is limited for RV systolic function quantitation, RV strain can be a useful tool. The diagnostic and prognostic impact of 2DE speckle-tracking RV longitudinal strain was evaluated, including other 2DE systolic indexes, in a group of PAH patients without severe impairment of functional capacity, chronic pulmonary thromboembolism or left ventricular dysfunction. Sixty-six group I PAH patients, 67 % NYHA functional class I or II (none in IV) were studied by 2DE to obtain: RV fractional area change, tricuspid annular plane systolic excursion, RV myocardial performance index, tissue Doppler tricuspid annulus systolic velocity. Global, free wall (RVFreeWSt) and septal RV longitudinal systolic strain were obtained. RV ejection fraction by cardiac magnetic resonance (CMR-RVEF) was also assessed. All patients were followed up to 3.9 years (mean 3.3 years). Combined endpoints were hospitalization for worsening PAH or cardiovascular death. Among all the 2DE indexes of RV systolic function, RVFreeWSt exhibited the best correlation with CMR-RVEF (r = 0.83; p

Hypocapnia and endothelial dysfunction might impair microvascular cerebral blood flow (CBF

a Pulmonary Function and Clinical Exercise Physiology Unit (SEFICE), Respiratory Division, Department ofMedicine, School ofMedicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil b Pulmonary Vascular Group, Respiratory Division, Department of Medicine, School of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil c Laboratory of Clinical Exercise Physiology (LACEP), Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen's University, Kingston, Canada d Respiratory Investigation Unit (RIU), Division of Respiratory and Critical Care Medicine, Department of Medicine, Queen's University, Kingston, Canada

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.

To the Editor: Pulmonary arterial hypertension (PAH) remains a disabling and frequently lethal disease despite remarkable advances in treatment. Cardiopulmonary exercise testing (CPET) has proved a valuable tool to objectively quantify disease severity and estimate prognosis in these patients [1–3]. Exercise intolerance is characteristically multifactorial in PAH. Among its potential contributing mechanisms, increased ventilatory response, deranged pulmonary mechanics, peripheral muscle impairment and reduced oxygen delivery have been more widely investigated [1–5]. In this context, a CPET-derived variable that conflates the effects of increased ventilation and poor O2 transfer and/or peripheral O2 utilisation is the O2 uptake efficiency slope (OUES) [6]. OUES is the slope of the linear relationship between O2 uptake ( V ′O2) and the logarithmic transformation of minute ventilation ( V ′E) during rapidly incremental exercise, i.e. it aims to reflect how effectively O2 is extracted from the atmosphere and taken into the body as exercise progresses. We recently found that a combination of increased sub-maximal exercise V ′E as a function of carbon dioxide output ( V ′CO2) and reduced O2 delivery/utilisation (as suggested by shallow V ′O2–work rate relationship) were independent predictors of negative outcome in PAH of mixed aetiology [7]. These findings prompted the hypothesis that OUES would combine the prognostic information provided separately by those variables, thereby being the single predictor of poor outcome in our cohort. In order to address this question, we revisited our dataset and contrasted OUES prognostic relevance with that of a range of resting and cardiopulmonary exercise responses to ramp-incremental cycle ergometry. In the previous report [7], we described results from a group of 84 patients in whom 16 PAH-related deaths and two …

The aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH). Case–control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients. Twenty patients from each group were tested. Bilateral severe keratitis was found in seven (35 %) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced (p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users (p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters. One-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil.