Laparoscopic sleeve gastrectomy is associated with a moderate risk of hemorrhagic complications (HC). There is a debate regarding the relationship between HC and high blood pressure in postoperative period.The aim is to clarify whether the postoperative blood pressure is an independent risk factor for hemorrhagic complications after laparoscopic sleeve gastrectomy.Medical records of 522 patients were reviewed. A case-control study of postoperative blood pressure was undertaken in patients with bleeding after LSG and matched controls. Patients who required surgical revision, due to the hemorrhagic complications within 72 hours, were identified as the cases. Controls were matched (1:1) with cases by age (±1 year), gender , staple line reinforcement (running suture versus haemostatic clips) and surgeon’s experience (>50 or <50 LSG procedures per year). 12-hour postoperative blood pressure was recorded.p = 0.15; mean difference − 11.6 (95% CI -29.5 – 6.1). Mean 12 hour diastolic pressure was also comparable. The detailed analysis of controls revealed a significantly higher systolic blood pressure measurements in 5th and 11th hour postoperatively, as well as higher diastolic blood pressure in 12th hour postoperatively. However, the differences were not clinically significant.17 patients after LSG with HC in postoperative period were matched with 17 controls. Patients who experienced hemorrhagic complications after LSG had non statistically significant decreased mean systolic blood pressure (mmHg) in 12 hours observation (130.7 ± 12.9 versus 139.1 ± 10.8); Compared with closely matched control subjects, patients with HC after LSG have decreased systolic blood pressure without clinical significance. Laparoscopic sleeve gastrectomy (LSG) is one of the most popular bariatric procedures . The proThe aim was to clarify whether the postoperative blood pressure is an independent risk factor for hemorrhagic complications after laparoscopic sleeve gastrectomy.We performed a case-control study. The medical records of 522 patients who underwent laparoscopic sleeve gastrectomy as a primary bariatric procedure were analyzed. All patients underwent surgery from January 2013 and May 2015 in a single high volume bariatric centre (> 300 laparoscopic bariatric procedures per year). The same cohort was used to develop prediction model for HC and construct risk calculator called SLEEVE BLEED . AntiplaPatients who required surgical revision due to the hemorrhagic complications within 72 h were identified as the cases. Hemorrhagic complications included bleeding from different sources, including staple line, omentum, short gastric vessels and abdominal wall as well as the presence of large hematoma . The posWe found 21 cases of patients with hemorrhagic complications. Mean age (years) of patients was 43.9 ± 10.4 ranging from 23 to 57. 38% were female and 62% were male. The incidence of bleeding in our material was 4.03%. The same database was used in development of risk model for hemorrhagic complications.Controls subjects were taken retrospectively from the rest of patients who underwent LSG from January 2013 to May 2015 and did not experienced any of following adverse events: hemorrhagic complications, gastric leakage or sleeve stenosis. All controls identified as potential matched controls for the cases.Controls were matched with cases by age (±1 year), gender , staple line reinforcement (running suture versus haemostatic clips) and surgeon’s experience (>50 or <50 LSG procedures per year). A control subject was selected for each patient with HC using algorithm described by Kawabata (1:1 matching procedure) . Cases fIn Laparoscopic Sleeve Gastrectomy five trocars were used. The dissection of the greater curvature was started 3 to 4 cm from the pylorus. The gastrocolic ligament was cut to the angle of His. The left diaphragmatic crus was exposed. A 36-French bougie was used to calibrate the sleeve. A stapler was introduced and fired consecutively along the length of the bougie until the angle of His was reached. We used two different staplers: (1) the Echelon Flex™ Powered Endopath® stapler  with gold cartridges, or (2) the Endo GIA™  with purple cartridges for the first 2 firings and blue cartridges for the remainder. The surgeon waited up to 20 s after closing the stapler before each firing process was initiated. Running suture was used to reinforcement staple line in some cases. If not – hemostatic clips were applied. Decision about the SLR was dependent on surgeon and was based on the intraoperative appearance of the staple line (visible bleeding etc.) and own experience.The resected stomach specimen was then removed by enlarging one of the 13-mm ports. After testing for leaks with methylene blue dye (100 mL), a drain was placed alongside the staple line.All patients after surgery were placed in post anesthesia care unit. Automatic 12 h blood pressure recordings were performed. In case of high blood pressure patients received single dose of 10 mg per orally Amlodipine. For analgesia we used morfine pomp (PCA), Paracetamol (Acetaminofen) and Metamizol. All patients underwent an additional test with methylene blue solution on postoperative day 1. If no leakage was detected, an oral diet was resumed. The patients were discharged on postoperative day 2.Observers were blind to the exposure and the data were collected retrospectively form medical records by single investigator. The risk of information bias is low. We analyzed large number cases of primary LSG (522) to minimize selection bias. According to the reports LSG constitute over 800 bariatric procedures per year in Poland , 12. Thut -test, or Wilcoxon signed ranks test. Dichotomous outcomes analyzed using McNemar’s test or Fisher’s exact test. The analysis of matched (dependent) data is different from unmatched (independent) data and is described in detail by Breslow and Day [Analysis was performed using SAS® software, University Edition . Continuous outcomes were analyzed using the paired  and Day .A total of 34 subjects (17 matched pairs) were included in the study. Table p = 0.15; mean difference − 11.6 (95% CI -29.5 to 6.1). Mean 12 h diastolic pressure was also comparable (80.6 ± 7.2 versus 81.6 ± 7.2); p = 0.49; mean difference − 3.1 (95% CI -13.3 to 7.1). The detailed analysis of cases revealed significantly lower mean systolic blood (SB) pressure (mmHg) in the 5th hour of postoperative observation , mean difference − 16.9 (95% CI -31.8 to −1.96) and in the 11th hour of postoperative observation , mean difference − 17.4 (95% CI -29.0 to −5.8). Likewise, the mean diastolic blood pressure in the 12th hour of postoperative observation was significantly lower in cases , mean difference − 12.9 (95% CI -25.6 to −0.1). Differences in the rest of blood pressure either SB or DB were not statistically significant.  in 12 h observation (130.7 ± 12.9 versus 139.1 ± 10.8); This study reports 12-h blood pressure profiles of patients after Laparoscopic Sleeve Gastrectomy compared with closely matched control subjects drawn from the database of patients who underwent LSG between January 2013 and May 2015 in a single, high volume bariatric institution. The mean systolic and diastolic blood pressure measurements in 12-h observations were comparable. Controls subjects had higher systolic blood pressure in 5th and 11th postoperative hour and diastolic blood pressure in 12th postoperative hour. However the measurements in both groups were within normal limits and were not clinically significant. What is more, there was no difference in antihypertensive intervention between the groups.Recently an observation was made that routine elevation of systolic blood pressure (SBP) to 140 mmHg at the end of stomach resection and oversewing the staple line minimized HC , 15–17. The limitation of our study is the size of our study group. Bleeding complications in our study occurred in 4.03% of all cases and it matches the rates in other observations, ranging from 3% to 5% . Since oCompared with closely matched control subjects, patients with hemorrhagic complications after LSG have a decreased systolic blood pressure without statistical and clinical significance. Therefore the level of postoperative blood pressure is not a risk factor for hemorrhagic complications after LSG.


Data on autonomic nervous system (ANS) activations in migraine patients are quite controversial, with previous studies reporting over- and underactivation of the sympathetic as well as parasympathetic nervous system. In the present study, we explicitly aimed to assess the cranial ANS in migraine patients compared to healthy controls by applying the cold pressor test to a cohort of migraine patients in the interictal phase and measuring the pupillary response.In this prospective observational study, a strong sympathetic stimulus was applied to 20 patients with episodic migraine in the interictal phase and 20 matched controls without migraine, whereby each participant dipped the left hand into ice-cold (4 °C) water for a maximum of 5 min (cold pressor test). At baseline, 2, and 5 min during the cold pressor test, infrared monocular pupillometry was applied to quantify pupil diameter and light reflex parameters. Simultaneously, heart rate and blood pressure were measured by the external brachial RR-method at distinct time intervals to look for at least clinically relevant changes of the cardiovascular ANS.p < 0.05), while both cardiovascular parameters and PLR dilatation velocity were similar in both groups at this time point.There were no significant differences between the migraine patients and controls at baseline and after 2 min of sympathetic stimulation in all the measured pupillary and cardio-vascular parameters. However, at 5 min, pupillary light reflex (PLR) constriction velocity was significantly higher in migraineurs than in controls  contains supplementary material, which is available to authorized users. A hallmark of migraine attacks is a concomitant variety of vegetative symptoms, such as loss of appetite, nausea or vomiting, with some patients even showing signs of activation of the cranial autonomic nervous system (e.g. parasympathetic system), such as lacrimation, sweating, rhinorrhea or nasal congestion –3. FurthThe advantages of pupillometric testing are that it a) assesses both the sympathetic and parasympathetic innervation simultaneously concerning the pupillary reflex, and that it is b) a well-established method to evaluate autonomic function in the innervation area of the cranial nerves for various conditions –8. The aNo. 133–13) and all patients gave their written informed consent.The experiments were performed at the Department of Neurology, University Hospital Munich, Campus Großhadern. The study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of the medical faculty of the Ludwig-Maximilians-University Munich  . The migThe control group consisted of 20 subjects . No one of the healthy controls fulfilled the criteria of migraine [The MIDAS was filled in by all subjects  and is a well-known and often used self-administered patient questionnaire to assess the impact of headache on daily life . There aIn general, the cold pressor test is used in clinical routine to assess the function of the ANS and the left ventricle. Temperature is a known stressor to affect heart rate (HR) and blood pressure (BP), therefore painful cold stress leads to a spike in activation of the sympathetic nervous system and consequently to the release of norepinephrine. The resulting pressor response is defined by an increase in HR and BP . There iTo roughly assess the response of the cardiovascular autonomic nervous system we measured the HR and the BP with the conventional external brachial RR-method on the right arm at fixed time points.− 2 and a duration of 200 ms [Pupillary constriction velocity in mm s− 1.Pupillary dilatation velocity (slow) in mm s− 1, i.e. velocity of pupillary dilatation at the end of the dilatation phase.Latency time in ms, i.e. the period from the initiation of the light stimulus until the start of pupillary constriction.− 1, i.e. velocity of pupillary dilatation at the beginning of the dilatation phase.Pupillary dilatation velocity (fast) in mm sAmplitude in mm, i.e. maximum change of pupillary diameter.Initial diameter in mm, i.e. pupillary diameter at the beginning of the measurement.Pupillary function was assessed with the monocular infrared “Compact Integrated Pupillograph (CIP)” . Subjects were seated comfortably in front of the CIP. The pupil was automatically detected by the infrared camera and the diameter was measured continuously over 2 s at a sampling frequency of 250 Hz. The light stimulus to measure the PLR was conducted by the integrated LED with an intensity of 10,000 cd mf 200 ms  and was In order to assess the response of the ANS during the cold pressor test, we decided to analyze – in accordance with the existing literature –9, 16 – We obtained standardized pain ratings with a numerical rating scale (NRS), from 0 (i.e. no pain) to 10 (i.e. maximum pain), of 20 subjects (10 in each group) to evaluate whether any measured differences in the ANS are a consequence of differences in pain perception.Data at three distinct time points were registered: T0: baseline before the cold pressor test; T1: two minutes during the cold pressor test; T2: five minutes during the cold pressor-test; T1’ as additional time point only for the measurement of blood pressure; i.e. immediately after dipping the hand into the iced water. All the obtained data is given as mean ± SD. For the pupillary response, each data point was an average of at least five subsequent registrations of the pupillary light reflex (one every 10 s). For the cardiovascular parameters, mean blood pressure and heart rate were obtained once at each time point.p < 0.05.Statistical analysis was done using SPSS 22.1 . The data distribution was parametric as tested by the Kolmogorov-Smirnov (K-S) test. Repeated analysis of variance (ANOVA) was used to compare parameters between multiple time points within both groups . We performed posthoc Bonferroni-correction for multiple testing. Whenever we found a significant effect in the ANOVA, then we applied an unpaired t-Test at any timepoint(s)  to detect the exact time point(s)  of the statistical difference. Statistical significance was considered at p < 0.01) with a significant impact of headache on the abilities of everyday life , a significantly higher number of headache days in the last 3 months (MIDAS A: 10.37 ± 10.93 vs. 1.30 ± 1.49), as well as an increased pain score (MIDAS B: 6.00 ± 2.11 vs. 1.75 ± 1.80) in the migraine group. A total MIDAS score above 10 indicates moderate disability.As expected, the MIDAS scores were significantly higher in the migraine group .p < 0.05) due to a continuous increase in pupillary constriction velocity in migraine patients, but not in controls (Ctr) from T0 to T2: T0 (Ctr: 5.12 ± 0.46 vs. migraineurs: 5.18 ± 0.70 mm s− 1), T1 (Ctr: 5.13 ± 0.46 vs. migraineurs: 5.37 ± 0.66 mm s− 1) and T2 (Ctr: 5.16 ± 0.53 vs. migraineurs: 5.59 ± 0.73 mm s− 1) , there was a significant interaction between time and group , but not at T0 or T1. We further applied an unpaired t-test to compare both groups at each time point separately. There was a significant effect for T2 (p = 0.0.42), while T0 (p = 0.82) and T1 (p = 0.33) were not different between both groups.Posthoc analysis by the Bonferroni-correction revealed that the migraine patients had a significantly faster constriction velocity at T2 (− 1) after the light reflex, there were no significant main effects for time or group and no significant interaction between time and group  from T0 to T2: T0 (Ctr: 0.72 ± 0.20 vs. migraineurs: 0.70 ± 0.16 mm s− 1), T1 (Ctr: 0.78 ± 0.15 vs. migraineurs: 0.73 ± 0.18 mm s− 1) and T2 (Ctr: 0.74 ± 0.14 vs. migraineurs: 0.77 ± 0.20 mm s− 1) . However, there were no significant differences between groups and no significant interactions between time and group    from 20 subjects (10 from each group). There was a significant effect of time on the pain ratings (p < 0.01). But we did not find any significant differences between both groups and no significant interaction between time and group , but reflect in general the balance between the sympathetic (primarily dilatation) and parasympathetic (primarily constriction) nervous system tonus.At baseline (T0) there was no significant difference in the pupillary and cardiovascular parameters between the migraineurs and the controls, indicating that there are no profound changes in the ANS of migraine patients under normal circumstances. This is in line with a recently published study by Cambron et al., who did not find differences of pupil parameters in migraine patients, neither in the interictal phase nor during migraine attacks . HoweverCorresponding to our findings, a previous study by Tassorelli et al. (15) demonstrated a miotic phase with a maximum at five minutes during the cold pressor test after an initial very short mydriasis in healthy volunteers. Our dataset implies that this physiological parasympathetic pupillary response to the cold pressor-test is more pronounced in migraine patients. This might indeed be an indirect correlate of at least slight parasympathetic dysregulation in migraine.Pupil dilatation to baseline directly follows pupil constriction. This redilatation process can be divided into two phases: the initial and rapid redilatation phase is rather an effect of withdrawal of the parasympathetic tone than sympathetic activation, whereas the later and slower dilatation phase seems to be an active process induced by peripheral sympathetic innervation . AltogetWhich pathophysiological mechanisms besides a primary cranial autonomic dysregulation might also contribute to the observed differences in cranial autonomic response between the migraine patients and healthy controls: First, it could be due to a difference of peripheral sensory perception and/or central pain processing. Previous studies could demonstrate cutaneous allodynia (CA) for usually not painful sensory stimuli, particularly thermal stimuli, in more than half of patients with episodic migraine during a migraine episode , 19. OneSecondly, habituation of sensory stimuli, which is mainly a thalamo-neocortical process, can play also a role. Previous studies have shown that migraineurs have deficits in sensory habituation after repeated stimuli of different sensory modalities  even in the interictal phase , 25. CopRegarding the higher lifetime rate of syncopes (migraineurs: 46% vs. Ctr: 31%) and particularly a higher lifetime risk for repeated syncopes (migraineurs: 13% vs Ctr: 5%) in migraine patients, changes in the cardiovascular autonomic system should be expected . Since wCortelli et al. did not find any impairment of the autonomic control of the cardiovascular system in migraineurs interictally . DominguIn our study migraine patients and Ctr did not exhibit any differences in sympathetic or parasympathetic regulation of the cardiovascular response at any timepoint (T0-T2) during the CPT. But as already mentioned, we did not apply the necessary gold standard measurements (heart rate variability and continuous blood pressure measurements) therefore to really make clear statements about that issue.One major limitation of this study is that as we did not have a continuous registration of blood pressure. Thus, we indeed cannot completely exclude clinically relevant fluctuations of blood pressure. We also did not analyze the power spectrum of heart rate variability by using electrocardiography (ECG), which could give further insight into ANS regulatory processes, as the extern brachial method with punctual measurement is not sensitive enough for this purpose. But we explicitly concentrated on the cranial ANS response during cold pressor-testing and only wanted to exclude major changes within the cardiovascular system such as presyncope/syncope, which in turn might affect the cranial ANS response. Furthermore, regarding the influence of emotions, food intake, and cortisol levels on the ANS, we did not explicitly randomize for these factors. Since it is very difficult to find healthy subjects, which are completely free of headaches, we also included such subjects in the control group with a history of occasional headache not fulfilling the current criteria of migraine or any other primary headache. This is also the reason, why we applied the MIDAS score in the control group and indeed found an increased total score of 0.40 ± 1.10. However, this score was really significantly different to the migraineurs and means at least only mild disability. Furthermore, the score matched with the self-rating reports of the healthy controls as not being a “headache patient”.In summary, our data indicate different activation thresholds of the cranial ANS in migraineurs in the interictal phase during sympathetic stimulation. Based on our findings, the role of upper brainstem parasympathetic dysregulation in the pathophysiology of migraine should be further examined and elucidated in more detail. Particularly, the underlying differences in somatosensory processing on the level of cerebral networks and neuronal ensembles might be a target for future therapy strategies.There is a difference in the autonomic control of the pupillary light reflex in migraine patients outside an attack compared to healthy controls during a sympathetic stimulus.There is probably no such difference in the autonomic cardiovascular response, indicating anisotropy of the cranial and cardiovascular ANS in migraine patients.There seems to be a more selective role of parasympathetic dysregulation in the cranial innervation area in the pathophysiology of migraine.Additional file 1:The cold pressor test in interictal migraine patients. It provides the anonymized data of pupillary, cardiovascular and pain response. (XLSX 17 kb)


To characterize hypertensive patients after admission to hospital considering the current status, compliance to treatment, habits and lifestyle, and knowledge and beliefs about the disease. This was an exploratory study with 265 hypertensive patients admitted to a medical inpatients unit of a university hospital. Data were collected in an interview over the telephone. The level of significance was set as p<0.05.2. The comorbidities were heart problem (52%), diabetes (49%) and stroke (25%). As to antihypertensive treatment, 75% were on use, 17.3% stopped taking them and 21.3% missed visits. The treatment sites were the primary care unit (49%) and hospital (36%). As for knowledge and beliefs, 25% believed hypertension is curable, 77% that treatment should last for the rest of their lives, and hypertension brings complications (84%). A total of 46.7% were controlled. The lack of control was associated (p<0.05) with non-white ethnicity and absence of heart problems. It was found that 32% of hypertensive patients had died. One hundred patients were interviewed, mean age of 64.15 (13.2) years, 51% were women, 56% non-white, 51% with primary education, 52% were retired, 13% were smokers, 38% used alcohol, 80% did not perform physical exercise, and the mean body mass index was 35.9 (15.5) kg/m There were significant deaths occurred after hospitalization and poor control of blood pressure, probably due to inadequate habits and lifestyles and non-compliance to antihypertensive treatment. According to the Surveillance of Risk and Protection Factors for Chronic Diseases by Telephone Survey (VIGITEL), the frequency of adults that reported a medical diagnosis of arterial hypertension was 24.8%, in 2014.2Arterial hypertension is recognized as one the major public health problems,3Data from the American Heart Association show that 40.6% of mortality due to cardiovascular diseases is related to an increase in blood pressure, with hypertension present in 69% of patients in the first episode of acute myocardial infarct, 77% of those with stroke, 75% with heart failure, and 60% with peripheral arterial disease.4For the year 2050, the estimate is for double the number of cases of coronary disease, stroke and hypertension, achieving 34 thousand cases per 100 thousand inhabitants.5 The absence of control of the disease predisposes towards complications. In a study performed in Brazil, which evaluated mortality due to stroke, hypertension was the basic cause of death;6 and, in an international study, the complications resulting from hypertension were responsible for 9.4 million deaths a year.7Besides the elevated prevalence of hypertension, we point out the unsatisfactory control of hypertensive patients diagnosed. A national review study showed a great variation in the rate of control, varying from 10.0% in Southern microregions, to 57.6% in a multicenter study in cities.9One of the mechanisms already used to evaluate control and compliance, as well as the involvement of organs, was the telephone survey, used nationally by means of the VIGITEL program to follow up hypertensive patients.i.e., after their hospital stay.Considering what was exposed, we question which are the events that take place after discharge of hypertensive patients, To characterize the follow-up of hypertensive patients relative to antihypertensive treatment after hospital discharge; to identify drug and non-drug antihypertensive treatment; to identify life habits and health styles; to identify the degree of knowledge about aspects related to hypertension and the treatments used; and to evaluate compliance with antihypertensive treatment.An exploratory-descriptive study was conducted, approved by the Research Ethics Committee, with official opinion no. 74378, CAAE: 04130112.1.0000.5392.10 which included adults admitted to the internal medicine inpatients unit of a university hospital in the city of São Paulo (SP), during the period from January 1, 2009 to December 31, 2009. The sample was calculated taking into consideration the estimate of prevalence of a 13% alteration of renal function, 5% variation, 5% type I error, 80% test power. With these parameters, the sample should have been made up of 386 patients ; socioeconomic status ; life habits ; habit of measuring blood pressure; knowledge and beliefs regarding hypertension and treatment. In the statistical analysis, a significance level of p<0.05 was considered. The relation among the variables was evaluated by means of Fisher’s exact test.The data collection instrument, based on a prior study,2) was 35.9kg/m2 (SD=15.5). , and the mean body mass index . .The most often reported comorbidities were heart problems  and diabetes; one fourth of the participants indicated having had a stroke. Most (59.0%) received orientation as to non-drug forms of treatment, the most frequent of which were losing weight and decreasing salt intake. It was noteworthy that 25% reported not using antihypertensive drugs, and 17.3% had not taken them in the previous 15 days . The maiAs to knowledge and beliefs, there was an expressive number of patients that believed that hypertension could not be cured; that the treatment should be extended for the rest of their lives; and that hypertension causes complications. Half of them indicated the highest grade for severity of the disease, and as to value for “high blood pressure,” the number of those who did not know was noteworthy . The mosOf the hypertensive patients that informed the value of their blood pressure, it was noted that 46.7% were not controlled. The lack of control was associated with non-white ethnicity and absence of heart problems (p<0.05) .datum that calls attention was that about two years after hospitalization, more than one third of the hypertensive patients died. Such an event may be justified by not following correctly the antihypertensive treatment, and consequently, by elevated pressure levels that can cause lesions in target organs. Low compliance with the treatments may be responsible for the inadequate control of the disease. Control of hypertension, despite being recommended by health policies,12 shows low rates, such as 45.5% in a study performed at a Primary Care setting13 and rates quite a bit lower in review studies.5 We point out that the lack of control was associated with non-white ethnicity, corroborating literature data,15 and the national survey, which showed that the risk of stroke was greater in black-skinned individuals, regardless of sex, and even considering hypertension as the basic cause of death.6 The lack of control was also associated with the absence of heart problems, probably considering greater compromise with health of hypertensive patients affected by heart problems.The first 17We also add that unfavorable characteristics of hypertensive patients, such as low income, difficulties in access to healthcare services, and greater prevalence of risk factors, may have contributed not only to the low degree of control, but also to the death of hypertensive patients. Some comorbidities, such as diabetes, hypercholesterolemia, and past history of stroke reflect an aggravating profile of health conditions. Diabetes, the most frequent associated disease, appears as a significant cardiovascular risk factor, and when associated with hypertension, it is more deleterious.20The adoption of healthy habits and life styles is an important tool in antihypertensive treatment of patients. Physical inactivity, obesity, and the prejudicial use of alcohol, added to smoking and hypercholesterolemia, are considered priority factors for intervention in hypertensive patients.22 but most of them did not know which blood pressure value can be considered as hypertension. Such data indicate the scarce information of these patients as to important aspects related to a chronic disease. Other aggravation factors that might contribute to lack of control of the disease were identified, such as not complying with drug treatment, mentioned by one fourth of hypertensive patients, missing the medical visits, and having stopped taking the medications in the previous 15 days due to forgetfulness, “my pressure was OK”, and only using the drugs when they felt ill. The reasons contributing to low compliance with treatment, and consequently, to unsatisfactory levels of control are complex and varied. They include from aspects linked to the disease, as a consequence of chronicity and the absence of specific symptoms, to drug treatment, even treatment for the rest of one’s life, undesirable effects, and complex dosing schedules. As to non-drug treatment, to the changes in habits and life styles. As previously demonstrated,10 the use of the telephone contact tool proved effective, in order to allow the characterization and follow-up of hypertensive patients, promoting measures for improving treatment of this clientele.We point out that knowledge and beliefs about hypertension are variables to be considered. Hypertensive patients were aware of complications caused by hypertension as reported in other studies,The strategies proposed by healthcare professionals to modify the morbidity and mortality profiles of hypertensive patients are imperative, as well as the use of the telephone contact tool for follow-up and care of hypertensive patients. Among the limitations, we point out the descriptive and exploratory nature of the study - although important, it was not possible to establish a cause and effect relation.The present study showed the important mortality index after hospitalization and a multiplicity of factors that can compromise the adequate follow-up of hypertensive patients, mainly after an episode of hospitalization, which is often due to complications from lack of control of the disease.


The study was primarily aimed at estimating the prevalence of hypertension and pre-hypertension and the risk factors of hypertension in the North Indian state of Punjab. It also aimed at assessing the magnitude of undiagnosed cases of hypertension in the community and ascertaining the blood pressure control status of those on treatment.A non-communicable disease risk factor survey (based on WHO-STEPS approach) was done in the state of Punjab, India in a multistage stratified sample of 5127 individuals. The study subjects were administered the WHO STEPS-questionnaire and also underwent anthropometric and blood pressure measurements.Overall prevalence of HTN among the study participants was found out to be 40.1% (95% CI: 38.8–41.5%) whereas prevalence of pre-hypertension, isolated diastolic and isolated systolic hypertension were 40.8% (39.5–42.2%), 9.2% (8.4–10.0%) and 6.5% (5.9–7.2%) respectively. Age group (45–69 years), male gender, social group, marital status, alcohol use, obesity and salt intake (> = 5 gms/day) were the risk factors significantly associated with HTN. Among all persons with HTN, only 30.1% were known case of HTN or on treatment, among whom nearly 61% had controlled blood pressure. Patients with uncontrolled BP were more frequently male, obese patients, with sedentary lifestyle and patients with diabetes.The study reported alarmingly high prevalence of hypertension, especially of undiagnosed or untreated cases amongst the adult population, a significant proportion of whom have uncontrolled blood pressure levels. This indicates the need for systematic screening and awareness program to identify the undiagnosed cases in the community and offer early treatment and regular follow up. In 2012, NCDs were responsible for around 38 million deaths per year, accounting for 68% of all deaths worldwide and 52% of all premature deaths. Over three quarters of those premature deaths were caused by cardiovascular diseases. CVD is the leading NCD which claimed 17.5 million lives in 2012 .[th of the total burden of hypertension still remains undiagnosed, although there is limited evidence in specific settings.[Previous studies in India in the last decade have reported varying prevalence of hypertension ranging from 17–47% in the adult population. However, they have mostly been limited to specific population sub-groups and in certain geographical pockets. A recentsettings.,14Thus, the current study (based on WHO-STEPS approach) was conducted in a large representative adult population of North India with the following objectives:estimate the prevalence of hypertension and pre-hypertension and their risk factorsassess the magnitude of undiagnosed cases of hypertension in the community, andascertain the blood pressure control status and associated factors among those on treatment for HTNPunjab is a state in northwest region of India bordering Pakistan and is one of the most prosperous states with a population of 2.7 million according to 2011 national census. Ranked sThe STEPS survey was undertaken in Punjab in 2014–2015 employing a multistage stratified sampling approach using the 2011 census sampling frame. In urban areas, a three-stage procedure was followed. In the first stage, wards were selected by Probability Proportional to Size (PPS) sampling. In the second stage, one Census Enumeration Block (CEB) was randomly selected from each sampled ward. In the final stage households were selected within each CEB using systematic random sampling. The rural sample were selected in two stages: the selection of Primary Sampling Units (PSUs), which are villages by PPS at the first stage, followed by the selection of households within each PSU at second stage using systematic random sampling. Out of a total of 100 PSUs, 60 were from rural areas and 40 were CEBs from the urban locality. From each selected PSU, 54 households were selected. The ultimate sampling units were the households and one individual in the age group of 18–69 years residing in the selected household was selected using the KISH method. The details of the study methodology are described elsewhere.Considering the prevalence of physical inactivity as 50%, alpha eA local language and pre-tested version of the WHO STEP Surveillance (STEPS) questionnaire (version 3.1) was used with minor adaptations. Socio deStandard procedures of measurement of anthropometric variables and blood pressure mentioned below have been described in detail previously. Height, For blood pressure measurement, electronic equipment  was used. It was validated as per the international validation protocol. After reCategorical variables are summarized using proportions and continuous variables using mean or median, whichever is applicable, with 95% confidence intervals. Chi-square test was used for comparison of proportions across groups and ANOVA test for comparison of means across groups. Multivariable logistic regression analysis  was performed to determine the predictors of hypertension, pre-hypertension, being under treatment and control of blood pressure. Variables entered into the multivariable regression model were selected on the basis of significance (p<0.2) in the univariable analysis. Statistical analysis was done using SPSS version 16.0.P-727, dated July 21, 2014). Informed written consent was taken from all participants. The study was also ethically approved by The Union Ethics Advisory Group, Paris, France.The Institute Ethics Committee of Post Graduate Institute of Medical Education and Research, Chandigarh approved the study , adults in the age group 25–44 years (49%), rural residents (61%) and belong to the general caste (47%). Nearly 15% were current alcohol users whereas around 6% were found to be current smokers. Around 96% of them used to have <5 servings of fruits and vegetables daily.Out of 5400, a total of 5127 individuals gave consent for the survey with a response rate 95%. Another 72 were removed from the analysis due to missing data thereby the effective sample size being 5055. Overall prevalence of HTN among the study participants was found out to be 40.1% (95% CI: 38.8–41.5%) whereas the prevalences of isolated systolic hypertension, isolated diastolic hypertension and prehypertension were 6.5% (95% CI: 5.9–7.2%), 9.2% (95% CI: 8.4–10.0%) and 40.8% (39.5–42.2%) respectively. Table 3 shows the mean SBP and DBP in different population groups. Both the mean SBP and DBP were significantly higher in hypertensive subjects compared to normotensives (p<0.001), whereas they were not significantly different in those who were previously diagnosed and were on treatment compared to those who were newly diagnosed.Table 4Among all persons with HTN, only 30.1% were known case of HTN or on treatment whereas the rest were newly diagnocsed or untreated. Among those already on treatment or known cases of HTN, 61% had controlled blood pressure. The proportion of undiagnosed cases of hypertension is more among males and younger individuals. Table 5On univariate analysis, the prevalence of HTN was found to be significantly associated with older age group (45–69 years), male gender, social group, marital status, obesity, diabetes and salt intake. Age group (45–69 years), male gender, social group, marital status, alcohol use, obesity and salt intake (> = 5 gms/day) were found to be the risk factors significantly associated with HTN in the multivariate regression model. Table 6 shows the factors associated with hypertension by the type of residence  and in different age groups (18–24 years and 45–69 years). Age >24 years and male gender were significantly associated with hypertension in both rural and urban residences. Being a current alcoholic, diabetic and obese were associated with HTN in urban areas, whereas association between salt intake (> = 5 gms/day) and HTN was found only in rural areas. Among respondents aged 18–24 years, male gender, urban residence, illiteracy and obesity were found to be the factors associated with HTN.The factors associated with pre-hypertension are age>25 years, male gender, obesity, diabetes, current smoking and salt intake > = 5gms/day. Among those who were previously diagnosed and already on treatment, males , obese  and those with sedentary activity  are less likely to have controlled blood pressure. The key findings of the present study are: 1) Around 40% of the general adult population have raised blood pressure or are known case of HTN; 2) ISH and IDH were found to be in 6.5% and 9.2% respectively; prehypertension was found in 40.8% of the population 3) Factors strongly associated with hypertension include older age group (45–69 years), male gender, social group, marital status, alcohol use, obesity and salt intake (> = 5 gms/day) 4) a large burden of undiagnosed cases of HTN exists among the adult population, a significant proportion of whom have uncontrolled blood pressure levels. 5) Males, obese patients, those with sedentary lifestyle and patients with diabetes were more likely to have uncontrolled blood pressure. It is highly likely that the high burden of pre-hypertension and hypertension is going to be the key driver of the epidemic of cardiovascular disease in India.Several studies have reported the prevalence of HTN in the range of 30–47% similar to the figures presented in this study.–10,12 ThAnother worrisome finding is the high prevalence of pre-hypertension. Slightly higher figures were reported in previous studies in India among the urban adult population in India.,32 PersoHigh BMI was independently associated with HTN especially in urban areas which is similar to the results in most other studies.,14,36–38Salt intake was found to be associated with HTN as reported in previous studies.,12,14,37The present study showed high prevalence of HTN among males similar to other large cross-sectional studies,,14 althoThe analyses show that nearly 70% of individuals with HTN were previously undiagnosed or untreated. Similar figures are also reported by few studies from India which put the proportion of undiagnosed cases in the community in the range of 60–80%, thereby indicating the need for aggressive screening programs.,30,36,38There were important differences between the sexes. The higher overall rates of diagnosis and blood pressure control among women as seen in other studies,38 probaThis study showed that patients with uncontrolled BP were more frequently male, obese patients, with sedentary lifestyle and patients with diabetes which is well supported in the literature from different settings.–50 The lThe strengths of the study are that it is population-based, employed a large multistage stratified sample representative of the general adult population with a high response rate and followed a robust methodology (WHO-STEPS approach). The study also adhered to STROBE guidelines for reporting the results. The presThe study reported alarmingly high prevalence of hypertension among the adult population in a representative North Indian population, calling for an immediate attention. The study also highlights a significant burden of undiagnosed or untreated cases of HTN in the community. This indicates the need for systematic screening and awareness program to identify the undiagnosed cases in the community and offer early treatment and regular follow up in order to prevent complications and premature mortality.S1 File(XLSX)Click here for additional data file.


Objective. Sodium intake is associated with cardiovascular outcomes. However, no study has specifically reported an association between cardiovascular mortality and urinary sodium concentration (UNa). We examined the association of UNa with mortality in a cohort of type 2 diabetes (T2D) patients. Methods. Patients were followed for all-cause death and cardiovascular death. Baseline UNa was measured from second morning spot urinary sample. We used Cox proportional hazard models to identify independent predictors of mortality. Improvement in prediction of mortality by the addition of UNa to a model including known risk factors was assessed by the relative integrated discrimination improvement (rIDI) index. Results. Participants  were followed for a median of 5.7 years, during which 254 cardiovascular deaths and 429 all-cause deaths were recorded. UNa independently predicted all-cause and cardiovascular mortality. An increase of one standard deviation of UNa was associated with a decrease of 21% of all-cause mortality and 22% of cardiovascular mortality. UNa improved all-cause and cardiovascular mortality prediction beyond identified risk factors . Conclusions. In T2D, UNa was an independent predictor of mortality (low concentration is associated with increased risk) and improved modestly its prediction in addition to traditional risk factors. Patients with diabetes mellitus, and particularly type 2 diabetes (T2D), represent a large and growing population at increased risk of cardiovascular events and mortality. Recent data have confirmed that patients with diabetes have approximately twice as high a risk of mortality and vascular diseases as individuals without diabetes . Blood pNa) and mortality in T2D patients. The measurement of spot UNa is a simple method for epidemiological approach and can easily be used in clinical practice. For this reason, our aim was to assess the relationship between spot urine UNa and mortality with an observational approach in a single center prospective cohort of T2D patients.Recent large-scale data have shown that estimated sodium intake was positively related to blood pressure . InteresThe present analyses include the subjects recruited in the SURDIAGENE study, a French single center inception cohort of T2D patients regularly visiting the Diabetes Department at Poitiers University Hospital, France . PatientThe primary outcome was the occurrence of all-cause death. Hospital records, interviews with general practitioners, and the French death registry were used by an independent adjudication committee to establish death and its cause. The secondary outcome was the occurrence of cardiovascular death, defined according to the International Classification of Diseases, Tenth Revision . Vital status of all study participants was confirmed through December 31, 2013.Blood samples and second morning urine samples were obtained in patients after an overnight fast. Seated blood pressure was measured twice at 3 min intervals using a semiautomated device  after 10 min of seated rest. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels were then calculated from the mean of the 2 consecutive measures.K) were determined by indirect potentiometry. Estimated daily sodium intake was derived from UNa measured on spot urine according to Kawasaki et al.'s [creat) was calculated as an estimate of the overall urine concentration [Serum and urine creatinine and urinary albumin concentrations were measured by nephelometry on a Modular System P . Renal function was estimated by glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology formula . Glycateet al.'s  and to Tet al.'s . This apet al.'s . The urintration . Glycosuχ2 test for categorical variables or parametric (ANOVA) or nonparametric  tests for continuous variables. Skewed variables were log-transformed in order to normalize their distribution. Associations between UNa and other variables were tested with Spearman's rank correlation test or linear regression analysis where estimates were standardized by calculating them for 1-SD increment of each continuous variable. To model the association between estimated sodium excretion and clinical outcomes, we used restricted cubic splines. Based on restricted cubic spline analysis for sodium excretion and cardiovascular death, we selected 5–6.99 g/day as the reference category because this was the range associated with the lowest risk. The time to event was plotted according to the tertiles of UNa, UK, and U : Pcreat with cumulative incidence curves, and comparison was made using the Log-rank test. We estimated the risk of outcome associated with UNa using a Cox proportional hazard model. The effect of interaction of some variables on the relationship between UNa and survival was examined by adding a corresponding interaction term in the model. Hazard ratios (HR) were standardized by calculating them for 1-SD increment of each continuous variable. A univariate model and two multivariate models were considered. The first multivariate model (Model A) was adjusted for age, sex, UNa, UK, U : Pcreat, and estimated 24 h Na excretion. Manual backward selection procedure was applied to identify the best fitted Cox proportional hazard model for independent variables in the prediction of all-cause and cardiovascular mortality. Variables associated with UNa were all selected and then removed from the model when P value ≥ 0.05 until all the remaining variables were significant. Generalized c-statistics [Na to the best fitted model and comparisons between nested models were performed by likelihood ratios tests. The relative integrated discrimination improvement (rIDI) index was calculated to assess the improvement in 5.7-year mortality risk prediction for UNa in addition to covariates of the best fitted model [Patient characteristics are expressed as means ± standard deviation (SD) or medians (interquartile range) for skewed distributions. Groups were compared using the atistics  were caled model . The 5.7−1 · 1.73 m−2 or history of renal replacement therapy at baseline, were omitted. Secondly, to test whether low UNa or low SBP reflects chronic heart failure (CHF), we excluded patients with cardiovascular history  at baseline. As we did not have information on CHF per se, history of cardiovascular disease was used as a surrogate for CHF. Thirdly, we used the competing risk model to estimate the subdistribution HR for cardiovascular death, while accounting for the competing risk of noncardiovascular deaths according to Fine and Gray method [ P values < 0.05 were considered statistically significant. Statistical analyses were performed with SAS version 9.3 .Three sensitivity analyses were performed. Firstly, patients with previous severe CKD, defined as eGFR < 30 mL·miny method . P valueNa was 89 ± 41 mmol/L. The mean value of 24-hour Na excretion was 4.6 ± 1.8 g/day. The clinical and biological characteristics of the patients are presented according to baseline UNa tertiles .The population studied included 1,439 patients with follow-up data. The mean value of Utertiles . InteresK, U : Pcreat, estimated 24 h Na excretion, NT-proBNP, and glycosuria .Urinary sodium concentration was associated with age, sex, history of cardiovascular disease, use of diuretics, use of insulin, eGFR, uACR, Uycosuria . Patientn = 58), infection (n = 41), and other causes (n = 76). When patients were classified according to the UNa tertile distribution, those in the low UNa tertile had the highest cardiovascular mortality (Log-rank P < 0.0001) as illustrated in K . The addition of UNa increased the c-statistic from 0.776 to 0.780 .The median follow-up was 5.7 years (interquartile range 3.1–8.8 years), during which time 429 all-cause deaths  and 254 cardiovascular deaths occurred . The causes of noncardiovascular death were adjudicated as follows: cancer , UNa was also an independent risk factor for cardiovascular death. In this model, cardiovascular mortality was 24% lower for every 1-SD increase of UNa (P < 0.0001) as detailed in In the best fitted model for cardiovascular death prediction . There was no significant difference of all-cause and cardiovascular death according to glycosuria . We found no interaction of glycosuria, use of diuretics, or use of insulin with the association between urinary concentrations and either all-cause or cardiovascular death. 24-hour Na excretion considered as a 3-category variable (reference group = 5–5.99 g/day) was not significantly associated with all-cause or cardiovascular mortality; even graphical representation of the relationship evocated nonlinear J-shape relationship. Considering Tanaka's formulas instead of Kawasaki's for estimating 24-hour Na excretion did not modify the results of the final Cox models.The addition of U−1 · 1.73 m−2 and no history of renal replacement therapy . In this subgroup, UNa was not correlated with SBP . All-cause and cardiovascular deaths were registered in 229 (22%) and 123 (12%) patients, respectively. Results were unchanged with a clear graded protective effect of UNa: all-cause and cardiovascular mortality were 19% and 21% lower for every 1-SD UNa increase in the corresponding best fitted model; P = 0.005 and P = 0.02, respectively.Because severe CKD is an established independent risk factor for cardiovascular complications, we focused on a subset of patients with eGFR ≥ 30 mL·minn = 1,151 patients), all-cause death and cardiovascular death were registered in 304 (26%) and 165 (14%) patients, respectively. Results were similar as UNa remained significant predictor of mortality . Accounting for the competing risk of noncardiovascular mortality in a Fine and Gray analysis (Na remained independently associated with a decrease in risk of cardiovascular death (P = 0.007).In the group of patients without any personal cardiovascular history at baseline , and glycosuria. Nevertheless, the extent to which UNa improves risk prediction is modest according to the rIDI and the change in c-statistics and its value in clinical practice remain to be determined.The present study reveals a significant negative prognostic value of UData from prospective epidemiologic studies focusing on estimated or measured 24 h urinary sodium excretion identified inconsistent association with cardiovascular complications –20. InteNa. The antinatriuretic effect of insulin may contribute to the relationship between insulin resistance and hypertension [Na tertile also require less antihypertensive therapy. The question whether low UNa may play a role in higher mortality in insulin-treated patients as recently reported [Nevertheless clinical trials have demonstrated that reduced sodium intake lowered blood pressure . Howeverrtension , and patreported  will neeNa constitutes a prognostic factor for all-cause and cardiovascular mortality in T2D patients. To the best of our knowledge, no similar conclusions had previously been reached. Interestingly, our data support the hypothesis that the kidney capacity to excrete water and solute in the urine is implicated in the occurrence of fatal cardiovascular complications. This hypothesis would benefit from reanalyzing previous studies. However, our current findings propose a shift of paradigm from simple sodium intake to a more complex phenomenon associated with cardiovascular death: the kidney's ability to excrete sodium. As sodium concentration is lower in urine compared to plasma, the kidney independently regulates the amount of water required to excrete solutes. Our data on UNa but also on U : Pcreat support the likelihood that a higher excretion of water leading to a lower UNa is particularly ominous. Though urinary osmolarity is lacking, this speculation needs validation.Our key finding is that UThe pathophysiology underlying such relationships remains unclear. The potentially involved biological systems are those contributing to the regulation of sodium and volemia. The natriuretic peptides and vasopressin, the renin-angiotensin-aldosterone system (RAS), or the sympathetic nervous system (SNS) could all play a role.Na was associated with low SBP levels in our population. Because these conditions could be present in CHF, we adjusted our analyses for NT-proBNP, a marker of CHF, and we analyzed separately patients without history of cardiovascular disease. Indeed Na and water excretion was impaired in CHF [Na. We also tried to determine whether low UNa could be related to arginine vasopressin (AVP), the hormone fine-tuning water excretion in the kidney collecting duct. Because AVP is difficult to measure, measurement of copeptin, the N-terminal part of the AVP prohormone, is now widely used as a proxy of AVP concentration [Na. Indeed the higher UNa, the higher copeptin concentration. In addition, as glycosuria may contribute to fluid loss in T2D patients, we confirmed that plasma copeptin was higher in patients with glycosuria compared to nonglycosuric patients (data not shown). As the deleterious effect of low UNa remained significant after adjustment for copeptin concentration, plasma copeptin concentration is unlikely to be the sole contributing factor between UNa and cardiovascular death.Low Ud in CHF  whereas ntration . High contration , 33. As We then examined the possible implications of RAS activation. This hormonal pathway was shown to be associated with several cardiovascular and renal outcomes following genetic and pharmacologic approaches . The RASNa as a valuable surrogate for overactivity of renal SNS requires future confirmation, it can be speculated that early detected SNS dysregulation may reveal possible targets for pharmacological intervention (such as beta blockers), but also for nonpharmacological interventions such as renal denervation or barostimulation that are currently under evaluation [A third explanation focused on renal SNS. Diabetes is associated with autonomic dysfunction and sympathetic/parasympathetic imbalance . Overactaluation .Na and measured daily urinary sodium excretion in our cohort was therefore beyond our scope. We based our analysis on a single voided morning urine sample, which represents usual individual solute [Some limitations in our study must be acknowledged. This study was not designed to collect 24-hour urine and exploration of the relation between Ul solute . MisclasWhile urinary sodium excretion rate is known to exhibit a daily (circadian) to weekly (circaseptan) pattern , 41, in Na may provide less intrasubject variability compared to one-time spot UNa, it is unlikely to affect intersubject variability. In addition, this approach of repeated urinary sampling seems not feasible for large epidemiologic studies. However, our study also has a number of strengths. The size of our cohort allows detection of low level associations. An independent adjudication committee validated all single events. Three independently measured urinary variables  provided similar trends.We performed no dietary assessment of salt or fluid intake, and information regarding timed urine volume was not available. Although 24-hour urine samples are theoretically more satisfactory as a surrogate for daily sodium excretion , they prNa measured in the morning can be proposed as new a biomarker of risk of all-cause and cardiovascular mortality, in type 2 diabetes patient.In conclusion, we have evidenced that U


There is an ongoing debate regarding the relevance of the 6-minute walking distance (6MWD) in systemic sclerosis (SSc) assessment, widely used as a usual test in these patients as well as an outcome measure in clinical trials. In this work, we aimed to assess the associations between the 6MWD and various disease parameters in patients with SSc.Consecutive patients followed in our SSc National Reference Centre were included in this cross-sectional study if they fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc. Data were systematically collected during a comprehensive standardized evaluation that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores ) and treatments.Associations of the 6MWD with various disease parameters were assessed by linear regression in univariate and multivariate analyses.The study population comprised 298 patients  42%; pulmonary arterial hypertension (PAH) 6%). The 6MWD was significantly and independently associated with gender, age, body mass index, baseline heart rate (HR), HR variation during the test, PAH, history of arterial thrombosis and C-reactive protein levels, as well as with the HAQ-DI score in a sensitivity analysis. Muscle involvement, joint involvement and ILD were not independently associated with the 6MWD.During SSc, the 6MWD is independently associated with initial HR and HR variation; with PAH but not ILD, suggesting that pulmonary vasculopathy may have a greater impact than parenchymal involvement on functional limitation; and with global markers of disease activity and patient disability. These results give clinicians further insight into how to interpret the 6MWD in the context of SSc.The online version of this article (doi:10.1186/s13075-017-1489-4) contains supplementary material, which is available to authorized users. Systemic sclerosis (SSc) is a severe condition classified within the connective tissue disease spectrum . Over thAmong the different tools available to evaluate SSc patients, the 6-minute walk test (6MWT) is simple, noninvasive, inexpensive and reproducible, and is frequently used in daily practice . InitialHowever, conversely to these diseases, SSc is a systemic condition associated with various extrapulmonary features  and with significant disability that can confound the interpretation of the 6MWT. In this multi-organ setting, the assumption that the 6MWD is an adequate surrogate marker for the severity of cardiopulmonary complications is no longer straightforward, and this has led clinicians to wonder what is actually being measured during this test in SSc . This isSeveral teams have tried to answer this question but their results are conflicting –30. For To address this issue, we performed a cross-sectional study and assessed the associations between the 6MWD and various disease characteristics in a large and well-phenotyped SSc patient population.We designed a cross-sectional study and recruited consecutive patients over 18 years old followed in the National Referral Centre for Systemic Sclerosis of Lille from November 2014 to August 2016. They were included in the study if they fulfilled the 2013 ACR/EULAR classification criteria for SSc . There wData were collected systematically by a physician in a standardized case-report form for all patients referred to our day-patient clinic. All of them underwent a comprehensive evaluation performed within the same day (except for transthoracic echocardiography (TTE) that could be performed up to 6 months before or after the 6MWT).2), blood pressure (BP) and heart rate (HR) were recorded at the beginning and the end of the test. Variations of (Δ) Borg score, SpO2, BP and HR were defined as the difference between their final and initial values.Patients underwent a non-encouraged 6MWT as recommended . The totOther data collected included patient and SSc characteristics, clinical parameters (including modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class), biological results (including C-reactive protein (CRP), Nt-pro-BNP and creatinin kinase (CK) levels), TTE (including estimated systolic pulmonary artery pressure (sPAP) and left ventricle ejection fraction (LVEF)), PFT  and diffusing capacity of the lung for carbon monoxide (DLCO)), composite scores (European Scleroderma Study Group Activity Index (EScSG-AI) , MedsgerCharacteristics of the population were described using the mean ± standard deviation (SD) for quantitative variables, and number (percentage) for qualitative variables.In order to study the associations between the 6MWD  as the dependent variable and the various explanatory variables, in a first step we conducted univariate analyses using linear regressions. Results were expressed using nonadjusted coefficients ) expressed in meters. To better identify relevant explanatory variables, linear regressions were then adjusted on the main potential confounding factors , disease duration, smoking history and SSc subtype).p < 0.10). Thirdly, we ensured that among these variables, those of interest were present . Fourthly, we excluded the variables that mediated the relationship between the 6MWD and organ involvements , so as not to attenuate the regression coefficients related to organ involvement variables. We also excluded collinear variables and composite scores. Fifthly, we ensured that the number of variables included in the model was consistent with the number of patients . Finally, we tested several potential interactions: between PAH or ILD and joint symptoms, muscle symptoms, smoking history or SSc subtype; and between ΔHR, initial HR and chronotropic drugs. None of the interactions tested was significant. Additionally, the HAQ-DI score was included in a separate regression model as a sensitivity analysis. Coefficients (95% CI) were expressed in meters. Regression diagnostics were performed.As a second step, we built a multivariate linear regression model using the following strategy. Firstly, we included a priori the six potential confounding variables already described. Secondly, we made a first selection of variables based on univariate analyses , decreased their SpOUnivariate analyses revealed several associations between the 6MWD and the collected parameters Table . To bettp < 10–3), age (p < 10–6) and BMI (p < 10–6) both before and after adjustment. Associations were observed with smoking habits and disease duration in nonadjusted analysis, but did not remain significant after adjustment. Although we found no association with cutaneous subtype, immunological profile or capillaroscopic anomalies in nonadjusted analysis, adjustment on confounding variables revealed a significant association of the 6MWD with the cutaneous subtype (p = 0.008).Regarding general patient and SSc characteristics, the 6MWD was associated with gender (p < 10–6), ILD (p = 0.02) and history of cardiovascular events  in nonadjusted analysis. Association with ILD was no longer significant after adjustment (p = 0.08). We also found significant associations of the 6WMD with NYHA functional class (p < 10–6), elevated Nt-pro-BNP levels (p < 10–6), echocardiographic markers of PH  and left-heart dysfunction (LVEF p = 0.03), and PFT results  in nonadjusted analysis. These associations remained significant after adjustment.Regarding cardiopulmonary parameters, the 6MWD was significantly associated with PAH (p < 10–3) and ΔHR (p < 10–3), both before and after adjustment. Significant associations with chronotropic drug intake were observed only in nonadjusted analysis.Other cardiopulmonary parameters measured during the 6MWT also displayed significant associations with the total distance, especially initial HR (p = 0.02) that became nonsignificant after adjustment on confounding variables. Similarly, there was no association with markers of muscular  and skin  involvements in nonadjusted analysis.Regarding extracardiopulmonary parameters, we observed an association with articular involvement (joint symptoms p < 10–3), CRP (p < 10–3), EScSG-AI (p = 0.001) and Medsger severity scores (p < 10–3), both before and after adjustment. We also found a markedly large association of the 6MWD with the HAQ-DI score (p < 10–3) in both analyses.Regarding global indicators of disease activity and severity, the 6MWD was significantly associated with hemoglobin , age  m per 1-year increment, p < 10–3), BMI  m per 1-kg/m2 increment, p = 0.03), history of arterial thrombosis  m vs no history, p = 0.04), PAH  m vs no PAH, p = 0.002), CRP  m per 1-mg/L increment, p < 10–3), initial HR  m per 1-bpm increment, p = 0.03) and ΔHR  m per 1-bpm increment, p < 10–6)  m for men vs women, 8 –3.9; –.7 m per p < 10–6)  m per 1-unit increment, In this cross-sectional study, we tried to identify the factors associated with the 6MWD in a large and fully characterized population of SSc patients. Our results can be summarized as follows: aside from demographic parameters, we observed significant and independent associations of the 6MWD with ΔHR and resting HR, with PAH and history of arterial thrombosis, and with CRP levels; we found no independent association of the 6MWD with ILD or musculoskeletal involvement; and in a sensitivity analysis, the HAQ-DI score was also independently associated with the 6MWD.2 [Although literature data are conflicting, the results of our univariate analyses mostly confirm findings from previous works, which observed associations of the 6MWD with age, BMI and cardiopulmonary parameters , but no major influence of musculoskeletal involvement –30. Mult2 , initial2  and DLCO2 , 28 wereAssociation between the 6MWD and ΔHR has never been studied previously in SSc. Interestingly, similar findings were made in IPF  and PAH Interpretation of this result in the context of the 6MWT is challenging. On the one hand, the lower increase in HR observed in some SSc patients could simply indicate lower exercise intensity due to limited functional capacities or a lack of motivation . On the Since the 6MWT is a submaximal exercise test, the diagnosis of chronotropic incompetence cannot be made here with certainty; and since detailed patient comorbidities are not available, the causes for the impaired chronotropic response in our population cannot be investigated fully. However, it is interesting to note that negative chronotropic drug intake was not independently associated with the 6MWD in our patients, making the hypothesis of a medication-induced chronotropic incompetence unlikely. Conversely, SSc is frequently associated with autonomic dysfunction  , but not with lung volumes assessed by spirometry . In SSc-However, if this result confirms that PAH contributes to impaired exercise capacities during SSc, we also observed in a previous work that the 6MWD correlated poorly with RHC parameters in SSc-PAH patients . Taken tAnother interesting finding of our study is the strong association observed between the 6MWD and the HAQ-DI score.Several teams have already reported similar results, both in univariate and multivariate regressions , 23. RemOverall, these results suggest that if the 6MWD is influenced to some extent by the objective severity of organ involvements, it is also greatly conditioned by the patient’s subjective impression of disability and quality of life impairment.. [. [An independent association between CRP levels and the 6WWD was observed in our population. A similar result was also found in previous work by Schoindre et al.  both in . [. . Interes. [. . In lineContrary to a common idea , it is iOur study draws strength from a large sample size and an important number of variables collected.Our study also has some limitations. We did not perform incremental exercise testing to correlate the 6MWD with objective physiological parameters collected during effort. Similarly, we did not study autonomic dysfunction to help explain the results observed with HR variation and ΔHR.In our multivariate regression, we chose to include only parameters relating to organ involvement  and exclude variables mediating them . Indeed, we believed that inserting the latter in our model could mask interesting associations of the 6MWD with organ involvement.Our work showed that, aside from demographic parameters, ΔHR, resting HR, PAH, history of arterial thrombosis, CRP levels and HAQ-DI score are important factors associated with the 6MWD in SSc, while pulmonary interstitial and musculoskeletal involvements seem to have no major influence. This suggests that the 6MWD should be interpreted not only as a marker of cardiorespiratory severity, but also as a global assessment of disease activity and patient disability. Further studies are warranted to investigate the possibility of a chronotropic incompetence as a cause for exercise intolerance in SSc patients.Additional file 1:presents additional methods, a complete list of data collected during the study and a definition of each collected item (DOCX 39 kb)Additional file 2:Table S1. presenting results of sensitivity analysis with inclusion of the HAQ-DI score in our multivariate regression model assessing the associations between 6MWD and SSc characteristics (DOCX 33 kb)is


The recovery responses of central and middle cerebral arterial (MCA) hemodynamics from the release of LBNP (~15 s) were evaluated. SV (via Modeflow method) and pulsatile and systolic MCA  normalized by mean MCA velocity (MCAv) significantly increased after the cessation of LBNP in both groups. ET exhibited the higher ratio of SV to aortic pulse pressure (SV/AoPP), an index of aortic compliance, at the baseline compared with SED (P < 0.01). Following the LBNP release, SV was significantly increased in SED by 14 ± 7% (mean ± SD) and more in ET by 30 ± 15%; nevertheless, normalized pulsatile, systolic, and diastolic MCAv remained constant in both groups. These results might be attributed to the concomitant with the increase in aortic compliance assessed by SV/AoPP. Importantly, the increase in SV/AoPP following the LBNP release was greater in ET than in SED (P < 0.01), and significantly correlated with the baseline SV/AoPP . These results suggest that the aortic compliance in the endurance athletes is able to accommodate the additional SV and buffer the potential increase in pulsatility at end-organs such as the brain.Aorta effectively buffers cardiac pulsatile fluctuation generated from the left ventricular (LV) which could be a mechanical force to high blood flow and low-resistance end-organs such as the brain. A dynamic orthostatic challenge may evoke substantial cardiac pulsatile fluctuation via the transient increases in venous return and stroke volume (SV). Particularly, this response may be greater in endurance-trained athletes (ET) who exhibit LV eccentric remodeling. The aim of this study was to determine the contribution of aortic compliance to the response of cerebral blood flow fluctuation to dynamic orthostatic challenge in ET and age-matched sedentary (SED) young healthy men. ET ( Exaggerated hemodynamic fluctuation would be a profound mechanical force to high blood flow and low-resistance end-organs   and superior compliance characteristics of the LV . To test our hypothesis, we applied lower body negative pressure (LBNP) release technique as previously used to elicit an immediate increase in central blood volume and blood pressure  and age-matched sedentary  subject were stratified according to their recent history of exercise training. ET had been participating in regular aerobic endurance training for 12 ± 4 h/week (mainly endurance exercise training) and engaging long distance running and/or swimming for 10 ± 2 years; while, untrained subjects did not regularly partake in regular aerobic and resistance exercise (1 ± 1 h/week). All subjects were healthy, normotensive (<140/90 mmHg), nonobese , nonsmokers, free of medication, overt chronic heart and lung diseases, head trauma as assessed by medical history. None of the subjects were taking cardiovascular-acting medication. Prior to the experimental sessions, each subject was familiarized with the equipment and the experimental protocol. Subjects were requested to abstain from food intake for 3 h, caffeinated beverages for at least 12 h, and strenuous physical activity and alcohol intake for at least 24 h before the testing. The subjects were allowed to drink water to keep well hydration.Twenty young healthy men voluntarily participated in this investigation. Each subject received a verbal and written explanation of the associated objectives, techniques of measurement and risks. In accordance with the Declaration of Helsinki, each subject provided written informed consent for participation and all protocols were approved by the Ethics Committee of the Human Research Institutional Committee of the National Institute of Advanced Industrial Science and Technology (No. 2013-434). Group of endurance-trained  and arterial blood pressure at rest, during 30 mmHg negative pressure (LBNP −30 mmHg) and after release up to 15 s. All measurements were conducted in an environmentally controlled laboratory with a quiet and air-conditioned room (24–25°C).After arrival at the laboratory, the subjects underwent body composition assessment , and supine rest at least 20 min. After cardiac data acquirement and instrumentation for LBNP testing, each participant was placed in a supine position inside the LBNP testing chamber. Once inside, they straddled a wood seat with their feet clear of the base of the chamber and sealed at the level the iliac crest. Following 6 min rest at ambient barometric pressure, negative pressure was gradually induced using a commercially available vacuum and quantified with pressure transducer was invoked. The LBNP test was terminated when the participant completed 4 min at LBNP −30 mmHg. During this experimental protocol, negative pressure was gradually increased and carefully monitored the signs of impending presyncope include dizziness, nausea, profuse sweating, or a rapid change in blood pressure defined as either a decrease in systolic blood pressure by 25 mmHg or a decrease in diastolic blood pressure by 15 mmHg within 1 min. When these signs were reported or observed, the experimental was stopped. These experimental procedures have been demonstrated in our previous research  was obtained using the formula: √(height×weight)/3,600 3]+ 0.6.  equipped with a multifrequency probe (2.5-MHz transducer). The end-diastolic interventricular septum (IVST) and LV posterior wall thicknesses (PWT) and LV end-diastolic dimension (LVEDd) and end-systolic dimensions (LVESd) were measured on M-mode images in the long parasternal view. LV ejection fraction (EF) and LV fractional shortening (FS) were calculated by Teichholz's method  was monitored by a metabolic cart equipped with a respiratory gas analyzing system . Doppler signal was stored at 200 Hz with an acquisition system  interfaced with a personal computer equipped with data acquisition software . Beat-to-beat time average velocity , systolic MCA velocity (MCAv), diastolic MCAv, and pulsatile (=systolic − diastolic) MCAv were obtained from 6 min for baseline, 4 min for LBNP testing, and 15 s for releasing LBNP stimulation by offline analysis, and the averaged values of each parameter were reported. Because normalized values of MCA systolic, diastolic, and pulsatile for mean  velocity (%)  have reported with strong correlation with carotid compliance  over the temporal window ipsilateral using 2-MHz transcranial Doppler (TCD) probe  The sampling depth was set from 42 to 55 mm, and the angle of the Doppler probe and the sampling depth were adjusted to optimize the signal quality for each subject according to standard procedures .t-test by groups was performed to determine the impact of continuous endurance training habits on variables of interest and the magnitude difference of recovery responses in central and cerebral hemodynamics from the release of LBNP. Simple correlation analysis was performed to identify the effect of aortic compliance at baseline to the response to the LBNP release. Statistical comparisons of variables were made utilizing a repeated-measures two-way analysis of variance (ANOVA) with a 3 × 2 design (LBNP × group). A Student-Newman-Keuls test was employed post-hoc when interactions were significant. Statistical significance was set at P < 0.05 and results are present as mean ± SD.Students' independent AoPP .Subjects' anthropometric parameters, systemic hemodynamics, and LV parameters are shown in Table F = 6.5, P < 0.01) and SV after the LBNP release in ET was significantly larger compared with SED (P < 0.01). Reported SV values in all figure and Table No subject showed the signs of impending presyncope during the LBNP testing. Before SV convert from value recorded via modelflow to value recorded via echocardiogram, we performed two-way ANOVA to verify the presence of significant response difference in SV to LBNP between groups. There was a significant difference between groups  in both groups. This finding is consistent with previous observation  but also the attenuated pulsatile fluctuation at cerebrovascular hemodynamics is an important determinant of cerebrovascular health. The change in pulsatile fluctuation may partially accommodate with compliant aorta. The greater amount of evidence has shown the age-related cerebral hypoperfusion and cerebrovascular disease (Davis et al., In the present, there are technical limitations that warrant mention. First, TCD measures blood flow velocity in the MCA rather than CBF. Blood flow velocity reflects blood flow only if the diameter of the blood vessel has measured. Early evidence suggested that the diameter of MCA appears to slightly change with LBNP −40 mmHg for 5 min (Serrador et al., AoPP. Additionally, SV/AoPP significantly elevated after the LBNP release in ET but not in SED, and the increase in SV/AoPP following a LBNP release was significantly correlated with the baseline SV/AoPP. These results suggest that the aortic compliance in the endurance athletes is able to accommodate the additional SV and buffer the potential increase in pulsatility at end-organs such as the brain.In conclusion, we found that systolic and pulsatile CBFV at rest were significantly lower in ET with superior proximal aortic compliance compared with SED group. SV and pulsatility index of MCA blood flow velocity significantly increased after the release of LBNP in both groups. The increase in SV was significantly greater in ET than in SED, whereas there was no significant group-difference in responses of pulsatile CBF. These results might be attributed to the concomitant with the increase in aortic compliance assessed by SV/TT, TI, SO, and JS conception and design of research; TT, TI, and JS performed experiments; TT, TI, and JS analyzed data; TT and JS interpreted results of experiments; TT and JS prepared figures; TT, SO, SM, and JS drafted manuscripts; TT, TI, SO, SM, and JS approved final version of manuscripts.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.


Their plasma ANG levels were detected using enzyme-linked immunosorbent assay (ELISA). Plasma ANG was 342.8 , 304.5 , and 279.7  ng/mL in the CHF group, CHD disease controls, and healthy controls, respectively, significantly higher in the CHF group compared with the others. Furthermore, among CHF group, ANG is dramatically higher in the HFrEF patients compared with the HFpEF patients. As for the diagnostic capacity of ANG, the area under the receiver operating characteristic curve was 0.71 (95% CI 0.63–0.78). We concluded that plasma ANG is elevated in CHD complicating CHF patients and may be a moderate discriminator of CHF from CHD or the healthy.Angiogenin (ANG) has been shown to be elevated in several cardiovascular diseases. To detect its levels and diagnostic capacity in coronary heart disease (CHD) patients complicating chronic heart failure (CHF), we performed this cross-sectional study and enrolled 616 CHD patients and 53 healthy controls. According to complicating CHF or not, the patients were divided into CHF group ( Chronic heart failure (CHF), as the terminal stage of all cardiovascular diseases, is a major and growing public health problem worldwide. Common causes of heart failure are coronary artery disease (CHD), high blood pressure, and diabetes , 2. WithANG, one of the most potent angiogenic factors, appears to be elevated in various cardiovascular disorders  male or female age ≥ 40 years; (2) diagnosed with CHD, complicating CHF symptoms or not; (3) willing to provide written informed consent. Patients were excluded if they had (1) clinically acute myocardial infarction   from each participant and the plasma was stored at −80°C until assay. All subjects signed an informed written consent to participate in the study that was approved by Ethical Committee of Zhongshan Hospital, Fudan University, China, which is according to the principles stated in the Declaration of Helsinki.Plasma ANG levels were tested in all subjects by enzyme-linked immunosorbent assay kit  according to the manufacturer's instructions. Briefly, standard or sample was added into per well and incubated for 1 hour. Subsequently, wash buffer, conjugate, substrate solution, and stop solution were added according to the instruction. Finally, we used a microplate reader to determine the optical density. Other biochemical tests were all performed using routine clinical autoanalyser assays in the Biochemistry Department of Zhongshan Hospital, including NT-proBNP, serum cholesterol, triglycerides, alanine aminotransferase, urea nitrogen, and creatinine.p < 0.05, 1 − β power of 0.90, and ratio of disease controls to CHF patients taking 2 : 1, a minimum of 89 disease controls and 45 CHF patients were required.We were unaware of previous studies assessing the cross-sectional differences in ANG between CHD patients complicating CHF or not to power our study. It had been previously reported that ANG levels in heart failure exceeded those of healthy controls ; we therR-square value was reported to explain the variation in ANG in response to the severity of disease. Receiver operator characteristic (ROC) curves were used to evaluate the performance of ANG, NT-proBNP, and LVEF, depicted by the mean area under the curve (AUC) with 95% CI. We treated p values < 0.05 as a statistically significant and used Stata 12.0 for Windows  to perform statistical analysis.Continuous variables were tested for normal distribution by Kolmogorov-Smirnov test and appropriately presented as mean (SD) or median . Categorical variables were shown as percentage. Comparisons between groups were performed by one-way ANOVA , as appropriate, with Bonferroni post hoc test for intergroup comparisons. Comparison between categorical data were using the chi-square test or a Fisher's exact test. Correlations between two continuous variables were performed using the Pearson correlation coefficient, or Spearman rank correlation for nonnormally distributed data. Ordinal regression analysis was used to determine changes in ANG levels in relation to disease severity, where the pseudo We recruited 616 CHD patients, in which 203 ones complicating CHF were set as CHF group and the other 413 CHD patients as CHD disease controls. Additionally, 53 healthy subjects were recruited as healthy controls . There wR2 = 0.0397, p < 0.001).Among CHF patients, plasma ANG levels showed no difference between different gender and those with or without MI history, hypertension, dyslipidemia, or diabetes mellitus status. Concerning the NYHA class, no difference of plasma ANG levels was observed between the NYHA I and NYHA II, but it elevated dramatically in the NYHA III-VI patients. . On ordip < 0.001), while its levels in HFpEF group were higher than CHD disease controls significantly  versus 304.5  ng/mL, p < 0.001) (With regard to observing disparity of plasma ANG levels between HFpEF (LVEF ≥ 0.50) and HFrEF (LVEF ≤ 0.40) group, we performed subgroup analysis of these two groups according to the guideline's LVEF classification criteria . In HFrE< 0.001) . However< 0.001) .p < 0.01) and positively correlated with NT-proBNP  among CHF patients.On bivariate analysis of patients and controls, levels of ANG were positively associated with fasting plasma glucose, deteriorating cardiac function , and blood lipids levels , while it had no association with age . In relap < 0.001), with a poorer performance compared to LVEF  or NT-proBNP levels   of ANG, which showed ANG was a significant but not a good discriminator  . ConcernChronic heart failure (CHF) is a major health problem worldwide and requires frequent readmissions to the hospital. Coronary heart disease (CHD) constitutes the major underlying causes of CHF and its mortality rates in general have declined for the past 25 years in most Western countries. Remarkable changes have taken place in the factors that contribute to the incidence of CHD complicating CHF, but the quantity of these patients is still large , 12.The cornerstone of diagnosis of heart failure is a comprehensive history and physical examination, combining laboratory testing including NT-proBNP and echocardiography. However, NT-proBNP reflects myocardial wall tension and increases with increasing age . And echANG is a 14 124 Da soluble protein member of the ribonuclease (RNase) superfamily-enzymes, and its pathophysiological role in angiogenesis is what most studies focused on –18. In tIn this study, we demonstrated ANG was elevated in the CHF patients compared with CHD patients or healthy controls. Furthermore, its level increased with the exacerbation of CHF, was higher in HFrEF than that in HFpEF patients, and was higher in NYHA class III-IV than that of class I or II. Meanwhile, plasma ANG levels in CHD patients were higher than that in healthy controls. However, ANG failed to be a good discriminator to identify CHF from the controls. All patients we enrolled were in stable phase coronary heart disease, and our results were in agreement with other studies where ANG might be a biomarker for heart failure , 19. TheOur pilot study has found serum ANG elevated in HFpEF patients compared with either hypertension or healthy controls using antibody microarray and validated in a relative small cohort . It is pAlthough plasma ANG levels showed poorer diagnostic capacity in comparison with NT-proBNP or LVEF and undefined predictive value for the lack of follow-up, it positively correlated with NT-proBNP and LVEF which imply increased severity and poor prognosis of CHF . MeanwhiThe limitation of this study is cross-sectional approach, so that it is difficult to detect ANG's role in the pathophysiology of CHF or CHD in this study. For the absence of follow-up data, it is hard to determine ANG's predictive role in prognosis of CHF patients complicating CHD, although our prior study showed angiogenin may predict all-cause death in HFpEF. In this study, we set relative loose inclusion standard, which is in accordance with the reality better. However, the data showed ANG may be a moderate discriminator of CHF from CHD or the healthy.In conclusion, ANG is elevated in CHD patients compared with healthy controls, and it is higher in the CHD patients complicating CHF, both the HFpEF and HFrEF, particularly in HFrEF subgroup. It may play a potent role in the progression of heart failure which needs further research.