Evidence regarding the detrimental effects of exposure to stress on glycemic control among diabetes patients has mainly focused on personal life events or acute trauma. However, the effects of continuous exposure to extreme stress on type 2 diabetes patients have rarely been studied. The aim of the current study was to examine the association of continuous exposure to rocket attacks with glycemic control and with risk factors for diabetes complications among civilian type 2 diabetes patients. We focus on patients residing in the Western Negev in the south of Israel that has been subjected to rocket attacks fired from Gaza since the end of 2001.1c, BMI, LDL cholesterol, blood pressure. General Linear Models (GLM) were used for analysis.A two-arm retrospective cohort study of type 2 diabetes patients, aged 35–70 years, residing in a region with chronic exposure to rocket attacks (N = 1697) and in a non-exposed comparison region in Israel (N = 3000). Data were retrieved from the Health Maintenance Organization (HMO)’s database for four time periods representing exposure: chronic—2008; elevated—2009 (post’Cast Lead’ operation); return to chronic—2010, 2011. Data included socio-demographic variables, HbA1c, the model yielded a significant main effect for time, a borderline significance main effect for region, and a significant time by region interaction: no differences in HbA1c levels between the regions in 2008 and 2009, followed by significant differences between the regions in 2010 and 2011 when HbA1c continued to increase in the exposed region but decreased in the comparison region. Regarding risk factors, a significant main effect for time for LDL cholesterol only, and significant main effects for region were found in all factors: BMI and LDL cholesterol were higher in the exposed than in the comparison region, but blood pressure values were lower.For HbAContinuous exposure to rocket attacks is associated with glycemic control and risk factors in a complex pattern. These preliminary findings require further studies of diverse types of civilian exposure to continuous extreme stress. Additionally, a small but significant difference was found between the two regions in SES: a higher proportion of patients (33 %) in the exposed region than those in the comparison region  were exempt from co-payments.Mean age was 59.5 (8.5), 53 % were men. Patients in the exposed vs. the comparison region were significantly younger [58.8 (9.4) and 59.9 (8.0), respectively, t test for continuous variables and χ2 tests for categorical variables. A series of General Linear Models (GLM) was conducted to examine the effect of region (between group differences) and time periods (within group differences) on glycemic control and risk factors and included interaction terms for region with time, controlling for age and sex. p value in all the models was set at p < 0.05 for statistical significance. Data of laboratory test results for some of the indicators and recorded blood pressure values were missing in the HMO database. This may be a source of selection bias because patients who do not come for regular follow-ups could differ from those who did; yet we found no significant differences by age, gender, SES or region in any of the measures.Descriptive statistics were assessed and bivariate differences between the two regions were tested using p = 0.065) main effect for region. Additionally, the model yielded a significant time by region interaction: There were no differences in HbA1c levels between the regions before (2008) or during the acute period (2009), and the levels increased in both regions from 2008 to 2009. However, in the follow-up years 2010, HbA1c level continued to increase in the exposed region but decreased in the comparison region. Examining the source of the interaction revealed significant differences between the regions only in 2010 and 2011, and significant differences within each region between the 2008 and all the other times . Yet, the effects of time, region and the interaction are minimal (<1 %).The GLM results are shown in Table p < 0.05, after Bonferroni correction).The GLM models of risk factors yielded a significant main effect for time only for LDL cholesterol, which improved over the years, and significant main effects for region in all risk factors. Compared to patients in the comparison region, patients in the exposed region had higher BMI and LDL cholesterol levels but lower blood pressure values. Additionally, the model for systolic blood pressure yielded a significant time by region interaction: the levels decreased in the comparison region over time , they fluctuated in the exposed region and were significantly different from those in the comparison region in 2008 and 2009 .Second, while we expected an increase in 2009 in the exposed area, following “Cast Lead” operation, the similar increase in the level of HbAsymptoms , even resymptoms . Others symptoms . Once th1c, as part of the neuroendocrine system role in response to stress. One assumption is that responses to acute stressful events that are protective and adaptive in nature differ from those to chronic stress which elicits neurochemical, neuroanatomical and cellular changes that may have deleterious consequences upon higher brain functioning [The increased risk for diabetes comorbidities was also expressed in the significantly higher levels of BMI and LDL cholesterol among patients in the exposed region, suggesting that they may have had more difficulties in adherence to healthy life style and/or impaired compliance to medications. Additionally, although systolic and diastolic blood pressure values were lower in patients in the exposed region, the decrease (in systolic BP) over time was smaller than in patient in the comparison region. In view of the absence of findings on changes in these medical factors in previous studies, our findings are preliminary. Further examination is required in order to understand the physiological mechanisms of the effects of the risk factors and in conjunction with HbActioning .Our findings suggest that the continuous chronic and acute stress periods of exposure to rocket attacks has complex pattern of consequences for glycemic control: no difference between the regions after several years of exposure , but an activation of reaction—poorer glycemic control—after an acute period. However, this pattern should be interpreted in the context of the study limitations. First, no causality can be assumed as we lack of data on glycemic control in the pre-exposure to rocket attacks period and the first years of exposure. Second, although the analyses controlled for demographic differences, it may be that despite our efforts in selecting similar towns and villages (not from a metropolitan area) in the comparison region, differences in the delivery of medical care between central and peripheral regions persisted. Due to our unmatched design we cannot rule out the possibility that patients in the comparison region differed on other important variables unknown to us, such as adherence to diabetes self-management or depression. A third limitation relates to the generalizability of our results. Continuous rocket attacks are a unique type of extreme traumatic stress, and reactions to other types of continuous traumatic situations may be different. Fourth, our reliance on data retrieved from the HMO database restricted our ability to adjust for additional confounders  and was compounded by missing test results for some of the indicators that, although no selection bias was detected, was subjected to other differences in ways we were unable to measure. Therefore, our preliminary findings should be further examined in studies with a matched case design of patients by age, gender, SES and duration of diabetes, and include a wider array of variables, and different patterns of exposure to chronic extreme stress. They will benefit from inclusion of more representative samples as well as other chronic patients in order to reach better conclusions about long-term effects.The current study, although being preliminary, provides data that, to our best knowledge, have not been studied before. These findings have significant implications for clinical practice. Health care professionals need to be aware of a potential association of continuous exposure to trauma with health outcomes for diabetic patients and probably for patients with other chronic diseases. This chronic exposure and the prospects for acute peaks of tension, may lead to allostatic load, and should be monitored for its potential effects on glycemic control and other implications of chronic diseases control and management in the long run. In addition to individual-level interventions, group stress management programs are another effective tool in a “real-world” setting to achieve clinically significant benefits for patients with type 2 diabetes , calling


Asthma exacerbations are important events that affect disease control, but predictive factors for severe or moderate exacerbations are not known. The objective was to study the predictive factors for moderate (ME) and severe (SE) exacerbations in asthma patients receiving outpatient care.p <0.1) factors were then subjected to multiple analysis by binary logistic regression.Patients aged > 12 years with asthma were included in the study and followed-up at 4-monthly intervals over a 12-month period. Clinical , atopic, functional, inflammatory, SE and ME parameters were recorded. Univariate analysis was used to compare data from patients presenting at least 1 SE or ME during the follow-up period vs no exacerbations. Statistically significant , women (nearly 70%), with moderate and mild persistent asthma (>80%). Twenty-seven patients (8%) had a SE and 183 had a ME (58.5%) during follow-up. In the case of SEs, the only predictive factor identified in the multiple analysis was previous SE  and inhalation technique (OR 3.572 95% CI 1.324-9.638). In the case of MEs, the only predictive factor found in the multiple analysis were previous ME .The primary predictive factor for SE or ME is prior SE or ME, respectively. SEs seem to constitute a specific patient "phenotype", in which the sole predictive factor is prior SEs. Asthma exacerbations affect the clinical course of the asthma patient. Although different studies have used different definitions of asthma exacerbation, it is generally accepted that severe exacerbations (SE) are those requiring urgent intervention, defined as prescription of systemic steroids  or dose increase of maintenance steroids for at least 3 days, visit to the emergency department or hospitalisation due to aggravation of symptoms. Moderate exacerbations (ME) have been defined as any deterioration in the patient's symptoms or lung function, beyond day-to-day variations associated with the disease requiring a change of medication but that do not meet severe criteria . TreatmeSeveral studies have attempted to determine which factors can predict SEs, and an evaluation of these elements can contribute towards reducing the impact of exacerbations and confirm the existence of a group to be “at risk” patients that merit special monitoring. Exacerbation predictors suggested to date include factors such as current control (based on the GINA severity classification), or clinical control tests –7. OtherAlthough a large number of studies in predictive factors for SEs in asthma have been published, most of these include patients seen in emergency departments or presenting with serious or "near fatal" asthma. Few studies have focussed on evaluating the predictive factors for exacerbation in patients receiving outpatient care, and even fewer have attempted to identify factors capable of predicting SEs, and a possible relationship between both types of exacerbation has not been confirmed.The aim of our study was to evaluate predictive factors for exacerbations in a large group of patients followed up for 12 months in an outpatient asthma clinic. To our knowledge, this is the first study in terms of setting (pulmonology outpatient clinics), type of patient (mostly mild to moderate), and type of exacerbation (both moderate and severe).Prospective study conducted from March 2007 to March 2010 in asthma outpatient clinics attached to a Pulmonology Department.Inclusion criteria were: patients aged over 12 years, previously diagnosed with asthma according to GINA 2006  clinicalOn the day each patient was recruited for the study, the researcher, following protocol, noted their epidemiological and clinical variables. Once they had been examined by the attending doctor, the patient was handed over to a registered nurse for ACT, FeNO, forced spirometry, and allergy testing, if this had not been performed previously. Patients with long-term treatment were told to suspend the last dose prior to undergoing functional tests. FeNO was measured by means of an electrochemical device . Forced spirometry was measured using Master Scope PC Viasys Healthcare spirometers and JLab, Lab Manager, V 5.3.0, software, following ATS/ERS  recommenPatients completed the ACT (Asthma Control Test) questionnaire, comprising 5 questions related to asthma symptoms and use of asthma medication during the 4 previous weeks . The senBased on the results of the patient-doctor interview and the functional tests, patients were assigned a level of severity  and the level of control was established according to GINA 2006  (controlSE (severe exacerbation): was defined as an exacerbation meeting at least 1 of the following conditions: a) use of systemic steroids, or increased maintenance dose - in this case, a course of oral steroids or an increase in the maintenance dose lasting from 3 to 30 days, based on symptom severity and the opinion of the attending pulmonologist; b) hospitalisation or treatment in the emergency department due to the need for systemic steroids to control the exacerbation.ME (moderate exacerbation), was defined as: aggravation of the patient's usual symptoms requiring increased rescue bronchodilator use at least for 2 days so the patient need finally to increase maintenance medication but no oral o sistemic steroids, no hospitalisation and no treatment in the emergency departement.Uncontrolled days were defined as the number of days during which the patient had to use rescue medication or increase their maintenance dose to control their asthma symptoms.Unscheduled medical care was defined as a spontaneous medical consultation requested by the patient due to symptoms they were unable to control by themselves.A complete blood count, including eosinophils, was ordered at the baseline visit.Patients were given a symptom diary and asked to note down all clinical events over the study period. The diary was checked at 4, 8 and 12 months of follow-up. During these follow-up visits, patients were evaluated according to their GINA level of control and ACT. Spirometry (reversibility testing) and FeNO testing were performed, and the patient was asked about the study variables . Treatment compliance was evaluated by the attending nurse on the basis of the patient's own assessment, and classified as good (more than 75% of the prescribed dose), fair (50% - 75% of dose), or poor (<50% of dose). Inhaler technique was also checked during the interview, and classified as correct or incorrect. At the final visit, a new complete blood count, including eosinophils, was ordered.All patients were asked to sign an informed consent form authorising inclusion of their clinical data in the study database. At no time were the patient's personal details entered into the database; instead, they were assigned a reference number that correlated with their medical records, which were stored in separate files under the custody of the researchers. This study was approved by the hospital's independent ethics committee.Data were analysed with the statistical analysis programme SPSS v. 17. Qualitative variables were expressed as percentages, and quantitative variables as mean plus standard deviation (SD), minimum, maximum and percentiles 25,50 and 75.t test was used for quantitative variables, while the related sample t test was used to analyse differences in follow-up variables. Prior to this, the groups were tested for homogeneity of variance (Levene's test). The Mann Whitney U test or the Wilcoxon matched pairs was used to compare ordinal independent variables. The Chi-square test was used to evaluate differences between qualitative variables.To analyse differences between patients presenting one or more SEs and MEs and the rest of patients, the independent samples All variables with a statistical significance of < 0.1 in the univariate analysis were included in the multivariate binary logistic regression model and the corresponding odds ratios (OR) were assigned to a 95% confidence interval.p <0.05.Statistical significance was set at A total of 407 patients were included in the study, of which 330 completed all follow-up stages 4, 8 and 12 months), and were included in the final analysis. Mean age was 39.2 (16.7) years, with women being in the majority (69.7%). Table 2 months,p <0.01), inhaler technique (p <0.03), number of serious exacerbations in the previous 4 months (p <0.001) and severity of disease (p <0.01).Twenty seven patients presented an SE during the follow-up period . When we evaluated the differences between patients presenting an SE during follow-up vs those that did not on the basis of their baseline general and clinical characteristics, pulmonary function and FeNO, the univariate analysis showed significant differences in the equivalent dose of inhaled steroids (p <0.01).Using these same variables to analyse 4-month follow-up data from patients with an SE at between 4 and 12 months, we also found significant differences in the number of previous SEs, (0-4 months)  and inhalation technique (OR 3.572 [95% CI 1.324-9.638]). When we included statistically significant variables from the 4-month follow-up, we also found SE in the previous 4 months to be the only associated factor (OR 6.889 [95% CI 2.018-23.512]), (Table p <0.001), number of SEs, (p <0.04), sex (p <0.04), equivalent maintenance dose of inhaled steroids (p <0.05), while borderline significant differences  were found in BMI (p <0.07) and postbronchodilator FEV1 (p <0.09). Analysing these same variables for patients with an ME at 4 and 12 months at the 4-month follow-up, we found significant differences in ACT (p <0.001), GINA control (p <0.001), previous ME episodes (0-4 months) (p <0.001), FENO (p <0.02), previous uncontrolled days (p <0.01), and absolute FEV1 (p <0.05).A total of 193 patients (58.5%) presented 1 or more moderate exacerbations over the 12-month follow-up period, univariate analysis of baseline data interview to compare patients presenting an ME and those that did not showed significant differences in the number of previous MEs  and MEs in the previous 4 months was t related with MEs (OR 1.702 95% CI 1.146-2.529).In this study, we prospectively evaluated asthma patients followed up in outpatient pulmonology clinics to determine factors that could predict an SE or ME in the following year. The multiple analysis showed that previous SEs at both the baseline interview and 4-month follow-up is the only predictive factor for SE in the future. The only predictive factor for ME at baseline visit was previous ME, while the 4-month follow-up ACT test score was a predictive factor.> 12 years in the US diagnosed with severe or difficult-to-treat asthma (TENOR study). In this project, the factor most strongly related with future exacerbations was recent exacerbations (OR 6.33). Other less important predictive factors were severity of disease (severe asthma) and level of control. These data were used in a more recent study [Several different studies have evaluated predictive factors for asthma exacerbations. However, the patient profile in these studies usually differs from ours, which included patients receiving treatment in pulmonology outpatient clinics. Under our inclusion criteria, most patients presented mild or moderate asthma, with a small group of severe asthma patients. Patients with more serious disease and with more previous exacerbations, or those taking oral steroids in the month prior to the baseline interview, were excluded. Our aim in including this type of patient was to study clinical and functional variables and inflammatory parameters without interference from changes in the patient's usual status brought about by intensive recent treatment with oral steroids. In view of the follow-up schedule (4-monthly), we did not include patients whose baseline severity required more frequent follow-up. Because of this, the results of our study cannot, a priori, be generalized to patients with more severe disease. As a result, relatively few of our study subjects presented an SE during follow-up . Nevertheless, the predictive factor uncovered in the multivariate analysis (previous SE) is consistent with the findings of other studies, such as Miller et al. in 2007 , a prospnt study  that inctions OR .33. Othent study  found thnt study , 20.In our series, we also found that SE in the 4 months prior to the baseline interview, and between this interview and the 4-month follow-up, can predict SE in the future (baseline or 4 to 12 months). Indeed, SE between the baseline interview and 4-month follow-up was the factor with the greatest effect size OR 6.889). This, therefore, appears to be important not only in patients with severe asthma, but also in patients with different levels of disease severity receiving treatment in outpatient clinics. Other predictors of exacerbation described in the literature include poor compliance with inhaled steroid therapy . This, t, high FeOther predictors of future exacerbations include the score obtained in some clinical questionnaires. In this respect, some studies have evaluated the benefits of the Asthma Control Questionnaire (ACQ) , the AstThe limitations of our study are mainly due to the type of patient included. The decision to exclude patients with more severe disease or more prior exacerbations probably prevented us from finding other predictive factors. Moreover, prior MEs at the baseline visit were limited to those occurring up to 4 months previously, but excluded the month immediately before starting the study. During this month, according to the protocol, study patients should not have taken systemic steroids. We did not investigate the origin of the exacerbation, and instead relied on the patient's own report. This was because they were mostly treated at the patient's primary healthcare centre or in hospital. We did not use a validated test to determine the level of therapeutic compliance, and instead relied on the patient's own reported compliance. This could underestimate the patient's adherence and the effect of this variable on future exacerbations.Finally as a limitation of our study is that it has a prospective and unblinded design, that could have influence on the collection of variables and results.Despite the foregoing, we believe our results can be extrapolated to the study population (patients with mainly mild to moderate disease in specialist. We also believe that these results could reveal a particular SE patient profile or phenotype, irrespective of other clinical, functional or inflammatory parameters.In conclusion, in our cohort of asthma patients followed-up for 1 year, the main predictive factor for future SE was prior SE, predictive factors for ME were prior ME.The primary predictive factor for SE or ME is prior SE or ME, respectively. SEs seem to constitute a specific patient "phenotype", in which the sole predictive factor is prior SEs.


Disruption of the intestinal barrier and bacterial translocation commonly occur when intestinal blood flow is compromised. The aim of this study was to determine whether liver resection induces intestinal damage.We investigated intestinal fatty-acid binding protein and insulin-like growth factor binding protein levels in the plasma of patients who underwent liver resection.We show that liver resection is associated with significant intestinal barrier injury, even if the Pringle maneuver is not performed.We propose the use of insulin-like growth factor binding protein-1 as a novel biomarker of intestinal damage in such situations. Several reports have revealed that in several clinical situations, such as burns Because blood transfusion secondary to intraoperative blood loss is associated with early- and long-term complications in patients subjected to liver resections, several strategies, such as total Eighteen patients who underwent liver surgery at Hospital Sirio Libanes in São Paulo (Brazil) were eligible for inclusion in this study. All patients had colon cancer. Surgeries were performed to resect one or multiple liver metastases. Only three patients, who required the Pringle maneuver, were excluded. Perioperative profile of the study population is shown in Central venous pressure was maintained at a low level (below 10 mmHg) during liver resection to reduce bleeding and to facilitate liver tissue manipulation. Seventeen patients underwent major liver resection (>3 segments), and one patient underwent a minor resection (segmentectomy). During the procedure, catheters were inserted to monitor the central venous and radial arterial pressures. Parenchymal resection was performed using bipolar cautery, sutures and vascular staples. Blood samples were obtained from the arterial line at the start of the procedure and 8h later. Blood was collected in EDTA-containing vacuum tubes, kept on ice, and centrifuged at 4°C; the plasma was stored at -70°C. Intestinal fatty acid binding protein (IFABP), a specific marker of intestinal barrier dysfunction p value of <0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism 5.0 for Windows.Data are expressed as the means±SD. The results were compared using Student’s t-test. A We found a significant increase in the plasma levels of IFABP , IL-6 F and IGFBPrevious studies have shown that, in patients undergoing liver resection, total or intermittent Pringle maneuvers are associated with an increase in IFABP plasma levels due to the loss of enterocyte membrane integrity. In addition to the Pringle maneuver, alternative strategies have been used during hepatic resection to minimize intraoperative blood loss, such as the pharmacological reduction of central venous pressure. However, we hypothesized that this strategy would reduce the arterial blood pressure, which might also compromise the intestinal blood flow. As previously demonstrated, reduction of intestinal blood flow is followed by intestinal barrier dysfunction and bacterial translocation In the present study, we observed a significant increase in IFABP blood levels, at 8h after hepatic resection, with a reduction of the central venous pressure during liver transection even without the Pringle maneuver , and a sIGFBPs are important physiological regulators of the interaction of insulin-like growth factors (IGFs) with their receptors within the gastrointestinal tract and liver In a previous study, intestinal epithelial cell damage and endotoxemia were demonstrated to occur after the Pringle maneuver during liver resection In conclusion, the present study demonstrated that, even without the Pringle maneuver, intestinal barrier dysfunction most likely occurs secondary to the reduction of intestinal blood flow induced by pharmacological manipulation of the central venous and arterial pressure.In the modern era of liver surgery, the Pringle maneuver has been restricted to situations in which major bleeding occurs. Future investigations are necessary to establish whether intestinal barrier dysfunction plays a role in the etiology of infectious or noninfectious perioperative complications. Intestinal barrier dysfunction may be an important concern in patients with small liver remnants. In fact, endotoxin translocation, secondary to intestinal barrier dysfunction, may induce liver damage A previous study in patients with biliary malignancy demonstrated that bacterial translocation can predict the occurrence of postoperative infectious complications after liver resection Thus, we propose that novel techniques to perform liver resections without the Pringle maneuver and without reduction of the central venous pressure should be explored because both of the latter procedures compromise the intestinal integrity. IFAPB is a reliable marker of intestinal injury even before such injury can be detected by histological analysis. The gut is the main producer of IGFBP-1, although other organs can produce it in smaller amounts. We suggest that IGFBP-1 is a novel marker of intestinal damage, but further studies are necessary to confirm this finding.Barbeiro HV performed the experiments. The remaining authors designed the project and wrote the manuscript.


The study was designed to examine if baroreflex sensitivity (BRS) could predict the short-term outcome of postural tachycardia syndrome (POTS) in children.Seventy-seven children subjects were included in the study. Among them, 45 children were in the POTS group and another 32 healthy children were in the control group. A ninety-day clinical follow-up was conducted and the symptom score before and after the follow-up was calculated for POTS patients by using POTS score system. Hemodynamics and continuous BRS monitoring were recorded by Finapres Medical System-FMS . According to the symptom score change during follow-up period, POTS patients were further divided into subgroup A (n = 24) with symptom score decreased by at least two points and subgroup B (n = 21) with symptom score decreased by less than two points. The predictive value of BRS in the short-term outcome of POTS in children was analyzed using receiver-operating characteristic (ROC) curve.BRS of POTS children was significantly higher than that of the healthy children . It was higher in subgroup B than that of subgroup A . BRS was positively correlated with HR change in POTS Group . Area under curve (AUC) was 0.855 , and BRS of 17.01 ms/mmHg as a cut-off value yielded the predictive sensitivity of 85.7% and specificity of 87.5%.BRS is a useful index to predict the short-term outcome of POTS in children. Its symptoms had significant associations with postural change. Main hemodynamic characteristics of POTS was a significant increase in heart rate at upright position compared with supine position, and the increase amplitude of heart rate is ≥40 heart beats/min, or the maximum heart rate is ≥120 heart beats/min . Studies/100,000 , while o/100,000 . Therefoet al. showed that POTS children had abnormality of autonomic nervous function [et al. showed that sympathetic activity of POTS patients increased abnormally, and the abnormality of autonomic nervous activity was involved in pathogenesis of POTS [Generally speaking, the POTS prognosis is related with its pathogenesis . The prefunction . Furlan, of POTS . Therefoet al. showed that the reduction of BRS was closely related to the occurrence of hypertension [BRS comprises basic mechanistic elements of regulating blood pressure. Carotid sinus and aorta arch sense the traction of vascular wall by blood pressure change, transmitting to cardiovascular regulatory center of medulla and hypothalamus, thus to regulate the activity of autonomic nervous system. Thus, BRS plays an important role in keeping the stability of cardiovascular function, especially the regulation of upright blood pressure change. Harrington, rtension . HoweverThis research included 45 POTS children, all of whom were admitted to the Department of Pediatrics of Peking University First Hospital because of orthostatic intolerance symptom from November 2013 to August 2015. They were diagnosed as POTS according to the clinical pictures and upright tilt test [Medical records and samples were obtained from November 2013 to August 2015. Authors had access to information that could identify individual participants during data collection. All the selected subjects had no history of fever and medication within two weeks. This research protocol was approved by Ethics Committee of Peking University First Hospital, Beijing, China and the informed consent was obtained from parents and guardians of all study subjects. We obtained informed written consent from the next of kin, caretakers, or guardians on behalf of the children enrolled in the study. The Ethics Committee of Peking University First Hospital for Clinical Study approved this consent procedure.(1) mainly elder children; (2) with orthostatic intolerance, such as dizziness and headache, amaurosis, palpitation, nausea, blurred vision and even syncope in severe cases, with orthostatic intolerance symptoms lasting for at least three months; 3) positive head-up tilt test (HUTT) with an increase in heart rate ≥ 40 heart beats/min or a maximum heart rate ≥120 heart beats/min when upright or tilt within 10 min, accompanied with orthostatic intolerance symptoms including dizziness and headache, amaurosis, palpitation and nausea, and blurred vision, and syncope might be cause in severe condition; (4) in addition, other diseases that could cause orthostatic intolerance symptoms including cerebral vascular diseases and organic heart disease were excluded [ positiveThe protocol for HUTT was according to the previously published literatures , 20. ChiFMS  with a finger sensor was used for continuously monitoring and collecting hemodynamic data generated beat-by-beat. HR, BP and BRS were measured using a model flow method. With a finger cuff, arterial blood pressure was obtained continuously and noninvasively by using the system and beatscope software with the volume-clamp technique maintaining the diameter of the artery under an inflated finger cuff at a set point, thereby determining arterial pressure with time changes. Diodes were located in the finger cuff, on either side of the finger, to detect changes in artery diameter and change the inflation of the cuff to remain the diameter at the set point. The cuff is inflated or deflated via an air bladder connected to an air hose and pump. The software, using a mathematical model, generates an aortic pulse waveform from the finger arterial pressure wave. This computation takes into account changes in the pulse pressure and waveform shape as the pressure pulse is transmitted down the brachial arteries to the finger arteries. With the Finapres finger cuff, together with beatscope software, left ventricular stroke volume was calculated and together with HR and BRS were calculated. The BRS was calculated at rest and in supine position. Parameters such as age, sex, body height and weight were also included in the computation for each individual subject –23. The Symptom scoring was applied to evaluate the effect of conventional therapy. Score was calculated according to occurrence frequency of clinical symptom of subjects to carry out respective score of clinical symptom when diagnosed and at follow-up of patients; symptom score when diagnosed was recorded as baseline score, and symptom score at follow-up was recorded as the end score. Score calculation was also applied to control subjects. Subjects were instructed to rate their symptoms for at least 3 months prior to completion of questionnaire by parent or subjects. Score included the following clinical symptoms: syncope, dizziness, chest tightness, nausea, palpitation, headache, blurred vision, hand shaking and cold sweat. The score calculation standard was provided below: 0 score, no symptoms; 1 score, symptoms less than once on average per month; 2 scores, 2–4 times on average per month; 3 scores, 2–7 times on average per week; and 4 scores, over once on average per day. All the scores were the sum of each symptom-based score. After children were diagnosed as POTS, baseline symptom scores were recorded, and scores were recorded again at follow-up according to symptom score system. Those whose end scores at follow-up decreased by more than 2 scores compared with baseline scores were assigned into subgroup A; while those whose end scores increased or decreased less than 2 scores compared with baseline scores were assigned into subgroup B –27.The conventional therapy was used for each POTS child in this research after diagnosis, including oral rehydration saline (ORS), exercise of autonomic nervous function and health education. The dosage of ORS was 1 bag/day. One bag of ORS contained 0.65 g of sodium chloride, 0.725 g of sodium citrate, and 0.375 g of potassium chloride. The exercise of autonomic nervous function used in this research mainly included upright training. The method of upright training was to stand against a wall , once a day, for 5–20 min. The training time was gradually extended according to the tolerance degree of upright position. In case of syncope aura or other disorders occurred, the training was terminated immediately –29. HealThe analysis was carried out with SPSS 16.0 software, and measurement data are expressed in mean ± standard deviation. Independent sample t-test was used for comparison of BRS between two groups, and variance of analysis was used for comparison among three groups. Pearson correlation analysis was used for correlation analysis, and chi-square test was used for comparison of rates. ROC curve was used to analyze BRS on prediction of the prognosis of POTS children, and area under curve indicated the value of the index on prediction of the result; area under curve between 0.5–0.7 indicated a relatively small predictive value, area under curve between 0.7–0.9 indicated a medium predictive value, and area under curve above 0.9 indicated a relatively high diagnostic value. Ninety-five percent of confidence interval of the curve area (not including 0.5 or p<0.05) indicated that the index had a value on prediction of the research result. P<0.05 indicated there was statistical difference.The POTS group included 25 males and 20 females, at the age of 12.5±2.5 years old. Control group consisted of 19 males and 13 females, at the age of 11.8±3 years old. Two groups had no statistical difference (p>0.05) in gender ratio, age, height, weight, systolic pressure at supine position, and diastolic pressure at supine position. The heart rate of POTS children at supine position, however, was lower than that of children in control group (p<0.05), and BRS value of POTS group was higher than that of children in control group (p<0.01) .The end symptom score at follow-up was lower than the baseline symptom score when diagnosed (p<0.01) in POTS group . The basNo statistical difference were found in gender ratio, age, height, weight, heart rate, systolic pressure at supine position, and diastolic pressure at supine position between the subgroup A and subgroup B (p>0.05) . There wBRS of POTS children was significantly higher than that of the healthy children . It was higher in subgroup B than that of subgroup A  .Correlation analysis of BRS and HR in POTS group: Heart rate change from supine to upright was positively correlated with BRS in POTS group .ROC curve of the predictive value of BRS for short-term outcome of POTS: The ROC curve showed that the area under the curve was 0.855 (95%CI 0.735–0.975). With BRS value of 17.01 ms/mmHg as a cutoff value, the predicted sensitivity was 85.7%, and specificity 87.5% .et al. showed that POTS patients were characterized by intolerance to movement and physical labor in addition to orthostatic intolerance [POTS has a relatively high incidence among school-aged children, with the proportion of girls higher than boys . In Chinolerance . TherefoThe pathogenesis of POTS mainly involved autonomic nervous dysfunction . BRS plaet al. showed that low blood volume might cause increase in BRS [et al [et al [The present study showed that BRS of children with POTS was significantly higher than that of control subjects . Convertino, e in BRS . In adulS [et al  and Fu, l [et al . While, l [et al . But in The present follow-up study showed that BRS of POTS in subgroup A was significantly lower than that in subgroup B . It was speculated that abnormal increase in BRS might affect disease prognosis. POTS patients with high BRS had a low threshold of blood pressure decrease caused by position change, and slight change in pressure might reflectively cause over activation of sympathetic nerve of children cases, resulting in a greater adverse impact on the prognosis if the increase value of heart rate was increased. As such, the present study suggested that baseline BRS might be a good index of predicating the prognosis of children with POTS, and the area under curve was 0.855, with a BRS value of 17.01 ms/mmHg as a cutoff value yielding the predicted sensitivity of 85.7% and specificity of 87.5%. Hence, detection of BRS could well predict the disease outcome of POTS patients, and the advantage of the detection was convenient, inexpensive, easy to perform and noninvasive in the prediction.The accuracy of the finger monitoring method of hemodynamics used in present study has been proved in previous studies and it can well reflect the real hemodynamics –50. HoweIn conclusion, BRS value is a useful index to predict the short-term outcome of POTS in children.


Autosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually develop end-stage renal disease (ESRD). We hypothesize that bone marrow mesenchymal stromal cells (BMMSCs) are renotropic and may improve kidney function via anti-apoptotic, anti-fibrotic, and anti-inflammatory effects. In this study, we aim to assess the safety and tolerability of a BMMSC infusion in ADPKD patients.2. Patients received autologous cultured BMMSCs (2 × 106 cells/kg) through the cubital vein according to our infusion protocol. We investigated safety issues and kidney function during the follow-up visits, and compared the findings to baseline and 1 year prior to the intervention.We performed a single-arm phase I clinical trial with a 12-month follow-up. This study enrolled six eligible ADPKD patients with an estimated glomerular filtration rate (eGFR) of 25–60 ml/min/1.73 m2 1 year before cell infusion declined to 26.7 ± 3.1 ml/min/1.73 m2 at baseline (P = 0.03) and 25.8 ± 6.2 ml/min/1.73 m2 at the 12-month follow-up visit (P = 0.62). The mean serum creatinine (SCr) level of 2 ± 0.3 mg/dl 1 year before the infusion increased to 2.5 ± 0.4 mg/dl at baseline (P = 0.04) and 2.5 ± 0.6 mg/dl at the 12-month follow-up (P = 0.96). This indicated significant changes between the differences of these two periods  in SCr (P = 0.05), but not eGFR (P = 0.09).There were no patients lost to follow-up. We observed no cell-related adverse events (AE) and serious adverse events (SAE) after 12 months of follow-up. The mean eGFR value of 33.8 ± 5.3 ml/min/1.73 mThis trial demonstrated the safety and tolerability of an intravenous transplantation of autologous BMMSCs. BMMSC efficacy in ADPKD patients should be investigated in a randomized placebo-controlled trial with a larger population, which we intend to perform.NCT02166489. Registered on June 14, 2014.ClinicalTrials.gov, The online version of this article (doi:10.1186/s13287-017-0557-7) contains supplementary material, which is available to authorized users. Autosomal dominant polycystic kidney disease (ADPKD) is a genetic ciliopathy disease characterized by progressive formation and enlargement of cysts in multiple organs. The kidneys are particularly affected and patients may eventually progress to end-stage renal disease (ESRD). ADPKD is the most common genetic renal disease  that affDespite recent advances in the identification of ADPKD pathogenesis, current treatments have been unable to completely cure or control disease progression. Tolvaptan, a vasopressin II receptor antagonist (V2RA), is the only drug that has passed a phase III clinical trial. Though it has the ability to reduce progression of height-adjusted total kidney volume (htTKV), it is associated with numerous adverse effects .Transplantation of mesenchymal stromal cells (MSCs) is a recent approach to treat renal disease , 7. MSCsWe hypothesize that MSCs are renotropic. Therefore, this study aims to assess the safety and tolerability of MSC infusion in ADPKD patients.We performed a single-arm phase I clinical trial at one trial center with a 12-month follow-up period. We investigated safety issues and kidney function during the follow-up visits, and compared the findings to baseline and 1 year prior to intervention. Table We evaluated both safety and tolerability of the cell infusion according to physical examination, adverse event (AE) assessments, and laboratory changes. Potential efficacy included changes in kidney length (KL) measured by ultrasound imaging, estimated glomerular filtration rate (eGFR) by the modification of diet in renal disease (MDRD) study formula, and glomerular filtration rate (GFR) by diethylenetriaminepentaacetic acid (DTPA) scan.We abstracted data that pertained to the “1 year prior to infusion” point from patients’ medical files in the clinic. We scheduled patient follow-up visits for clinical and laboratory assessments at specified intervals of 1, 3, 6, 9, and 12 months after the cell infusion.2; (5) ability to understand and willingness to sign a consent form. Exclusion criteria consisted of: (1) pregnancy or breastfeeding; (2) positive history of associated cardiovascular disease; (3) diabetes that required medical intervention; (4) other systemic diseases that involved the kidneys such as cancers, autoimmune diseases, blood diseases, and liver diseases; (5) hospitalization due to illness 2 months prior to study entry; (6) life expectancy less than 2 years; and (7) allergies to the cell culture ingredients.Inclusion criteria were: (1) both genders; (2) ADPKD confirmed by sonography imaging or genetic testing; (3) age 18 to 60 years; (4) eGFR 25–60 mL/min/1.73 mPrimary endpoints consisted of the numbers, type, and severity of AEs related to the cell infusion. We recorded AEs and serious adverse events (SAE) during follow-up visits and whenever patients reported any symptoms. We recorded the type and grade of AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We sent these reports to the Data Safety Monitoring Board (DSMB) of the study. Secondary endpoints consisted of changes in eGFR (as an existing surrogate endpoint)  from basAdditional file 6 cells/cm2 in a 150-cm2 culture flask with alpha modified Eagle medium  supplemented with 100 IU penicillin and 100 IU streptomycin , 10% Hyclone defined fetal bovine serum , and 1% L-glutamine . Phase-contrast microscopy of the BMMSC cultures demonstrated a low heterogeneous population that predominately consisted of long, spindle-shaped cells. For each patient, we characterized the cells for immunophenotypic properties that included surface marker expressions for MSCs - phycoerythrin (PE)-conjugated CD105, CD44, CD73  and fluorescein isothiocyanate (FITC)-conjugated CD90  along with those that were negative for hematopoietic stem cell (HSC) surface markers PE-conjugated CD34 and FITC-conjugated CD45. Negative isotype controls included nonspecific mouse IgG1-FITC/IgG1-PE and IgG2a-FITC that were substituted for the primary antibody. All samples were analyzed by flow cytometry  and win-MDI2.9 software. Additional file Once the patients’ laboratory viral tests were normal . The cells were diluted in 10 ml of normal saline and loaded into 10 ml sterile syringes. For each patient, we prepared approximately 1–2 × 106/kg) through the cubital vein according to our infusion protocol.We infused autologous cultured MSCs (1–2 × 10t test to compare variables at two time points (baseline and 12 months after cell infusion). We compared variables at three time points  by the repeated measures ANOVA test. A two-sided P value of <0.05 was considered statistically significant. We used SPSS for statistical analyses .Data are written as mean ± standard deviation (SD). Following normal distribution of parametric data, we used the paired All six patients completed the trial. No patients were lost to follow-up. Table We discharged all patients 2 h after the cell infusion and observed no AEs during this time. The bone marrow puncture site healed within 72 h and the intravenous infusion site healed within 24 h without any related complications. In total, we recorded 1 SAE and 37 AEs during the 12-month follow-up in all patients  and one acetaminophen tablet (500 mg) due to severe back pain 3 weeks after his cell infusion. His blood urea nitrogen (BUN) and SCr levels elevated 24 h after celecoxib and acetaminophen. We advised him against using these types of medications. Instead, we prescribed physiotherapy for pain relief. After 1 week, his BUN and SCr values returned to previous levels. We referred him to the orthopedic surgeon who performed a lumbosacral magnetic resonance imaging (MRI) scan without contrast. According to the MRI report, the patient had L4/L5 disc demyelination and a central disc protrusion with significant canal and left foraminal stenosis. He underwent surgery 1 week later. After surgery, his pain reduced and cleared completely within 10 days.We did not detect any SAEs or AEs related to the cell infusion in any of the patients during the 12-month follow-up. The results showed no significant differences in laboratory parameters, which we evaluated for safety issues after 1, 3, 6, 9  and 25.8 ± 6.2 ml/min/1.73 m2 at the 12-month visit (P = 0.62). Figure P = 0.04) and 2.5 ± 0.6 mg/dl at the 12-month follow-up (P = 0.96). There was a significant change between the differences of these two periods  in SCr (P = 0.05) but not in eGFR  and diastolic (P = 0.43) BP did not significantly change 12 months after the cell infusion (Table Systolic (ic P = 0.3 BP did P = 0.06). The median right KL at baseline was 19.1 ± 2 cm which increased slightly to 19.5 ± 2 cm at 12 months  to 12 months after the cell infusion . We observed a slight, nonsignificant decrease for eGFR at 12-month follow-up that could not be considered exactly due to the intervention.However, the mean eGFR level noticeably decreased from 1 year before intervention to baseline  control in management of ADPKD . AccordiFranchi et al. performed the only preclinical study that used allogeneic MSCs in a PKD rat model. They showed the beneficial effect of a single intravenous infusion for improvements in systolic HTN and fibrosis. Although the infusion did not affect cyst size and number, it had a significant improvement on cortical and parenchymal vasculature density, which resulted in better tubular function and improvements in creatinine clearance seen in the intervention group in the autosomal recessive polycystic kidney disease (ARPKD) model . They alThere is a growing body of clinical research which indicates that a systematic MSC infusion is safe under different conditions , includiADPKD progression is associated with several pathways such as apoptosis , fibrosiRecent experimental studies reported that MSCs predominantly improved kidney tubular regeneration by secretion of growth factors, cytokines, and chemokines which decrease apoptosis, inflammation, and fibrosis , and subRapamycin decreases the proliferation of CD133+ and CD24+ cells and cyst formation in vitro through inhibition of the mechanistic target of rapamycin (mTOR) in PKD . In our The mitogen-activated protein kinase (MAPK) family is involved in proliferation, apoptosis, and fibrosis in PKD. MSC-derived conditioned medium has been shown to inhibit p38 mitogen-activated protein kinases (p38) and extracellular signal-regulated kinase (ERK) activity (MAPK family) as well as induce antiapoptotic effects in an AKI rat model .Various studies illustrated that downregulation of pro-inflammatory cytokines reduced cyst formation and inflammation in ADPKD –40. MSCsFollowing ADPKD progression, renovascular architecture disrupts where there is the vessel network around the cyst , 41. VasRAS inhibition improves BP and TKV, and prevents the spread of cyst formation in experimental animal models and humans , 45. MSCTaken together, following the safety and tolerability results of our study, the next step is to test the efficacy of MSC in ADPKD patients.The current trial limitations included our inability to demonstrate the efficacy due to the study design that consisted of a small sample size, lack of a control group, short follow-up period, the single cell infusion, and not using htTKV as a surrogate endpoint.This trial demonstrated that an intravenous infusion of autologous MSCs was safe and well tolerated in ADPKD patients. We could not assess the efficacy due to the trial design. Our findings should be investigated in a randomized placebo-controlled trial with a larger population, which we intend to perform.Additional file 1: Table S1.Table S2. Safety assessment of the mesenchymal stromal cell (MSC) infusion in 1 year following baseline visit of study patients. Table S3. Laboratory parameters at baseline, 1, 3, 6, 9, and 12 months of follow-up. Table S4. Changes in renal function parameters and blood pressure (BP) 1 year before, and at 1, 3, 6, 9, and 12 months after mesenchymal stromal cell (MSC) infusion. (DOCX 70 kb)Method of kidney ultrasound imaging. DTPA kidney scan method. Cell parameters for the study patients. Additional file 2: Figure S1.Characterization of the patients’ bone mesenchymal stromal cells (MSCs). (DOCX 781 kb)


In addition, in specific situations,pulse oximetry and flow-volume loops during and after exertion are measured. TheCPET provides joint data analysis that allows complete assessment of thecardiovascular, respiratory, muscular and metabolic systems during exertion,being considered gold standard for cardiorespiratory functionalassessment.6Cardiopulmonary exercise test (CPET) has been gaining importance as a method offunctional assessment in Brazil and worldwide. In its most frequentapplications, CPET consists in applying a gradually increasing intensityexercise until exhaustion or until the appearance of limiting symptoms and/orsigns. The following parameters are measured: ventilation; oxygen consumption(VOThe CPET allows defining mechanisms related to low functional capacity that cancause symptoms, such as dyspnea, and correlate them with changes in thecardiovascular, pulmonary and skeletal muscle systems. Furthermore, it can beused to provide the prognostic assessment of patients with heart or lungdiseases, and in the preoperative period, in addition to aiding in a morecareful exercise prescription to healthy subjects, athletes and patients withheart or lung diseases.Similarly to CPET clinical use, its research also increases, with the publicationof several scientific contributions from Brazilian researchers in high-impactjournals.Therefore, this study aimed at providing a comprehensive review on theapplicability of CPET to different clinical situations, in addition to servingas a practical guide for the interpretation of that test. Inpractice, maximum VO2 (VO2 max) is defined as the highestvalue reached, despite progressive increase of the load applied, with thedevelopment of a plateau in the VO2 curve during an incremental exercisetest. When no plateau can be identified, the highest value obtained at the end of anexhausting exercise is characterized as peak VO2, which, in practice, isused as VO2 max. Mean values at intervals of 10 to 60 seconds should bemeasured depending on the protocol . The response isinfluenced by a central mechanism (cardiovascular and/or pulmonary) and peripheralfunction .6 The normal values depend on severalfactors, such as: age, sex, weight, height, physical activity level, geneticvariability and ethnicity. Different equations to predict the normal values ofVO2 max or peak VO2 have been determined from differentpopulations. Although the equation proposed by Wasserman and Whipp6 is the most frequently used, anational equation7 seems to be moresuitable for Brazilians.2' is used as a synonym for VO2 max throughoutthis text. Peak VO2 is considered abnormal when below 85% of thepredicted value.6 It has been usedas a universal marker5 that can broadly reflect disease severity in patients with heartfailure (HF), pulmonary hypertension, hypertrophic cardiomyopathy (HCM), chronicobstructive pulmonary disease (COPD) and restrictive pulmonary disease, in additionto physical fitness level.8 The VO2 value measured in the first ventilatorythreshold (VT1) or anaerobic threshold (AT) is determined by the nonlinear increaseof pulmonary ventilation (VE) in relation to VO2. From the physiologicalviewpoint, AT represents the upper limit of workloads during exercise, which can besustained over a prolonged period of time without progressively increasing bloodlactate and consequent pulmonary hyperventilation.6 Peak VO2 and AT values are influenced bygenetic predisposition, diseases, exercise and aerobic training types. The normalmean AT values expected for adults are around 40% to 65% of peakVO2.6 The ATvalues are important for the individualized prescription of exercise, as well as forthe diagnosis of anemia, physical unfitness, myopathies and cardiopathies in thepresence of values lower than the predicted ones.6The term 'peak VOPulmonary ventilation (VE): expressed as liters per minute, is thevolume of air moved in and out of the lungs. It is determined as the product ofrespiratory rate by the volume of air exhaled at every cycle . Atrest, 7 to 9 L/min are ventilated, but in athletes that value can reach 200 L/min atmaximal exertion.6 Ventilationincreases continuously during progressive effort on CPET and undergoes additionalincreases influenced by the anaerobic metabolism resulting from the accumulation oflactic acid, well defined as the first and second ventilatory thresholds. Periodic(or oscillatory) ventilation is defined as the resting oscillatory pattern thatpersists in ≥ 60% of the effort with an amplitude ≥ 15% as compared tomean resting values.9 It reflectsdisease severity and relates to worse prognosis in patients with HF.5Respiratory coefficient or respiratory exchange ratio (R): expresses theratio between CO2 production and O2 consumption(VCO2/VO2). It is currently the best non-invasiveindicator of maximal or quasi-maximal exercise intensity. Values above 1.0 canreflect intense exercise, but those ≥ 1.10 are those searched on CPET, andhave been accepted as a parameter of exhaustion or quasi-exhaustion.72) and for carbon dioxide(VE/VCO2):Ventilatory equivalents for oxygen (VE/VO are the ratios between pulmonary ventilationand O2 consumption (VE/VO2) or CO2 production(VE/VCO2). Both decline from rest to submaximal exercise intensities,with VE/VO2 reaching minimum values before AT, when its progressiveincrease occurs, caused by the increase in ventilation to eliminate extraCO2 production. That results in lactate buffering by bloodbicarbonate.6 Later,VE/VCO2 increases , resulting from ventilatory increase  in response to blood pH reduction due to the progressiveaccumulation of lactic acid at muscle level.6 The VE/VO2 reflects the ventilatory need for acertain O2 consumption level, being, thus, an index of ventilatoryefficiency. Patients with inadequate ratio between pulmonary ventilation andpulmonary perfusion  ventilate inefficiently andhave high VE/VO2 values (pulmonary disease and HF).6 Peak values above 50 have beenuseful to diagnose patients suspected of having mitochondrial myopathy.10 On the other hand,VE/VCO2 represents the ventilatory need to eliminate a certain amountof CO2 produced by active tissues, being influenced by partial pressureof carbon dioxide (PaCO2). In addition, VE/VCO2 slope is therelationship between VE, plotted in the Y axis, and VCO2, in the X axis,both measured as L/min. The VE/VCO2 slope can be determined in submaximaltests.11 It relates tochanges in the ventilation-perfusion relationship or hyperventilation. TheVE/VCO2 slope reflects the severity and prognosis of patients withHF, pulmonary hypertension, HCM, COPD and restrictive pulmonary disease.122 partial pressure (PETCO2):End-tidal CO reflectsventilation-perfusion within the pulmonary system, and, indirectly, cardiacfunction.6 Its value rangesfrom 36 to 42 mmHg, with 3- to 8-mmHg elevations during moderate intensity exercise,reaching a maximal value with subsequent drop, due to VE increase, characterizingRCP.1 Abnormal values canrepresent disease severity in patients with HF, HCM, pulmonary hypertension, COPDand restrictive pulmonary disease.122 pulse):Oxygen pulse (O is the ratio between VO2(mLO2/min) and heart rate (HR - bpm). Its meaning is betterunderstood by observing the Fick equation: VO2 = HR x systolic volume(SV) x arteriovenous oxygen difference [(A-V)O2 diff]. Considering that,in many clinical situations, (A-V)O2 diff does not substantially changein incremental exercise, O2 pulse represents SV, and, in a way, leftventricular performance. Thus, VO2 ≅ HR x SV or VO2/HR≅ SV. Under certain circumstances, the morphological analysis of its curveaids in the diagnosis of ventricular dysfunction and important effort-inducedmyocardial ischemia.6Breathing reserve (VE/MVV): represents the ratio between maximalventilation during exercise (VE) and maximum voluntary ventilation (MVV) at rest,both variables in L/min. Equations to predict MVV can be used (forced expiratoryvolume in the first second - FEV1 x 40), although it can be measureddirectly on pre-test spirometry. Normal values are greater than 0.20. However, inboth athletes and those performing strenuous exercises, a higher fraction ofbreathing reserve can be physiologically used. It is useful in the differentialdiagnosis of dyspnea related to pulmonary mechanism.62/ΔWR Relationship:ΔVO relationship betweenVO2 (Y axis in mL.min-1) and workload (X axis in Watts),measured only during exercise on a cycle ergometer with ramp protocol, whose valueis progressively and linearly incremented until maximal effort. It is useful in thediagnosis of patients suspected of having myocardial ischemia with left ventriculardysfunction on exertion. Its normal value for adults is 9mL.min-1.W-1 (the lowest limit being 8.6mL.min-1.W-1).2 value is the cardiorespiratory optimalpoint (COP).13 It is a submaximalvariable that reflects the best integration between the respiratory andcardiovascular systems. Although it is easy to obtain, further studies are requiredto determine its clinical applicability and prognostic meaning. Oxygen uptakeefficiency slope (OUES) was widely studied, being measured by the relationshipbetween VO2 and the logarithmic transformation (base 10) of VE. The OUESprovides information on the severity of HF.14 Similarly to VE/VCO2 slope, it does not requirea maximal test. T1/2VO2 is the time necessary for a 50% dropin VO2 measured at peak exercise (from the beginning of recovery) untilthe third minute of recovery. It decreases with physical training and its increaseis negatively associated with the prognosis of HF patients.15 Circulatory power is the productof peak systolic blood pressure (SBP) by peak VO2, while ventilatorypower is peak SBP divided by VE/VCO2 slope. Both have prognostic value inHF.16 Finally, theassociation of CPET with measurements of cardiac output and SV, by use ofnon-invasive hemodynamic analysis (impedance cardiography - ICG), can providevariables, such as ΔQ/ΔVO2 slope to assesscoronary artery disease (CAD), HF and some myopathies.10Other variables: the minimum VE/VO18Considered class IIa indication - optimized prescription of exercise to healthyindividuals, individuals with heart or lung diseases entering a program ofregular exercise - and class IIb indication - athletes -,1 it is still rarely used withsuch purposes by clinical cardiologists.The CPET is considered the best method to assess aerobic performance, and,mainly, to support aerobic exercise prescription.18 For individuals with heartdiseases and high-performance athletes, such benefits have been widelyestablished. Prescription errors, both insufficiency and excess, in suchindividuals can have a negative impact on the results expected from a trainingprogram.By use of the joint analysis of exhaled gases, work and/or exertion performed andthe behavior of hemodynamic variables, mainly HR, a more comprehensivefunctional assessment can be obtained. Thus, a more precise and individualizedprogram of aerobic exercise can be outlined. Apparently healthy individuals whoengage in moderate- to high-intensity aerobic practice can benefit from CPETregarding exercise prescription and performance assessment.19 The exercise intensity at which VT1 occurscharacterizes the highest submaximal level tolerated by a certain individual forlong time periods. Because that exercise intensity varies even between twoindividuals with identical maximal functional capacity , its precise determination via CPETenhances and refines the quality of aerobic exercise prescription. In practicalterms, HR values in different points of maximal CPET are used to establish thebases for a more objective prescription. More often, the following values areconsidered: HR at rest with the individual lying down (resting HR), maximal HR(HRmax), HR at AT, HR at RCP, and HR at the 'R = 1' point. Traditionally,exercises have been prescribed based on the intensity related to HR, but theworkload related to thresholds and maximal effort can also be used.20 When the objective is to train up to a moderatesubjective intensity that can be sustained for long periods, we set the limit atthe AT. Between the AT and RCP, the exercise intensity is higher, but usuallystill tolerated for prolonged periods, with wide individual variations. Finally,the training can be performed above the RCP, with very intense and much moredifficult to sustain exercises, which can be of the interval type .20Briefly, for the prescription of aerobic exercises, the most relevant dataobtained from CPET are HR and exercise intensity at which the ventilatorythresholds occur, especially, AT or VT1.21 These protocols are used to prescribe steady-state aerobicexercise  or interval exercise, with an important componentof "anaerobic" exercise, alternating rhythms and intensities .There are numerous protocols that can be used for both healthy individuals andthose with diverse patologies.22 phenomenon, characterized by aprogressive increase of HR, instead of remaining in steady-state, despite of aconstant intensity of exercise. However, for patients using HR-controllingdevices or on regular use of medications with negative chronotropic action,specific care should be taken so that the HR-based prescription obtained on CPETcan remain valid. The most obvious case is that of patients on beta-blockers ona single daily dose, which make HR during exercise vary according to the timeinterval between medication administration and exercise performance.23 To minimize thatchronopharmacological effect, such patients should undergo CPET at the timeclosest to that of regular exercise. In patients with pacemakers,resynchronization devices and atrial fibrillation, the HR measured by these HRsensors is inaccurate. For those individuals and some athletes whose trainingintensity is based on load or velocity, exercise can be prescribed based onvelocities or loads relative to thresholds. Some studies have suggested that theload relative to 'R = 1' bears the best correlation with maximal exertion inmetabolic balance.24However, the quality of that prescription, based on HR derived from CPET, dependson some factors. It is convenient that CPET be performed with a ramp protocol,minimum duration of eight minutes, on an ergometer more similar to the aerobicexercise that will be prescribed . Longer protocols tend to allow greater differentiation and precisionin identifying the exercise intensity that corresponds to the thresholds. It isworth noting that data collected during a CPET performed in an air-conditionedroom can differ from those obtained during a walk or cycling or even a longrunning (more than 45 minutes) at open air locations and under more adverseclimate conditions, in which there may be a cardiovascular drift13 which widens the CPET value for prescription ofprimarily aerobic exercises. Finally, other potentially relevant variables can be obtained via exhaled breathanalysis, including some that do not require maximal exertion, such asmechanical efficiency analysis and COP,2, VCO2 and VE. In addition, thevariables VE/VO2, VE/CO2, VCO2/VO2and R, as well as the metabolic points AT and RCT, are useful parameters toindicate accurately the maximal aerobic capacity, to quantify functionalrestriction, to measure the response to drug therapy and to guide physicaltraining prescription.Chronic heart failure (CHF) is a systemic syndrome, and reduced functionalcapacity is one of its main features. The cardiovascular deficit has a directinfluence on other organs and systems, such as the pulmonary, renal and skeletalmuscular ones. CPET is considered "gold standard" for the functional assessmentof patients with CHF, propitiating diagnostic and prognostic data derived fromdirect measurement of VO26The Brazilian Society of Cardiology guidelines for the management of patientswith CHF present CPET as class I indication in the assessment of both hearttransplantation candidates and dyspnea mechanisms. The use of CPET is class IIindication for exercise prescription, and to assess the severity, prognosis andresponses to therapeutic interventions in CHF.2, AT < 40% of the predicted VO2 max,O2 pulse < 85% and as a plateau, increased VE/VCO2,reduced OUES, wide breathing reserve and usually normal O2saturation.2 PeakVO2 is the specific and direct measure of functional capacity.Several studies have shown its independent prognostic capacity in CHF. Accordingto the Brazilian guidelines for heart transplantation, a peak VO2lower than 10 mL.kg-1.min-1 is class I indication for thatprocedure, while a peak VO2 below 12mL.kg-1.min-1 (patients on beta-blocker) or below 14mL.kg-1.min-1, is class IIa indication, particularlyfor those with other criteria of worse prognosis (VE/VCO2 slope >35).27 Weber etal.2 results: class A = VO2 > 20mL.kg-1.min-1; class B = VO2 16-20mL.kg-1.min-1; class C = VO2 10-15mL.kg-1.min-1; and class D = VO2 < 10mL.kg-1.min-1. It is worth noting that, for peakVO2 value to have prognostic accuracy, the test has to meet therequirements of a maximal test .The response to CPET of a patient with CHF is characterized by: reducedVO2 slope, OUES,T1/2VO2, HR recovery in the first post-exertionminute, presence of periodic ventilation, and PETCO2 andO2 pulse behaviors.Other important variables measured via CPET that add independent prognostic valuefor patients with CHF are: VE/VCO2 slope > 34 were athigher risk for hospitalization due to decompensation, and for death. Otherauthors,32 assessing the prognostic valueof VE/VCO2 slope in CHF, have shown it to be a variable withexcellent independent value, even higher than that of peak VO2, andimportant to patients who reach only submaximal exertion. In a population withCHF due to Chagas disease, Ritt et al.33 have reported that the best cutoff point for worseprognosis was VE/VCO2 slope > 32.5, thus earlier than thosereported by studies on other etiologies. Arena et al.2 slope values: class I, VE/VCO2 ≤ 29.9;class II, 30-35.9; class III, 36-44.9; class IV, ≥ 45. In 2 years,event-free survivals  for classes I-IV were 97.2%, 85.2%, 72.3% and 44.2%,respectively (P < 0.0001). Assessing a population of patients via CPET forheart transplantation, Ferreira et al.35 have found a VE/CO2 slope cutoff point of≥ 43 as ideal to determine the indication for heart transplantation. Theuse of VE/VCO2 slope as a criterion for selection of candidates fortransplantation could reclassify correctly 18.3% more patients than the classicpeak-VO2-based criteria (p < 0.001).35Chua et al.,36 have describedthat variable behavior, whose cutoff point and independent prognostic value weresubsequently assessed by other authors. A cutoff point < 1.47 L/mindetermines a group with more severe CHF.14In addition, OUES has an independent prognostic value. Initially, Baba etal.1/2VO2 is identified in patients with CHF. Studyingpatients with VO2 ≥ 15, between 10.1 and 14.9, and ≤ 10mL.kg-1.min-1, Groote et al.38 have reported T1/2VO2values of 108 ± 44.6, 137 ± 58.7, and 176 ± 75 seconds,respectively.38 Inpatients with no heart disease, T1/2VO2 is usually < 90seconds.39T40 relatedto changes in post-exertion autonomic balance. In CHF, it is also an independentfactor of mortality, even in patients on beta-blockers.41 The cutoff point establishedfor that population was ≤ 16 bpm in an active recovery protocol . Its clinical usefulness has beenassessed for heart transplantation indication in patients in the intermediaryzone of peak VO2 (VO2 10.1-13.9mL.kg-1.min-1), in whom, the HRR analysis aggregatedvalue to peak VO2 and VE/VCO2 slope. The prognosis ofpatients with altered HRR and VE/VCO2 slope was comparable to that ofthose with VO2 < 10 mL.kg-1.min-1.42The kinetics of HR recovery (HRR) is a well-established prognostic marker inpatients with CAD,44 The presence of periodic ventilation increased the riskof patients with reduced peak VO2 and elevated VE/VCO2slope.45Wide oscillations in ventilation during exertion relates to cardiovascular eventsand death in patients with CHF. That pattern, analogous to the Cheyne-Stokesrespiration, was named periodic ventilation. The occurrence of periodicventilation during exertion (characterized by an amplitude variation > 5L/min for at least three cycles) was related to an up to three-fold highermortality in patients with CHF .2diffusion at alveolar level is PETCO2 at rest. Mean values < 33mmHg after 2 minutes at rest were independently correlated with worse prognosisand greater mortality in CHF .46Another index that reflects the dynamics of pulmonary changes and CO2 pulse can be assessed regarding its absolute value and its behaviorduring exertion. A plateau is usually related to an insufficient increase in SVon exertion. An O2 pulse < 85% of the predicted value correlatesindependently with major cardiovascular events in CHF. Among patients with peakVO2 < 14.3 mL.kg-1.min-1 andO2 pulse < 85% of the predicted values, mortality was greaterthan among those with only one of those parameters altered . O2 pulse could also reclassify the riskof patients into intermediate zone of peak VO2 for transplantation(10-14 mL.kg-1.min-1). Patients in the O2 pulse< 85% zone had mortality similar to those with VO2 < 10mL.kg-1.min-1.47O2 slope data toSeattle Heart Failure Model could improve the prognostic ability of that score,reclassifying 40% of the patients into a more appropriate risk category (p =0.002).48Each CPET variable correlates with the interaction of HF with another organ orsystem. Thus, the joint analysis of those variables can better stratify the riskof those patients. The CPET variables can be combined into risk scores in CHF.Levy et al. have shown that the addition of VE/VCO2, VE/VCO2 slope, OUES andperiodic ventilation) were 4.10 (CI: 3.16-5.33), 5.40 (CI: 4.17-6.99), 8.08 (CI:4.19-15.58) and 5.48 (CI: 3.82-7.86), respectively.49To determine the prognostic significance of CPET in CHF, Cahalin et al. haveconducted a meta-analysis of studies published until 2013 and calculated theodds ratios (OR) of each prognostic variable. The OR of the main prognosticvariables assessed , 11-15  and > 15 . In three years, the mortality of patients withscore >15 was 12.2%, in comparison to 1.2% in those with score < 5. Arecent analysis51 applied thatscore to class B patients according to Weber heart failure classification. In the three-year follow-up, patients with score≥ 10 had an event-free survival equivalent to that of Weber class Cpatients, and those with score < 10 had a prognosis equivalent to that ofWeber class A patients.For those not dealing with CPET on a daily basis, the assessment of each variablecan be unpractical. Myers et al.The CPET plays a preponderant role in the assessment of patients with CHF, notonly regarding the selection of candidates for transplantation, but also todetermine the prognosis and help with the therapeutic decision. 1 During incremental exercise, themyocardial unbalance between O2 offer and demand triggers a sequenceof metabolic changes that can ultimately lead to the insufficient physiologicalelevation of SV. On CPET, this is observed as a depressed, in plateau ordeclining shape curve of O2 pulse.CPET can help to assess myocardial ischemia in patients with suspected CAD, aclinical condition where a significant ischemic load, during exercise, isexpected to negatively influence systolic myocardial performance.2 pulse; 2) VO2 curve andelevation; and 3) relationship between VO2 variation and loadvariation, in watts, in this case, exclusively, on cycle ergometer.52Three CPET variables are indicated to assess the presence and severity ofmyocardial ischemia: 1) O2 diff tends to remain constant during incrementalexertion, except for rare cases of anemias, hemoglobinopathies, some congenitalheart diseases and COPD, in which there is a significant drop in peripheraloxygen saturation. Except for those clinical conditions, one can infer that SVbehavior during incremental exercise is reflected by the equation:VO2/HR = SV. The VO2/HR ratio, called "oxygen pulse"and measured in milliliters per beat, reflects the O2 volume ejectedinto the aorta at every systole. Likewise, SV, also measured in milliliters perbeat, reveals the blood volume ejected into the aorta at every systole. Thus,those two variables, despite being numerically different, reflect leftventricular hemodynamic behavior during CPET.Usually, (A-V)O2/HR curve as a function of time, which shouldhave the increasing morphology of a parabola, is as important as the numericalO2 pulse value during the incremental phase of CPET. Theidentification of a curve with a plateau or decline indicates a reduction inO2 pulse and SV during exercise, and can indicate myocardialischemia53  of undetermined origin or dyspnea of multiple causes have evidencedpractical use: to differentiate dyspnea of cardiocirculatory primary origin fromdyspnea of pulmonary ventilatory etiology or that related to problems in theventilation-perfusion binomial; to quantify the different mechanisms ofmultiple-cause dyspnea; to identify an unsuspected or underestimated circulatorycomponent; and to identify a psychogenic or simulation component.62 The first stepis to assess peak VO2 and to determine the percentage of thepredicted value achieved. Pulmonary, cardiovascular and metabolic diseases orphysical unfitness can account for VO2 reduction. Then, breathingreserve should be assessed, and, when low, it can identify underlying pulmonarydisease. Breathing reserve lower than 20% is found in pulmonary diseases;however, as already described, highly-trained individuals or those in situationsof extreme exertion can also consume their ventilatory reserve on maximalexertion as a compensatory mechanism, but, in such cases, peak VO2will not be significantly reduced.The differential diagnosis of those pathologies requires pragmatic interpretationof CPET data.2 saturation. A drop greaterthan 4% on peak exertion as compared to resting is characteristic of pulmonarylimitation. High VE/VCO2 slope and PETCO2 < 33 mmHg atrest and/or elevation greater than 8 mmHg during exertion suggest respiratorymechanisms as the cause of dyspnea.63The following step is the analysis of O2 pulse and ΔVO2/ΔWR ratiocan identify heart disease, if the curves show plateau or decline, reflecting aninadequate SV to the load imposed.64 However, individuals with lung disease and some degree ofpulmonary hypertension can also develop a plateau of O2 pulse. Thecombination of plateau of O2 pulse with a decrease in O2saturation, VE/VCO2 slope > 40 and reduced PETCO2 (<33 mmHg at rest or < 36 mmHg at AT) strongly suggests pulmonary hypertensionor a pathology with pulmonary vascular impairment.65Observation of O2, early AT, ventilatory inefficiency (high VE/VCO2slope), inefficient O2 uptake (reduced OUES), plateau ofO2 pulse or of ΔVO2/ΔWR ratio, withnormal ventilatory reserve, PETCO2 < 33 mmHg at rest and/orincrease < 3 mmHg during exertion, in addition to lack of drop inO2 saturation.63Patients with dyspnea due to cardiovascular limitation have reducedVO2 andincreased ΔVO2/ΔWR (cycle ergometer), but they do notmeet the criteria for pulmonary or cardiovascular limitation. Extremelyphysically unfit patients can have reduced AT and increased HR/VO2ratio. On the other hand, a low R, despite the sensation of extreme fatigue onBORG scale, points to a peripheral mechanism as the cause of limitation toexertion.Patients with physical unfitness and anemia have reduced VO2 slope), reduced PETCO2 at AT, sudden changesin the ventilatory pattern with phases of tachypnea and hypopnea, and extremelyincreased respiratory rate on exertion. Usually, the ventilatory reserve isnormal and O2 saturation has a physiological behavior.Patients with hyperventilation have reduced ventilatory efficiency , but an R compatible with submaximalexertion (<1), in addition to apparent chronotropic deficit.Studying 39 patients with asthma of difficult control, McNicholl et al. havereported that, in 14 of them, the persistent complaint of dyspnea was explainedby hyperventilation, preventing the undue increase of the dose ofbronchodilators in those patients.64The inability to increase ventilation to levels that allow high gas exchange isone of the mechanisms that explain dyspnea on exertion. That phenomenon can beobserved on CPET and is usually interpreted as ventilatory limitation. Althoughcharacteristic of obstructive scenarios, it can occur in restrictive diseases,such as interstitial pulmonary diseases, and in abnormalities of the thoraciccage. The criterion that defines ventilatory limitation is arguable, but, whenthe breathing reserve at peak exertion is lower than 15%, limitation isconsidered to occur, especially when R is lower than 1.0.67The severity of COPD is determined based on symptoms and spirometry results.Pulmonary function tests at rest, however, do not accurately predict the gradeof intolerance to exertion.2 continues to be the best index ofaerobic capacity, as long as patients exercise to their limit. However, otheraspects should be considered when interpreting the CPET of patients with COPD.There is a combination of low ventilatory capacity and high ventilatory demand,increasing the sensation of dyspnea. The perception of lower limb exertion isoften exaggerated in such patients and can be a limiting factor, especially intests performed on a cycle ergometer.2 Another factor that can significantly contribute to thedevelopment of unbearable dyspnea during exercise is dynamic hyperinflation.With the increase of respiratory flow during exercise, the air is held in thelungs, causing a progressive increase in residual volume, thus reducing theinspiratory capacity , being, however, more specific for the diagnosis of EIB.Exertion-induced bronchospasm (EIB) is the acute narrowing of airways resultingfrom exercise. Its clinical manifestations include "chest wheezing", cough,dyspnea or chest pressure usually 5 to 10 minutes after exercise, and, lesscommonly, during exercise. Its diagnosis requires a specific protocol withrepeated post-exertion spirometry, typically at 5, 10 and 15 minutes. A drop inFEV1 equal to or greater than 10% as compared to that of pre-exertion isdiagnosed as EIB.In addition, CPET has been used to the early detection of pulmonary vasculardisease. However, the pathophysiological aspects of pulmonary hypertension areworth considering to understand and interpret the findings in the clinicalcontext.69 and dyspnea on exertion isusually its earliest symptom. The pulmonary circulation has high capacitance,and normal mPAP values are frequently observed at the early stages of pulmonaryvascular disease. For an increase in mPAP levels at rest to occur, more than 50%of the pulmonary circulation needs to be obstructed, resulting in a relativelylate diagnosis of pulmonary vascular disease.70Pulmonary hypertension is defined as mean pulmonary artery pressure (mPAP) equalto or greater than 25 mmHg,71 and healthyindividuals can reach much higher values.72 In addition, there are not enough data to conclude thatpatients with that "abnormal hemodynamics" will progress to true pulmonaryhypertension at rest.The identification of pulmonary hypertension during exertion requires the use ofa pulmonary artery catheter for direct measurement during exercise. This is partof the invasive (or advanced) CPET, available only at a few centers. Onelimitation is that the definition of pulmonary hypertension on exertion, mPAPgreater than 30 mmHg, is arbitrary,2 ratio at AT and peak exertion areSBP lower than 120 mmHghad extremely elevated in patients with pulmonary hypertension, higher than thatof patients with HF and same functional class.73 In addition, low PETCO2 values at the end of expiration,both at rest and exercise, were associated with pulmonary hypertension.CPET can provide information to help the clinician suspect pulmonary hypertensionwhen assessing a patient with dyspnea of undefined etiology. TheVE/VCO2 ratio greater than 37 and PETCO2 below 30 mmHg at AT could indicate pulmonaryvascular disease. Exceptionally low PETCO2 values (below 20 mmHg) are uncommon in other diseasesand increase the suspicion of pulmonary hypertension in patients assessed fordyspnea on exertion.74It has been suggested that, in the absence of acute hyperventilation ,VE/VCO2 lower than 10.4 mL.kg-1.min-1and peak SBP lower than 120 mmHg had worse prognosis.75 The guidelines of the European Society ofCardiology70 recommend that peakVO2 values greater than 15.0 and lower than 12.0mL.kg-1.min-1 indicate good and bad prognosis,respectively. However, that parameter should not be assessed isolated, but bepart of a comprehensive assessment to determine pulmonary hypertensionseverity.CPET can be used to assess both the severity of pulmonary hypertension inpatients with established disease and the response to therapy. Studyingidiopathic pulmonary arterial hypertension, Wensel et al. showed thatindividuals with peak VO2 ratio at AT and VE/VCO2 slope havebeen associated with pulmonary hypertension prognosis, with values equal to orgreater than 54 and 62, respectively, indicating shorter survival.73 However, that relationshipseems not to apply to all forms of pulmonary hypertension. A more elevatedVE/VCO2 slope was observed in pulmonary hypertension due tochronic pulmonary thromboembolism as compared to pulmonary arterialhypertension. It is worth noting that, in pulmonary hypertension due to chronicpulmonary thromboembolism, VE/VCO2 slope did not associate withfunctional class, suggesting no relationship with severity and high values atearly phases.76 Anotherparameter associated with the worse survival of patients with pulmonary arterialhypertension is the presence, on CPET, of signs of right-to-left shunt duringexercise.77In addition, VE/VCO78In the pediatric population, the use of CPET is similar to that of the adultpopulation, but with specific particularities related to the childhood universe.Environmental conditions should allow children to adapt to the test, thereforeenabling good performance assessment.79allowing the determination of pathophysiological causes that limit functionalcapacity.80 Protocolsand ergometers (treadmill and cycle ergometer) are selected according to theobjectives and experience of the laboratories conducting the tests. Rampprotocols, however, are currently the most often applied.CPET has been very useful to assess healthy individuals and those with complexcongenital heart diseases,81 have evidenced lower cardiovascular (evidenced by lowerO2 pulse) and respiratory (lower PETCO2) efficiencies,higher respiratory rate and VE/VO2 at peak exercise and at AT level.However, healthy children have higher metabolic efficiency .Comparing the cardiorespiratory responses of healthy children with those ofhealthy young adults, Prado et al.82 reducedactivity of phosphofrutokinase-1 83 and of lactate dehydrogenase,84 and higher proportion of muscle fibers of slowcontraction.85The literature indicates possible reasons for the immaturity of the anaerobicmetabolism of children during physical exercise, such as lower muscular glycogenlevels,86 Other variables derived from CPET areextremely useful to measure the response to exercise. OUES indicates systemicand pulmonary perfusion, and correlates strongly with peak VO2. Inchildren without heart diseases, OUES increases with theirdevelopment.80However, according to the study by Dias et al.,86 in congenital heart disease, an associationwas identified between OUES and functional impairment severity in 59 children inthe late postoperative period of congenital heart disease correction. Thoseauthors have reported that reduced OUES was associated with low peakVO2  in 90% of the cases,confirming the presence of a cardiovascular disorder during exertion.In addition, children with heart diseases usually have lower aerobic potency thanyoung adults and children without heart diseases.In addition, ergospirometric assessment has been extremely useful in thefollow-up of partially or completely treated complex congenital heart diseases,as an aid to indicate the ideal time for new therapeutic interventions. 87 have reportedthe reference values of the major ergospirometric variables of adults withcongenital heart disease, and have correlated their data with those in theliterature to guide the recreational, sports and professional activities ofthose individuals.Kempny et al.2 pulseand peak VO2, and ventilatory variables (VE/VCO2 slope)provides more comprehensive and objective data about the true functionalcapacity of children and adolescents with congenital heart disease. We providemajor examples: after late correction of Fallot tetratogy, evolution withpulmonary insufficiency and possible right ventricular dilation and dysfunctioncan indicate exchange or, currently, implantation of new prostheses, such asMelody's.89 CPET canindicate the best time for intervention, when the morphology of theO2 pulse curve shows a depression or early plateau, in additionto ventilatory inefficiency characterized by high VE/VCO2 slopevalues. After late correction of transposition of the great arteries accordingto Mustard's or Senning's technique, an older method, many children showworsening of their metabolic efficiency (more reduced peak VO2 andexcessive ventilation - greater VE/VCO2 slope), which does not occurwhen submitted to Jatene's surgery, considered the ideal technique.Additionally, CPET allows the analysis of gas exchange in other more complexcongenital heart diseases with pulmonary hypertension, such as Eisenmenger'ssyndrome.89Thus, the association of cardiovascular variables, such as OCPET has been a valuable complementary resource in the follow-up of patients withcongenital heart diseases to both assess the exercise capacity and indicate theideal time for new therapeutic approaches, providing objective, diagnostic andprognostic information on the patient's true cardiopulmonary functionalstatus.


Treatment of pregnancy-related hypertensive disorders, such as preeclampsia (PE), remain a challenging problem in obstetrics. Typically, aggressive antihypertensive drug treatment options are avoided to prevent pharmacological-induced hypotension. Another major concern of administering antihypertensive drugs during pregnancy is possible adverse fetal outcome. In addition, management of hypertension during pregnancy in chronic hypertensive patients or in patients with prior kidney problems are carefully considered. Recent studies suggest that PE patients are at increased cardiovascular risk postpartum. Therefore, these patients need to be monitored postpartum for the subsequent development of other cardiovascular diseases. In this review article, we review the antihypertensive drugs currently being used to treat patients with PE and the advantages or disadvantages of using these drugs during pregnancy. Preeclampsia (PE) is a clinical entity characterized by either the new onset of hypertension and proteinuria or end organ damage after 20 weeks of gestation. It is one of the major pregnancy-related hypertensive disorders and can occur postpartum. Additional clinical signs and symptoms include headache, visual disturbance, epigastric pain, thrombocytopenia, and abnormal liver function . These cTraditionally, the clinical diagnosis of PE is made when new-onset hypertension in the second half of pregnancy is associated with new-onset proteinuria. However, following the observation that some patients show evidence of multiorgan damage without proteinuria, under certain circumstances PE can be diagnosed without proteinuria. In the absence of proteinuria, the diagnosis can be made if any of the following is present: abnormal liver function, thrombocytopenia, renal insufficiency, pulmonary edema, visual impairment, or cerebral symptoms. According to the 2013 report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy, PE can be diagnosed when either (1) systolic blood pressure is greater than or equal to 140 mmHg or diastolic blood pressure is greater than or equal to 90 mmHg on two occasions at least 4 h apart in a previously normotensive patient or (2) systolic blood pressure is greater than or equal to 160 mm Hg or diastolic blood pressure is greater than or equal to 110 mmHg and hypertension can be confirmed within minutes to facilitate timely antihypertensive therapy. In addition to hypertension, proteinuria must be measured as greater than or equal to 300 mg per 24 h urine specimen, as a protein ratio greater than or equal to 0.3, or as a urine dipstick protein of 1+ (if a quantitative measurement is unavailable) . Preexisting chronic hypertension is a principal risk factor for PE , and it Besides delivery of the fetus, the mainstay treatment for PE is control of hypertension with medication when indicated . VariousAll antihypertensive medication can potentially cross the placenta. At this time, there are no randomized control trials to base a recommendation for the use of one antihypertensive agent over another. However, certain medications are effective in lowering blood pressure with an acceptable safety profile in pregnancy. The choice of therapy depends on the acuity and severity of hypertension. In addition, whether parenteral or oral therapy is preferred must be considered when choosing a particular drug.Methyldopa stimulates the central alpha-adrenergic receptors by a false neurotransmitter (α-methylnorepinephrine), which results in a decreased sympathetic outflow of norepinephrine to the heart, kidneys, and peripheral vasculature. Methyldopa has been used extensively in the management of elevated blood pressure in pregnant women. In addition, its long-term safety for the fetus has been demonstrated. In the CHIPS (Control of Hypertension In Pregnancy Study) trial, preeclamptic women treated with methyldopa may have had better outcomes compared with those treated with labetalol . HoweverLabetalol lowers blood pressure by blocking β- and α-adrenergic receptors. In addition, it can better preserve uteroplacental blood flow compared with other β-blockers. It has a rapid onset of action (2 h) compared with methyldopa. Randomized clinical trials comparing labetalol to either methyldopa or nifedipine have shown labetalol to be safe for use in pregnancy . LabetalNifedipine is a calcium channel blocker that has been used in pregnancy without any major issue. Long-acting nifedipine is preferred over short-acting nifedipine as the short-acting version of the medication can cause a significant drop in blood pressure, possibly leading to a reduction in uteroplacental perfusion. However, as discussed below, more recent evidence suggest that immediate release oral nifedipine, under certain conditions, may be considered for safe reduction of BP. Long-acting nifedipine can be given as a sustained release tablet in doses of 30–90 mg once daily. The dosage can be increased at 7- to 14-day intervals, reaching a maximum dose of 120 mg a day , the use of an antihypertensive is recommended . LabetalIt is well known that antihypertensive agents do not prevent eclampsia (seizure). Although magnesium sulfate is not recommended as an antihypertensive agent, it has been used over the years for the prevention of seizure in preeclamptic women with severe features and for managing recurrent seizures in eclampsia. However, limited double-blind, placebo-controlled trials have shown that there is no a significant difference in occurrence of eclampsia between patients with pre-eclampsia without severe features treated with magnesium sulfate and those given placebo . The AmeWhen treatment of hypertension in PE is indicated, management generally depends on the acuity and severity of the hypertension as well as comorbidities. The choice of agents, for the most part, depends on availability of an agent and the experience of the provider. Some authorities have recommended labetalol coupled with calcium channel blockers as first-line drugs in PE patients with chronic hypertension, further suggesting these agents be maxed out before starting another agent. In acute-onset severe hypertension, it is recommended to give intravenous labetalol, hydralazine, or oral nifedipine as first-line agentsWomen with a history of PE experience a 2-fold increased risk of long-term cardiovascular disease and an approximate 5- to 12-fold increased risk of end-stage renal disease. Recognizing PE as a risk factor for future renal and cardiovascular disease will allow for identification of a population of young women who at high risk of developing cardiovascular and renal disease. The current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, because of a lack of studies on screening and prevention in formerly preeclamptic women, these recommendations are based on low levels of evidence. Hence, research is needed on mechanisms of late disease manifestations and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women .OO, LJP, PC conceived, wrote sections of the manuscript, revised the first draft, and finalized the manuscript. All authors contributed to manuscript revision as well as read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer MC and handling Editor declared their shared affiliation.