The determinant factors for baseline baPWV were age, duration of hypertension, and baseline systolic blood pressure (SBP) in multivariate linear regression analysis, similar with baseline haPWV ). In multivariate linear regression analysis, the decrease in DBP at 6 months (ΔDBP0-6mo) and baseline baPWV were significantly associated with the decrease in baPWV at 6 months (ΔbaPWV0-6mo). The associated factors of the change in haPWV at 6 months (ΔhaPWV0-6mo) were baseline haPWV, ΔDBP0-6mo and change in log-transformed plasma renin activity. Our result suggested that reversal of arterial stiffness in APA patients occurred early after adrenalectomy and determined by baseline vascular condition, hemodynamic factors, and humoral factors.Primary aldosteronism not only results in hypertension but also stiffer arteries. The time course and factors predicting the reversal of arterial stiffness after treatment are unclear. We prospectively enrolled 102 patients with aldosterone-producing adenoma (APA) from March 2006 to January 2012. We measured the pulse wave velocity (PWV) between brachial-ankle (baPWV) and heart-ankle (haPWV) before, 6 and 12 months after their adrenalectomy. After treatment, the PWV decreased significantly during the first 6 months (both  Primary aldosteronism (PA) is characterized by excessive autonomous production of aldosterone and the consequent physiological effects. Owing to the advances in research and screening, PA, once considered to be a rare disease, is now recognized to be one of the most common causes of secondary hypertension, accounting for 5~13% of all hypertensive patients234568In addition to cardiac effects, high level of aldosterone can also cause vessel endothelium dysfunction, collagen synthesis in the vascular wall, increased arterial wall stiffness, and atherosclerosis1011121314The consequences resulting from long-term exposure to excessive aldosterone are reversible after treating PA, including improvements in myocardial fibrosis and arterial wall stiffness and decreases in CIMT1417et al. groupArterial wall fibrosis not only increases the thickness but also the stiffness. Pulse wave velocity (PWV) has been widely used as a non-invasive tool to evaluated arterial wall stiffness15A total of 102 patients (45 men) with aldosterone producing adenoma (APA) were enrolled in this study, and the clinical records are listed in p < 0.001) and also in heart-ankle PWV (haPWV) . However, baPWV and haPWV increased slightly but not significantly in the subsequent 6 months .  6 months after adrenalectomy . .In factor analysis of baseline baPWV, age, duration of hypertension (from diagnosis to enrollment), the administration of angiotensin-converting enzyme inhibitors or clonidine, number of anti-hypertensive agents, height, baseline systolic blood pressure (SBP), baseline diastolic blood pressure (DBP) and baseline serum creatinine level were significantly correlated factors. In linear multivariate regression analysis, age, duration of hypertension and baseline SBP are independently associated with baseline baPWV. Age, duration of hypertension, baseline SBP and baseline DBP are independently associated with baseline haPWV .0-6mo) was significantly correlated with baseline SBP, baseline DBP, baseline baPWV, baseline Log PAC, the change of SBP in the first 6 months (ΔSBP0-6mo), the change of DBP in the first 6 months (ΔDBP0-6mo), and log-transformed the decrease in plasma aldosterone concentration at 6 months (ΔLog PAC0-6mo). In multivariate linear regression analysis, the independent associated factors of ΔbaPWV0-6mo were baseline baPWV  and ΔDBP0-6mo . In multivariate linear regression analysis, the independent associated factors for the change of haPWV in the first 6 months (ΔhaPWV0-6mo) were baseline haPWV , ΔDBP0-6mo  and log-transformed the change in plasma renin activity at 6 months (ΔLog PRA0-6mo)   .There are four major findings in this study. First, the determinant factors of arterial stiffness, as measured by PWV, were age, history of hypertension, and baseline SBP. Second, arterial stiffness, blood pressure, plasma potassium level and PAC improved within the first 6 months after adrenalectomy in APA patients. Third, the benefits of adrenalectomy for APA patients including reversal of arterial stiffness, hypertension and decreased PAC diminished beyond 6 months after the operation. Fourth, baseline arterial stiffness and ΔDBP contributed to the degree of improvements in arterial stiffness (represented by ΔPWV).Compared with EH patients, PA patients have a higher incidence of cardiovascular events, including coronary artery disease, stroke, and atrial fibrillation2221521et al.et al. , which is not idential to our study . However, the correlation coefficient between basline DBP and baseline baPWV was lower than that between baseline SBP and baseline baPWV  in our study. Both studies showed that baseline SBP had a stronger association to baseline PWV than baseline DBP.PWV has been widely used as a non-invasive measurement of arterial stiffnesset al. showed only ΔDBP (but not ΔSBP) was significantly correlated with ΔPWV. The reasons of different results between both studies need further investigations.The improvement of PWV (ΔPWV) was another story. In the current study, both ΔSBP and ΔDBP were moderately to highly correlated to ΔbaPWV . Besides, both ΔSBP and ΔDBP were highly correlated to ΔhaPWV . In contrast, a previous study done by Strauch et al., but not our previous studyIn the current study, the baseline aldosterone level (either before or after log-transformation) was not correlated with baseline PWV. This indicates that a single set of PAC data may not precisely reflect the chronic impact of aldosterone or the local concentration at a tissue level21PA patients have increases in both central-elastic and peripheral-muscular arterial stiffnessOur results showed a clear time course in improvements in hemodynamic status, biochemical condition, and vascular damage in APA patients after adrenalectomy. Interestingly, the recovery of arterial stiffness occurred within the first 6 months, and no further improvements were observed in the subsequent 6 months. In addition to arterial stiffness, other clinical features including hemodynamic and biochemical data improved within the first 6 months after surgery. It appears as though the improvements in PWV were parallel to improvements in hemodynamics and biochemistry. We also noted another interesting finding, that PAC seemed to have a compensatory rebound 6–12 months after adrenalectomy. One possibility is that the aldosterone-secreting function of the remaining adrenal gland is suppressed by contra-lateral adenoma before surgery. In the first 6 months after adrenalectomy, the aldosterone-secreting function of the remaining adrenal gland does not recover fully, and then it improves in the subsequent 6 months. However, further studies are needed to validate the physiological response after adrenalectomy in APA patients.0-6mo and 4.2% in ΔhaPWV0-6mo). Besides, the independent associated factors for ΔbaPWV0-6mo and ΔhaPWV0-6mo were different in multiple linear analysis. The causes of above-mentioned differences of excess aldosterone removal by adrenalectomy on different types of vessels and their clinical meanings need further investigation.In the current study, we measured baPWV and haPWV. baPWV evaluated muscular peripheral arteries and haPWV evaluated the combination of muscular peripheral arteries and elastic central arteries. In a previous study, PA pateints had both higher central and peripheral PWV than EH patientsThis study includes the largest APA PWV cohort to date. However, there are still several limitations to this study. First, we could not provide more frequent follow-up data  within the first 6 months after adrenalectomy. The detailed time course of improvements in PWV, hemodynamic data, and biochemical data could therefore not be determined precisely. Second, there was no tissue proof to explain the improvements in arterial stiffness. However, it is difficult to obtain serial vascular biopsies from PA patients only for study purposes.In conclusion, reversal of arterial stiffness in APA patients occurred early after adrenalectomy and determined by multiple factors including the baseline vascular condition, hemodynamic factors, and humoral factors.We prospectively enrolled 102 patients with APA who were prepared to undergo adrenalectomy from March 2006 to January 2012. These patients were registered in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database, which was constructed for quality assurance in two medical centers , Taipei; Taipei University Hospital, Taipei), four metropolitan hospitals , and two local hospitals in vitro using a commercial radio-immune assay kit . The study was approved by the Institutional Review Board of National Taiwan University Hospital. Informed consent was obtained from all participants. The methods in the study were carried out in accordance with the approved guidelines.A detailed medical history was recorded and the biochemistry parameters were measured at the first evaluation. The PAC was measured using a commercial radio-immune assay kit . PRA was measured as the generation of angiotensin-I APA was identified on the basis of the following four conditions: (1) autonomous excess aldosterone production as evidenced with an plasma aldosterone to renin ratio (ARR) > 35, a TAIPAI score > 60%3738PWV was measured using an automatic waveform analyzer  after the patients resting for 15 minutes in a supine positionBlood samples were obtained 6 months and 1 year after adrenalectomy to evaluate basic biochemistry data, PAC, and RPA. Blood pressure and PWV were also recorded. Hypertension was considered being cured if no anti-hypertensive medication was needed to maintain a blood pressure of 140/90 mmHg or less within 1 year. Patients who were cured from hypertension within 1 year but later developed hypertension were still considered as cured. Patients with residual hypertension and an ARR great than 30 at follow-up period would further undergo a saline loading test to exclude the possiblility of residual hyperaldosterone status (such as adenoma or hyperplasia at the other side)t-test was used to compare pre- and post-treatment variables. Pearson’s correlation analysis was used to validate associations between baseline PWV, changes in PWV after treatment. Significant determinants in Pearson’s correlation test (p < 0.05) were then tested in multivariate linear regression analysis with stepwise subset selection to identify independent factors to predict ΔPWV0-6mo. PAC, PRA and ARR were log-transformed before analysis because of their non-normality, as tested by the Kolmogorov-Smirnov test. P values less than 0.05 were considered to be statistically significant.Continuous variables were expressed as mean ± SD. The paired How to cite this article: Liao, C.-W. et al. Time course and factors predicting arterial stiffness reversal in patients with aldosterone-producing adenoma after adrenalectomy: prospective study of 102 patients. Sci. Rep.6, 20862; doi: 10.1038/srep20862 (2016).


FTO rs9939609 and MC4R. rs17782313 with elevated blood pressure in the Chinese Han population, and analysed the relationship between the rs9939609 and rs17782313 variants.In this study we investigated the association of We tested the rs9939609 and rs17782313 variants with the sequence-retrieval method.FTO nor MC4R risk alleles (p < 0.05), and that of the controls carrying only the A or C alleles (p < 0.05). No association between the FTO or MC4R genes with daytime hypertension was found in this Chinese population (p > 0.05).The increase in odds ratios of the A allele of rs9939609 and the C allele of rs17782313 for nocturnal blood pressure were 1.37 and 1.69. The nocturnal blood pressure of participants simultaneously carrying the A and C alleles was significantly higher than the blood pressure of those carrying neither Our data suggest that the rs9939609 and rs17782313 variants may be significantly associated with nocturnal but not daytime blood pressure levels and their combined effects were significant in this Chinese Han population. Elevated blood pressure increases the risk of experiencing cardiovascular events such as myocardial infarction and stroke. Current observational data suggest that body mass index (BMI) may have a causal role in the aetiology of hypertension, but this may be influenced by confounding and reverse causation.1FTO gene and obesity in children and adults.5Genetic factors play an important role in the development of hypertension. Recent studies have revealed a strong association between common variants in introductory studies on the FTO protein is a key link between the central nervous system and energy balance. It was found to be ubiquitously expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure.FTO risk variant may not be associated only with obesity and BMI, but also with elevated nocturnal blood pressure.MC4R gene, encoding for the melanocortin 4 receptor, was the first locus at which mutations were associated with dominantly inherited morbid human obesity, and was the commonest genetic cause of human obesity.MC4R, was similarly associated with obesity [OR = 1.30 (1.20–1.41)] in populations of European origin.FTO rs9939609 and the risk allele C for MC4R rs17782313, regardless of BMI.FTO rs9939609 had a positive association with BMI and neck circumference, and MC4R rs17782313 in women, but a negative association with diastolic and mean blood pressure in hypertensive men in southern Brazil.13The FTO and MC4R gene polymorphisms with hypertension in the Chinese Han population and analysed the relationship between FTO rs9939609 and MC4R rs17782313 variants.In the present study, we investigated the association of The subjects were divided into two groups comprising a daytime hypertension group (575 patients) and a night-time hypertension group (583 patients). The number of control subjects was 1 200. We recruited by physical examination 2 358 non-related individuals, aged 50 to 70 years (1 175 men and 1 183 women), who all belong to the Han nationality from the Hubei province of China.The study was carried out in the examination centre at the ZhongNan Hospital of Wuhan University. Daytime normotension was defined as daytime blood pressure < 135/85 mmHg.2), (4) diabetes mellitus, (5) renal dysfunction (serum creatinine > 180 mmol/l), (6) liver disease, (7) severe physical or mental disease , (8) pregnancy, and (9) substance abuse, including alcohol.A selection criterion was that these subjects were not on any hypotensive drugs or had stopped taking the drugs a week earlier. Additional selection criteria were the absence of (1) secondary hypertension, (2) diastolic blood pressure (DBP) 110 mmHg on blood pressure-lowering medication, (3) gross obesity (BMI > 35 kg/mClinic normotension was defined as blood pressure < 130/80 mmHg with or without blood pressure-lowering medications. Clinic-measured blood pressure (clinic BP) was the average of three seated measurements taken one minute apart by specially trained nurses. Ambulatory BP measurement devices  were set to measure the BP at 20-minute intervals for 24 hours.MC4R rs17782313 were designed using the primer 5 software . The MC4R rs17782313 and FTO rs9939609 variants were genotyped using sequence retrieval .Each subject donated 5 ml of blood for genomic DNA extraction. For genotyping procedures in our study, refer to a previous report.FTO rs9939609 and MC4R rs17782313 variants that were found to be significant were evaluated by computing odds ratios and 95% confidence intervals (CI). All data were presented as means ± SD. The clinical and biochemical characteristics between these genotypes were compared by one-way ANOVA; p < 0.05 was considered significant. All analyses were adjusted for gender, age and geographical region.Statistical analysis was performed using SPSS 11.5 for Windows. Genotype and allele frequencies were compared with the Hardy–Weinberg equilibrium model and then analysed using chi-squared testing and contingency tables, respectively. Allelic and genotypic associations of the The basic characteristics of the participants are shown in Table 1.MC4R and FTO on daytime hypertension were first investigated independently of each other. All the genotype and allele frequencies of FTO rs9939609 and MC4R rs17782313 were in Hardy–Weinberg equilibrium (p > 0.05). The frequencies are presented in The effects of FTO rs9939609 on daytime hypertension are shown in p > 0.05). The A allele frequency and the AA frequencies were not obviously different between the daytime hypertension group of patients and the controls.The effects of MC4R rs17782313 on daytime hypertension are given in MC4R and the Chinese Han population with regard to daytime hypertension (p > 0.05). The C allele frequency and the CC frequencies were not obviously different between the daytime hypertension group of patients and the controls.The effects of FTO rs9939609 on nocturnal hypertension are shown in 2 = 18.54 and χ2 = 19.39, respectively; p < 0.05). The A allele frequency and the AA frequencies were significantly higher in the patients than in the controls, as seen in Table 3. The increase in odds ratio of the A allele for the nocturnal blood pressure group was 1.37 (95% CI: 1.19–1.58). The genotypic odds ratio for elevated nocturnal blood pressure was 1.82 (95% CI: 1.38–2.41) for the AA genotype, and 1.39 (95% CI: 1.10–1.75) for the AT genotype.The effects of MC4R rs17782313 on nocturnal hypertension is shown in 2 = 15.21 and χ2 = 12.88, respectively; p < 0.05). The C allele frequency and CC frequencies were significantly higher in the patients than in the controls, as seen in The effects of FTO rs9939609 and MC4R rs17782313 on nocturnal hypertension is shown in FTO nor MC4R risk allele , and the BP of the controls carrying only the A or C alleles  The combined effects of Obesity and BMI are known to be associated with hypertension. Increases in BMI lead to an increase in the burden of hypertension. However, Ernsberger and Haskew found increasing prevalence of obesity as well as average BMI levels were accompanied by significant decreases in blood pressure level and prevalence of hypertension.et al. found both nocturnal and daytime systolic blood pressure predicted cardiovascular events independently of clinic systolic BP levels.17Gregg FTO and MC4R genes with nocturnal blood pressure in the Chinese Han population (p < 0.05). The combined effects of FTO and MC4R played an important role in nocturnal blood pressure levels in this population. Nocturnal blood pressure levels of the participants carrying three or four risk alleles were higher than those with neither FTO nor MC4R risk allele (p = 0.008), those with one risk allele (p = 0.025), and those with two risk alleles (p = 0.041). The mechanism may be related to the FTO protein, which is a key link between the central nervous system and energy balance.In our study, the analysis demonstrated a significant association of the FTO gene function is unknown but based on its predicted structure, the FTO gene encodes for a non-haeme (FeII) dioxygenase with a potential role in adaptation to hypoxia, lipolysis or DNA methylation.FTO protein is expressed in almost all tissues; at the cellular level it has a nuclear localisation.FTO gene in other complex disorders are unknown.The FTO rs9939609 and the risk allele C for MC4R rs17782313, regardless of BMI.FTO rs9939609 had positive associations with BMI and neck circumference and MC4R rs17782313 in women, but a negative association with diastolic and mean blood pressure in hypertensive men in southern Brazil.Various studies have shown cardiovascular risk factors such as type 2 diabetes mellitus,This study has some limitations that should be taken into account when interpreting the results. The analysis of genotype by gender was exploratory and it was underpowered to detect small differences. Therefore, some associations that achieved statistical significance in the overall analysis remained only as a trend towards that association. The association of gene variants with anthropometric indices should be confirmed in further studies with statistical power to carry out analysis by gender.FTO and MC4R genes were risk factors for nocturnal hypertension in this Chinese Han population, and their combined effects played an important role in nocturnal hypertension. However, even if a gene were considered associated with hypertension in certain populations, to expand the conclusion to all human populations is arbitrary. Furthermore, in the investigation of hypertension, obesity or diabetes, not only genetic factors but other factors, such as environment or geographic location could play a role. All these factors could have different effects on obesity or diabetes and they could impact on each other. Therefore whether or how a single gene could be associated with nocturnal hypertension is a complicated question. To decipher this, one would need long-term studies with numerous patients. FTO is a new gene reported by Yi-Cheng and co-workers in 2007,We found that the


The health-enhancing benefits of physical activity (PA) on hypertension and diabetes have been well documented for decades. This study aimed to determine the association of PA with systolic and diastolic blood pressure as well as blood glucose in the Malaysian adult population.Data were extracted from the 2011 National Health and Morbidity Survey (NHMS), a nationally representative, cross-sectional study. A two-stage stratified sampling method was used to select a representative sample of 18,231 Malaysian adults aged 18 years and above. The PA levels of the respondents were categorised as low, moderate or high according to the International Physical Activity Questionnaire (IPAQ)-short form. Blood pressure and fasting blood glucose levels were measured using a digital blood pressure-measuring device and finger-prick test, respectively.p = 0.02) whilst no significant association was noted between PA level and diastolic blood pressure (DBP). In contrast, respondents with low (adjusted coefficient = 0.17) or moderate (adjusted coefficient = 0.03) level of PA had significantly higher blood glucose level as compared to those who were highly active (p = 0.04).Systolic blood pressure (SBP) level was positively associated with PA level (A significant negative association was observed between PA level and blood glucose only. Future studies should employ an objective measurement in estimating PA level in order to elucidate the actual relationship between PA, hypertension and diabetes for the development of effective interventions to combat the increasing burden of premature-mortality and cardiovascular disease-related morbidity in Malaysia. Hypertension and diabetes are major and common risk factors for cardiovascular disease. Cardiovascular diseases (CVDs) account for approximately one third of deaths worldwide, with high blood pressure being the leading cause of cardiovascular death in the South East Asia Region. Together with a number of lifestyle risk factors , high cholesterol, low fruit and vegetable intake and physical activity), high blood pressure and high blood glucose account for 61 % of cardiovascular deaths and more than 75 % of deaths from ischaemic and hypertensive heart disease globally [In Malaysia, the prevalence of hypertension among adults aged 18 years and above has been persistent at 32.2 % in 2006 . TherefoFor decades, a plethora of epidemiological studies have demonstrably proven the metabolic and cardiovascular benefits of physical activity (PA), either alone or in conjunction with dietary changes in reducing the risk of hypertension and diabetes –7. FindiNonetheless, despite established evidence of the beneficial relationship between PA, hypertension and diabetes, there is a lack of national data reporting on the association of PA with systolic and diastolic blood pressure as well as blood glucose level among the Malaysian population. Therefore, in the present study, we aimed to determine these associations by analysing data obtained from the National Health and Morbidity Survey (NHMS) 2011 among Malaysian adults aged 18 years and above, while adjusted for other potential confounders. Findings from this study could provide evidence-based information to assist policy-making decisions pertaining to primary prevention and treatment of hypertension and diabetes, as well as interventional strategies.Data were extracted from a cross-sectional multi-ethnic population-based study, the 2011 NHMS, which was conducted from April to July 2011, across 13 states  and 2 Federal Territories  in Malaysia. Samples were selected using a two-stage stratified sampling method, by which the first stage stratification was performed by states and the second stage stratification was performed by urban/rural localities. The urban area is defined as a gazetted administrative area (a carefully mapped area with definite boundaries which had been notified in the government gazette for public information) with adjoining built-up areas of more than 10,000 people while a gazetted administrative area of less than 10,000 people is defined as a rural area. The Malaysian Department of Statistics (DOS) provided the Primary Sampling Units (PSUs) or Enumeration Blocks (EBs) for first stage sampling and Secondary Sampling Units (SSUs) or Living Quarters (LQs) for second stage sampling according to the 2010 census.A total of 794 EBs  were systematically selected from all EBs in Malaysia via a probability-proportional-to-size sampling technique. Subsequently, 12 Living Quarters (LQs) or Secondary Sampling Units (SSUs) were randomly selected from each EB. Finally, all households and eligible household members within the selected LQs were included in the sample. Details of the sampling method and calculation of sample size have been described elsewhere . For theThe data collection was conducted from April 2011 to July 2011 by trained interviewers via face-to-face interviews using a standardised questionnaire; whilst clinical assessment, which included measurement of blood pressure and blood glucose level, was performed by trained staff nurses. To ensure a higher response rate, only selected respondents who were not at home after at least 3 attempted visits were excluded from the survey.Category 1 LowThe International Physical Activity Questionnaire-short form (IPAQ-SF) estimates the overall PA level of an individual in MET-minutes/week by determining the duration (in minutes) and number of days (in one week) of engagement in three specific types of activity  across a comprehensive set of domains  in the past seven days. MET or metabolic equivalent is a unit that is used to estimate the amount of oxygen used by the body during physical activity. A MET-minutes/week is computed by multiplying the MET score of an activity  by the minutes and days (or sessions) of engagement. Respondents were classified into three levels of PA as low, moderate or high according to the cutoff of total MET-minutes/week in each category  as follo3 or more days of vigorous-intensity activity of at least 20 min per day, or5 or more days of moderate-intensity activity and/or walking of at least 30 min per day, or5 or more days of any combination of walking, moderate- or vigorous-intensity activities achieving a minimum total PA of at least 600 MET-minutes/weekCategory 2 Moderatevigorous-intensity activity on at least 3 days achieving a minimum total PA of at least 1500 MET-minutes/week, or7 or more days of any combination of walking, moderate- or vigorous-intensity activities achieving a minimum total PA of at least 3000 MET-minutes/week.Category 3 HighIndividuals who do not meet the criteria for Category 2 (moderately active) and 3 (highly active) were considered to have a ‘low’ PA level or were physically inactive.Blood pressure level was measured twice in an interval of 10 min by a trained nurse using a calibrated digital blood pressure-measuring device, OMRON HEM-907. This device was evaluated for compliance to both the American Association for the Advancement Medical Instrumentation (AAMI) and British Hypertension Society (BHS) protocols for accuracy for a non-invasive blood pressure-monitoring device using single observer readings . Both knRespondents were asked to fast for at least 6 h for the measurement of fasting blood glucose level using a validated CardioChek PA Analyser  via fing2 in kg/m2) was used to classify respondents into underweight, normal, overweight and obese based on the cut-off points recommended by the World Health Organization (WHO) [SECA bodymeter 206  and TANITA318 digital weighing scale  were used to measure the height and weight of respondents to the nearest 0.1 cm and 0.1 kg, respectively. Anthropometric measurements were taken twice and the average values were used for data analysis. Body mass index  and socio-demographic variables . Multivariable linear regression (MLR) or ordinary least square was performed to elucidate the associations of PA levels with SBP, DBP and blood glucose while controlling for gender, locality, age, ethnicity, educational level, household monthly income, employment and marital status, body mass index status and smoking status. Missing data were excluded from analyses and it was ignorable since the NHMS 2011 had taken a 20 % non-response rate into consideration at the sample size calculation stage. All statistical tests were conducted at a 95 % confidence interval (CI).Of the 18,231 eligible respondents aged 18 years and above, 99.1, 99.3 and 97.5 % of them responded to the PA, hypertension and diabetes modules of the questionnaire, respectively. The mean age (SD) of the respondents was 42.0 (16.0) years. The characteristics of respondents are provided in Table P < 0.05). However, such association was not significant between PA level and diastolic blood pressure (SDP) in the adjusted MLR analyses (Table P < 0.05). Respondents with low level of PA had significantly higher blood glucose level as compared to those who were moderately or highly active (reference group), and also, those who were moderately active had significantly higher blood glucose level than their highly active counterparts  analyses demonstrated that PA level was positively associated with systolic blood pressure (SBP)  was unlikely as blood pressure of respondents were measured twice at a 10-min interval using calibrated devices, OMRON HEM-907 by trained nurses. Therefore differential misclassification of hypertensive respondents as highly active, or normal respondents as lowly active could occurred as a result of information bias as the use of IPAQ in the estimation of PA level was rather subjective and subjected to recall bias and tendency of respondents to report a socially desirable response, which may lead to an over-estimation of PA. Lee and his colleagues who performed a systematic review on the validation of IPAQ-SF with objective measurements stated that IPAQ-SF typically overestimated physical activity by an average of 84 % . TherefoIn contrast, a significant negative association was observed between PA and blood glucose among Malaysian adults. The present findings were consistent with those reported from other cross-sectional studies , 7, 12 aDespite the cross-sectional nature of the study and the use of a subjective instrument (IPAQ) in the estimation of PA level, the large sample size and its representativeness as well as the high response rate were the major strengths of the present study. In addition, underestimations of the prevalence of hypertension and diabetes among the population were unlikely as measurements of blood pressure and fasting blood glucose levels were taken properly by trained nurses using calibrated devices rather than self-reported.Generally, a significant dose–response relationship was observed between physical activity and blood glucose, but not between physical activity and blood pressure. Nonetheless, in order to elucidate the true association between physical activity and hypertension or diabetes, the use of an objective instrument for the estimation of the physical activity level is highly recommended for future study.


The association between malnutrition and worse outcomes as pressure ulcers and mortality is well established in a variety of setting. Currently none investigation was conducted in patients with long-term consequences of the acquired brain injury in which recovery from brain injury could be influenced by secondary complications. The aim of this study was to investigate the association between various nutritional status parameters  and pressure ulcers formation and short-term mortality in minimal conscious state patients.In this prospective, observational study of 5-months duration, a 30 patients sample admitted to a Neurological Institute was considered. All patients underwent a complete medical examination. Anthropometric parameters like mid-arm circumference and mid-arm muscle circumference and nutritional parameters as serum albumin and blood hemoglobin concentration were assessed.2 test = 6.47).At univariate and logistic regression analysis, mid-arm circumference , mid-arm muscle circumference , hemoglobin  and albumin  were inversely associated with pressure ulcers. The area under the ROC curve for albumin to predict sores was 0.76 (p = 0.02) and mortality was 0.83 (p = 0.03). Patient with lower albumin had significantly higher short-term mortality than those with higher serum albumin (p = 0.03; χAlbumin, haemoglobin and mid-arm circumference are inversely associated with pressure ulcers. Albumin is a prognostic index in MCS patients. Since albumin and haemoglobin could be affected by a variety of factors, this association suggests to optimize nutrition and investigate on other mechanism leading to mortality and pressure ulcers. Several studies have suggested that hospitalized patients with a poor nutritional status experience worse outcomes such as prolonged length of stay, pressure ulcers and mortality in comparison to those well-nourished –4. UnforSerum albumin and blood haemoglobin concentration are commonly used as indexes of nutritional status, although both have several weakness , 7.Hypoalbuminemia has been shown to increase mortality in different clinical settings –10, inclAlthough this issue has been widely studied especially in the first weeks or months after a brain injury , 14, 16,The aim of this investigation was to identify the biochemical and anthropometric indexes of nutritional status associated to pressure ulcers and to verify whether albumin predicts short-term mortality in MCS patients.In this prospective, observational study of 5-months duration starting in November 2013, we enrolled patients diagnosed with MCS who were admitted to a Neurological Institute.A convenience sample of 30 patients admitted to a Neurological Institute in Crotone, Italy, fulfilled all criteria and participated in the study . They were also all those who, at the time of the study, were hospitalized in the part of the Institute dedicated to MCS patients .Patients were eligible for inclusion if they met the standard clinical diagnostic criteria for MCS . These pExclusion criteria were as follows: premorbid history of developmental, psychiatric or neurological illness, spinal cord injury, co-existing systemic disease with a limited life expectancy.The investigation was carried out in agreement with the Helsinki Declaration and all laws and relative to patients’ rights and was approved by the local ethic committee. Written informed consent was obtained from each patient’s legal surrogate .Grade 1: Nonblanchable erythema of intact skin.Grade 2: Partial thickness skin loss involving epidermis and/or dermis: the pressure ulcer is superficial and presents clinically as an abrasion, blister or shallow crater.Grade 3: Full-thickness skin loss involving damage or necrosis of subcutaneous tissue that may extend down to, but not through, underlying fascia: the pressure ulcer presents clinically as a deep crater with or without undermining of adjacent tissue.Grade 4: Extensive destruction tissue necrosis, or damage to muscle, bone or supporting structures with or without full-thickness skin loss.The European Pressure Ulcer Advisory Panel (EPUAP) description was used to define the pressure ulcers as “an area of localized damage to the skin and underlying tissue caused by pressure, shear, friction and/or a combination of these things” . We usedThe nutritional state was assessed by a trained dietitian while pressure ulcer development by internists according to the study protocol and neurological signs, such as spastic hypertonia or seizures signs, by neurologists. Data collection was performed by dietitian. No particular nutritional scheme was pursued in the Institute apart the administration of 1.3–1.5 g/kg of proteins at each patients.2).The participant’s caloric intake was deduced from the medical record. Body weight was measured with a calibrated lift scale in the morning, with the subjects lightly dressed, subtracting the weight of clothes. Height was estimated from knee height by a validated equation for mobility-impaired individuals . BMI wasSkin fold thickness was measured three times at the triceps (TSF) with the GIMA Skinfold Caliper  , 24 and Mid-arm circumference (MAC), a measures of muscle mass, was assessed at the level of the mid-point between the acromiale  and the radiale , on the mid-line of the posterior surface of the arm . Mid-armBody composition was estimated by using a bioelectrical impedance analysis (BIA)  to calculate the Total Body Water (TBW), Fat Mass (FM), Muscle Mass (MM), total Fat-Free Mass (FFM), extra-cellular water (ECW), intra-cellular water (ECW) and phase angle (PA) . Since pEnergy needs were calculated with the Harris-Benedict equation .The estimation of total energy expenditure (TEE) was performed by SenseWear Armband , a wireless multisensory activity monitor normally worn on the upper right arm over the triceps muscle, halfway between the acromion and olecranon . These lThe body composition assessment was performed by a dietitian and TEE estimation by a biotechnologist.Venous blood was collected in the morning into vacutainer tubes (Becton & Dickinson) and centrifuged within 2 h. Serum glucose, creatinine, calcium, iron , transferrin (v.n. 250–400 mg/dl), albumin (n.v. 3.70–5.30 g/dl) were measured using the commercially available ELISA assay kits. Red blood count (RBC) and white blood count (WBC) were measured with flow cytometry, hemoglobin  with Spectrophotometric assay. Quality control was assessed daily for all determinations.2 test was performed to analyze the difference in the prevalence between groups. Pearson correlation was used to identify the variables eventually correlated to the pressure ulcers  given that the continuous variables were normally distributed. The logistic regression analysis was used to test the association between pressure ulcer  and the nutritional parameters, adjusting for confounding variables selected among those with p < 0.1 at univariate analysis. Since MAC and MAMC as well as hemoglobin and albumin may be closely linked, to avoid that the one disappearing over the other in the regression due to this, we performed three models including, in the Model I, MAC and hemoglobin, in the Model II, MAMC and hemoglobin and, in the Model III, MAC and albumin. Furthermore, the area under the receiver operating characteristic (ROC) curve was used to analyse the capacity of albumin to predict pressure ulcers and mortality formation. We estimated 5-months cumulative mortality rate stratified by albumin levels using the Kaplan–Meier method. We used Pearson’s χ2 test or Mantel extension test for trend for the analysis of discrete variables. Significant differences were assumed to be present at p < 0.05 (two-tailed). All comparisons were performed using SPSS 20.0 for Windows .Data are reported as mean ± standard deviation (SD). ANOVA test was used to compare the means between groups categorized by albumin level ; A χTable 9 patients had pressure ulcers at basal observation  and 11 patients had pressure ulcers at the end of the study . In particular, only 1 patient reported a Stage II trochanter pressure sores while all other had stage I ulcers at the heel.When we categorized the population according to albumin levels, only a significant difference of hemoglobin concentration was found  Fig. . An albu2 test = 6.47; df 2; p = 0.039). MCS patients with lower serum albumin had significantly higher short-term mortality than those with higher serum albumin.Short-term mortality during a 5-months period was analyzed. Figure In this population we demonstrated an inverse association between some nutritional depletion indicators such as albumin and haemoglobin levels, as well as indexes of skeletal muscle wasting (represented by MAC and MACM) and pressure ulcers. Furthermore, a low albumin concentration (<3.1 g/dl) predicted pressure ulcer formation as well as mortality. Particularly, we found that MCS patients with lower serum albumin had significantly higher short-term mortality than those with higher serum albumin. This is an unprecedented finding, never investigated to date in patients with the long-term consequences of traumatic and non-traumatic acquired brain injury. To our knowledge, limited research has been conducted studying MCS patients, especially the factors associated with pressure ulcers and mortality have never been studied in this particular population.A low serum albumin level is yet reported to be a predictor of mortality in most populations –15 and, As suggested by albumin, prealbumin and phase angle, in this investigation the overall population was moderately malnourished Table . HoweverNevertheless serum albumin has been shown to be associated with pressure ulcers and mortality in different clinical settings , 33–35, Furthermore, our study could have an impact on the complexity of the management of patients with severe brain injury, especially in the presence of difficulties of taking accurate weight and height measurements . In factIn addition, our study is relevant as it has demonstrated that MCS patients may have a possible perception of suffering . TherefoThis study has several limitations that must be addressed. The sample size is small. We enrolled patients with a rare clinical condition, as in other investigations . HoweverLimited research has been conducted studying the factors associated with mortality and pressure ulcers in MCS patients. Hypoalbuminemia, regardless of its cause, is a negative prognostic index in MCS patients, which should not go ignored. Furthermore, for the first time, a simple anthropometric parameter as MAC was showed to be associated with pressure ulcers development suggesting the link between pressure ulcer and cachexia rather than underfeeding. Thus, in these patients the nutritional treatments could be optimized but other mechanisms leading to hypoalbuminemia and malnutrition need to be yet explored. A long-term prospective study is required to confirm our results.


The introduction of ophthalmodynamometric measurement of retinal venous pressure (RVP) now permits the quantification, or at least an approximation, of the real pressure in the retinal veins.We measured the RVP of healthy control subjects, patients with diabetes without diabetic retinopathy (nonDR) and patients with diabetes and diabetic retinopathy (DR).The mean ± SD RVP for the control, nonDR and DR groups were 23.4 ± 7.33, 22.5 ± 5.78 and 37.7 ± 10.1 mmHg, respectively. In the diabetes patients with DR, the RVP was markedly and significantly increased, and this result was significantly age dependent. RVP was not increased in the group of diabetes patients without DR. In our tested population, diabetes had a minor influence on intraocular pressure.Regardless of the cause, a marked increase in RVP in diabetes patients with DR is clinically relevant, as it reduces perfusion pressure and increases transmural pressure. The reduced perfusion pressure contributes to hypoxia, and the increased transmural pressure can facilitate retinal edema.Diabetes is an increasing burden, and DR is one of its most severe complications. Strategies to recognize the risk for DR and to develop personalized prevention and therapy therefore have major implications.NCT01771835.ClinicalTrials.gov ID:  Diabetic retinopathy (DR) is one of the leading causes of blindness and visual impairment . NonprolHyperglycemia and disease duration are the main risk factors for both the incidence of NPDR and the conversion to PDR . HoweverAlthough diabetes mellitus (DM) is primarily an endocrinal disease, it also affects both the large and small vessels in different parts of the body. Thus, diabetic complications are broadly classified as microvascular  and macrovascular  complications .In clinical settings, visual acuity, fundus examination, optical coherence tomography (OCT) and fluorescein angiography (FA) are routinely used to diagnose DR and to monitor its progression. The retinal vascular system is of particular interest for its early involvement and easy accessibility. Several studies -8 have sIndeed, RVPs higher than IOPs have been observed under several conditions ,11,12. OAn increase in RVP is of major relevance, as it decreases ocular perfusion pressure  ,14 and iWe tested the hypotheses that a) RVP in DM patients is different from normal controls and b) RVP in DM patients with and without retinopathy is different.This study was carried out at the eye clinic at the University of Basel. The protocol was approved by the institutional ethics committee of the Medical Faculty of the University of Basel. Each subject signed an informed consent form before entering the study.We measured RVP a) in 254 eyes of 127 healthy control subjects, b) in 40 eyes of 20 patients with diabetes without diabetic retinopathy (nonDR) and c) in 54 eyes of 27 patients with diabetes and diabetic retinopathy (DRP). We did not distinguish between proliferative and nonproliferative DR, nor did we stage the severity of DR. Most of the patients with diabetes were under the care of internists at the Medical Faculty of the University of Basel, and the blood sugar, blood pressure and lipids of all the patients were well controlled.The healthy controls were not on any medication. Exclusion criteria for all three groups were any additional eye disease; IOP values were not an exclusion criterion. By chance, the lowest IOP value was less than 10 mmHg and the highest value was more than 20 mmHg. The subjects with IOP above 20 mmHg showed no signs of glaucomatous optic neuropathy.We had conducted a pilot study in which the RVP of all the subjects was measured by two investigators, and the averages of the resulting values were identical. For this reason, the subjects included in the present study were measured by one of the two investigators. Both eyes of each subject were examined by a trained ophthalmologist to determine whether the subject qualified for inclusion in the study. On the day of the study, IOP was measured with a noncontact tonometer, after which the pupils were dilated with Tropiphen® (tropicamide 5 mg and phenylephrine 10 mg) eye drops. The central and hemiretinal veins on the disc surface were examined for the presence of spontaneous pulsation. If pulsation was observed, RVP was taken as equal to IOP. If no venous pulsation was observed, RVP was measured after the application of one drop of Alcaine®  for topical anesthesia.A contact lens dynamometer (CLD) was used to measure RVP. The FDA-approved CLD  consists of a three-mirror Goldmann lens with a ring-shaped attachment containing several precision sensors affixed to the rear. The sensors continuously measure the force that the ophthalmologist exerts on the eye by means of the contact lens. The CLD is connected by a thin, flexible cable to a central unit approximately the size of a handheld calculator. A liquid crystal display shows the delta pressure in millimetres mercury, based on a calibration curve. The CLD, along with a contact fluid , was placed on the cornea. Pressure was increased until one of the segments of veins on or close to the optic nerve head started to pulsate; the required pressure is called ocular dynamic force (ODF). The RVP was calculated as the sum of the ODF and the IOP . If sponThe term RVP used herein refers to the pressure in the retinal veins close to the optic nerve and not generally in the retinal veins.p-value was calculated using analysis of variance (ANOVA) for independent groups. For RVP and IOP, the overall p-values were calculated using ANOVA based on linear mixed effects models. For gender, p-value was based on the chi-square test. To assess the differences in RVP and IOP among the study groups, a linear mixed effects model was performed. Mixed effects models are suitable techniques to account for multiple correlated measurements within a subject.Descriptive statistics of all the eyes are presented as means and SD or counts and percentages for all study groups. For age, the overall p-values.The dependent variables were RVP or IOP, and the independent variables were study group, age and eye side. Thus, the results were adjusted for age and eye side. Subject ID is treated as a random factor to account for potential correlation between the left and right eyes. The results are presented as differences of the mean between the two diabetes groups and the controls with corresponding 95% confidence intervals and In addition, the dependence of RVP on age was estimated for each study group using a nested mixed effects model and expressed as a regression slope.The results are presented both without and with age matching. To balance the age distribution between the DR group and the controls, a propensity score matching  was perfp-value <0.05 was considered significant. All analyses were conducted using the R statistical software package, version 2.15.1 [The dependence of RVP and IOP on age in the matched and unmatched study groups is presented graphically. A n 2.15.1 . Mixed eThe demographic description of the entire population tested is provided in Table The frequency of spontaneous venous pulsation was 24% in the control group, 25% in the nonDR group and 0% in the DR group.The patients with diabetes, particularly the ones with DR, were significantly older Table . Therefop < 0.001, slope = 0.52, 0.26–0.78). All other matched and nonmatched dependencies on age were not significant.There was a highly significant dependence of RVP on age for the nonmatched DR group (We tested the hypothesis that a) RVP in DM patients is different from normal controls and b) RVP in DM patients with and without retinopathy is different.In our tested population, the RVP of the group of diabetes patients without DR was not higher than that of the control group Table . The reaThe RVP of the diabetes patients with DR was markedly and significantly higher than that of the control subjects and the diabetes patients without DR Table . This inIn addition, we found in our tested population that diabetes had a minor influence on IOP Table .Limitations of the study include lack of blood pressure measurement, lack of differentiation among types of diabetes, unknown duration of diabetes and gender differences between the control and DR groups. Theoretically, the higher RVP in the group of patients with DR might be caused by different blood pressures in the groups. However, this is very unlikely for the following reasons. 1) There is no indication in the literature that RVP is blood pressure dependent ,19. 2) AA number of questions remain open. We do not know whether the increase in RVP with age reflects the duration of the disease or stage of severity. Furthermore, we do not know the cause of the RVP increase. It could be due to structural changes in the veins or the structures around the veins , or it cVascular and hemodynamic changes in the retina of patients with DM are well known and have often been reported . While bDiabetes also leads to variations in retinal vascular calibre and in particular to a widening of retinal venular calibre in patients with DR ,25. In tFuture studies are required to confirm the increase in RPV in patients with DR. The study design should consider other parameters as well, such as blood pressure, age, type and stage of diabetes and therapy.Regardless of the cause, a marked increase in RVP in diabetes patients with DR is clinically relevant, as it reduces perfusion pressure and increases transmural pressure. The reduced perfusion pressure contributes to hypoxia, and the increased transmural pressure facilitates retinal edema; hypoxia and edema are major components of DR. While increased RVP contributes to retinal hypoxia, such local hypoxia might increase RVP, thus inducing a vicious circle .Clinical and scientific implications of our findings are at present still open. Further studies are needed to establish the relationship between RVP and different factors such as blood pressure, duration of diabetes, or HB1c level. We also must compare diabetes type 1 with diabetes type 2 and NPDR with PDR. Of special interest is the question whether an increased RVP predicts the development of a future DR and whether it modifies the course of an existing DR. We like to know the relationship between RVP and retinal hemorrhages and whether an increased RVP predisposes to a retinal vein occlusion. Of special interest is the question whether we can reduce RVP and if so, whether this may help to prevent or modify DR. If this will be the case, we will be one step further in the direction of a predictive, preventive and personalized medicine.


P < 0.001) and dP/dt max . SGS shortened mean ARI from 304 ± 23 msec to 283 ± 17 msec (P < 0.001), although one patient required parasympathetic blockade. Dispersion of repolarization (DOR) increased in four patients and decreased in one, consistent with animal models. QT interval, T-wave duration and amplitude at baseline and with SGS were 415 ± 15 msec versus 399 ± 15 msec (P < 0.001); 201 ± 12 msec versus 230 ± 28 msec; and 0.2 ± 0.09 mV versus 0.22 ± 0.08 mV, respectively. At the level of SGS performed, no increase in arrhythmias was seen. Percutaneous low-level SGS shortens ARI in the RVOT, and increases blood pressure and LV contractility. These observations demonstrate feasibility of percutaneous SGS in humans.Modulation of human cardiac mechanical and electrophysiologic function by direct stellate ganglion stimulation has not been performed. Our aim was to assess the effect of low-level left stellate ganglion (LSG) stimulation (SGS) on arrhythmias, hemodynamic, and cardiac electrophysiological indices. Patients undergoing ablation procedures for arrhythmias were recruited for SGS. A stimulating electrode was placed next to the LSG under fluoroscopy and ultrasound imaging; and SGS  was performed. We measured hemodynamic, intracardiac and ECG parameters, and activation recovery intervals (ARIs)  from a duodecapolar catheter in the right ventricular outflow tract. Five patients underwent SGS . Stimulating catheter placement was successful, and without complication in all patients. SGS did not change heart rate, but increased mean arterial blood pressure (78 ± 3 mmHg to 98 ± 5 mmHg,  The autonomic nervous system powerfully regulates all aspects of cardiac function, and its electrophysiology  from the right ventricular outflow tract in the presence of dobutamine . All patients received the consent form for the study to review >1 week before presenting for the procedure and written informed consent was signed by all patients. Detailed clinical history, examination, and echocardiographic assessment were performed. Two of five patients were on antiarrhythmic medications; oral Metoprolol Tartrate 25 mg twice daily (held for 1 week prior) in one patient; and carvedilol 12.5 mg twice daily in another patient. None of the patients had a history of autonomic disorders, and had not previously undergone any neuromodulation procedures.Monitored Anesthesia Care (MAC) was provided to all study patients using intravenous propofol infusions (50–100 mcg/kg/min), titrated to moderate sedation. Supplemental oxygen via facemask was delivered to all patients. Electrophysiologic catheters were placed via percutaneous vascular access . An arterial sheath (4F) was placed in the femoral artery. All patients had continuous 12-lead electrocardiographic recordings. A decapolar catheter was placed in the coronary sinus, while quadripolar catheters were placed in the high right atrial, right ventricular, and His bundle positions under fluoroscopic guidance. From the His bundle catheter, atrioventricular conduction [Atrial to His signals ] and His-Purkinje conduction [His signal to earliest electrocardiographic QRS complex ] were measured. A duodecapolar catheter (20-pole) was placed in the right ventricular outflow tract.Stellate ganglion stimulation was performed prior to the electrophysiology study and catheter ablation.Once the patients were under MAC, a stimulating peripheral nerve catheter for left SGS was inserted via Tuohy needle as recently described Abdi et al. . In the Stimulation was initiated at 5 Hz, 5 mA and titrated until a hemodynamic response was observed (increase in blood pressure), typically >20–30 sec of stimulation. Stimulation parameters for each subject are shown in the table.From the arterial line, hemodynamic monitoring was performed, and a >10% increase in mean arterial pressure was used as a marker for SGS. From the arterial pressure waveform, the rate of rise in pressure over time (dP/dt) was taken as a surrogate for contractility, as it was not measured directly with conductance catheter.Unipolar electrograms were recorded from the duodecapolar catheter placed in the right ventricular outflow tract using an electrophysiologic acquisiton system . Recordings were filtered at 0.05–500 Hz. Activation recovery interval (ARI) analysis was performed as previously described Ajijola et al. .P value ≤0.05 was considered statistically significant.Values are expressed as mean ± standard error. ARIs before and during SGS in the same subject were analyzed with a Wilcoxon signed-rank test. Comparisons with more than two groups were performed with the Welch's ANOVA, given the non-normal distribution. The values across subjects were compared using the one-tailed Wilcoxon signed-rank test. A Five patients referred for electrophysiology study and ablation underwent SGS . The characteristics of the study patients are shown in the table. All patients had structurally normal hearts, mean left ventricular ejection fraction 62 ± 3.6%. Percutaneous placement of the SGS Catheter was successful in all patients Fig.A and no Stimulation was initiated at 5 Hz and 5 mA for 20–60 sec, and was confirmed by the appearance of stimulation artifact saturating the electrocardiographic and intracardiac electrogram channels ; diastolic blood pressure ; mean arterial pressure ; and pulse pressure   from 1148 ± 244 mmHg/sec to 1645 ± 493 mmHg/sec (P = 0.03).SGS increased systolic blood pressure  but shortened the AH interval , and did not significantly affect the HV interval   . In all the other subjects, SGS resulted in ARI shortening  but did not significantly change QTc ; R-R interval ; T-wave duration ; or T-wave amplitude   intervals; RR interval; T-wave duration and amplitude; and TThe main findings of the present study are as follows: (1) low-level SGS using a percutaneous ultrasound- and fluoroscopy-guided stimulating catheter is feasible, does not result in severe arrhythmias, and can be safely achieved without complications; low-level left SGS results in (2) inotropic but not chronotropic response; (3) predominantly an increase in repolarization heterogeneity; and (4) shortening of RVOT ARI and QT interval, but not QTc, T-wave amplitude or duration. These findings demonstrate that percutaneous SGS is a useful approach for studying the influence of sympathoexcitation in humans. To our knowledge, this work represents the first demonstration of percutaneous direct stellate ganglion stimulation in humans.Anesthetic blockade of the stellate ganglion has long been used for treating a variety of clinical conditions including complex regional pain syndromes and ventricular arrhythmias  increases inotropy but not chronotropy, while right SGS results in both chronotropy and inotropy  shortens, with no significant impact on the QTc  is thought to be a marker for increased risk of ventricular arrhythmias  or mental stress-induced sympathoexcitation in humans. That percutaneous direct stellate ganglion stimulation can be achieved safely without significant complications from catheter placement, or from life-threatening arrhythmias or hemodynamic disturbances, suggests that this method of sympathoexcitation may be a valuable research tool. This is especially true since four of the subjects presented for ablation of symptomatic and frequent premature ventricular contractions. Second, hemodynamic, electrocardiographic, and electrophysiologic measures of sympathetic stimulation could be readily obtained and interpreted, indicating that the set up utilized in this study can be applied relatively readily in other settings. Additionally, validation of a variety of assumptions and extrapolations on the workings of the cardiac SNS can be performed by directly stimulating the stellate ganglion without the need for surgical exposure of the ganglia.The present study is limited by the small sample size, although appropriate for the demonstration of feasibility. Electrograms were recorded from the RVOT only, therefore, the impact of SGS on ARIs in other regions of the heart was not examined. Additionally, SGS was performed using a unipolar set up, resulting in saturation of the surface and intracardiac recordings. This limited the assessment of dynamic changes during SGS.In summary, the findings of the present study indicated that percutaneous low-level SGS in humans is feasible, has no acute or long-term complications, and yields meaningful hemodynamic, electrocardiographic, and electrophysiologic data. One patient was on carvedilol (last dose was the day prior to procedure), however, a significant response to SGS was still observed in BP, dP/dt, and ARI. Further studies utilizing direct stellate ganglion stimulation are warranted to validate existing animal data, and to identify novel physiologic functions of the sympathetic nervous system in man.None declared.


In order to characterize the intracranial pressure-volume reserve capacity, the correlation coefficient (R) between the ICP wave amplitude (A) and the mean ICP level (P), the RAP index, has been used to improve the diagnostic value of ICP monitoring. Baseline pressure errors (BPEs), caused by spontaneous shifts or drifts in baseline pressure, cause erroneous readings of mean ICP. Consequently, BPEs could also affect ICP indices such as the RAP where in the mean ICP is incorporated.A prospective, observational study was carried out on patients with aneurysmal subarachnoid hemorrhage (aSAH) undergoing ICP monitoring as part of their surveillance. Via the same burr hole in the scull, two separate ICP sensors were placed close to each other. For each consecutive 6-sec time window, the dynamic mean ICP wave amplitude  and the static mean ICP, were computed. The RAP index was computed as the Pearson correlation coefficient between the MWA and the mean ICP for 40 6-sec time windows, i.e. every subsequent 4-min period (method 1). We compared this approach with a method of calculating RAP using a 4-min moving window updated every 6 seconds (method 2).The study included 16 aSAH patients. We compared 43,653 4-min RAP observations of signals 1 and 2 (method 1), and 1,727,000 6-sec RAP observations (method 2). The two methods of calculating RAP produced similar results. Differences in RAP ≥0.4 in at least 7% of observations were seen in 5/16 (31%) patients. Moreover, the combination of a RAP of ≥0.6 in one signal and <0.6 in the other was seen in ≥13% of RAP-observations in 4/16 (25%) patients, and in ≥8% in another 4/16 (25%) patients. The frequency of differences in RAP >0.2 was significantly associated with the frequency of BPEs (5 mmHg ≤ BPE <10 mmHg).Simultaneous monitoring from two separate, close-by ICP sensors reveals significant differences in RAP that correspond to the occurrence of BPEs. As differences in RAP are of magnitudes that may alter patient management, we do not advocate the use of RAP in the management of neurosurgical patients. Monitoring of intracranial pressure (ICP) is crucial in the intensive care management of neurosurgical patients -4. The cThe mean ICP is always determined against a baseline pressure (i.e. zero or reference pressure). A major weakness of this is that the mean ICP value that is displayed to the physician or nurse becomes erroneous if this baseline pressure is spontaneously altered during ongoing monitoring . Such baIn a recent prospective, observational study on 16 patients with aneurysmal subarachnoid haemorrhage (SAH), we reported a high frequency and severity of BPEs . Being rAneurysmal SAH patients who need continuous ICP monitoring as part of their intensive care management were enrolled in the study. Their intensive care management was not influenced by their participation.The study was approved by The Regional Ethics Committee, REK South-East (2010/1328B) and Oslo University Hospital (2010/16315), Oslo, Norway. Inclusion was by oral and written informed consent, either by the patient herself/himself or by the closest family member.A prospective, observational study design was used to determine the frequency and severity of BPEs, and how BPEs affect scores of ICP and ICP indices. These data were re-analyzed in order to investigate the frequency and severity of differences in RAP. Moreover, we compared two different methods of calculating the RAP.Two Raumedic NeuroVent P  ICP sensors were placed in the brain parenchyma via the same burr hole, either during aneurysm surgery, or during placement of an external ventricular drain (EVD). The location of the ICP sensors was verified postoperatively by cerebral computer tomography (CT) scanning.Both sensors were connected to the MPR-1 monitor , which in turn was connected to a laptop computer running Sensometrics Software . The digital sampling rate of pressure signals from the two sensors (Sensors 1 and 2) was 100 Hz. The raw data files were stored on the computer. Recordings from the two sensors continued throughout the time period the patient was in need of ICP surveillance.As previously described, the ICP signals were analyzed according to the methodology implemented in Sensometrics Software Figure  17]. An. An17]. The software incorporates an automatic procedure for determining the correlation coefficient (R) between the ICP wave amplitude (A) and the ICP level (P), the RAP, during consecutive 4-min time periods. The RAP-index is the Pearson correlation coefficient between the MWA and the mean ICP during 40 6-sec time window periods. Computation of RAP has previously been described by others . Since w(ii) Method 2. This method incorporates a moving time window. A new RAP value is updated every 6 second. Consequently, every 6 second, the ‘oldest’ averaged value drops out and the ‘newest’ drops in. This approach was previously described by others , except BPEs were defined as differences in mean ICP in combination with close to identical MWAs (difference between sensors <0.5 mmHg), as recently described in this journal . In thisThe study enrolled a total of 16 aSAH patients, 8 females and 8 males, with median age 58 (ranges 39 – 74) years (Table Table Simultaneous 4-min RAP scores (determined according to method 1) from Signal 1 and Signal 2 are presented in Table Table The 6-sec RAP observations of the 16 patients are shown in Table Table Figure The main observation of this study was a marked difference in RAP indices [moving correlation coefficient (R) between the ICP wave amplitude (A) and the ICP (P)] obtained from simultaneous registrations from two separate, close-by ICP sensors of the same type. The discrepancy in RAP between signals 1 and 2 was independent of the use of a moving window with frequent updates. The occurrences of differences in RAP were associated with occurrences of baseline pressure errors (BPEs). While the number of patients was rather small (n = 16), the number of RAP observations was high , with a median number of RAP-observations for each patient .ICP derived indices were introduced in the early 1990’s to enhance the diagnostic information of ICP monitoring ,12. In pIn contrast, as compared to RAP scores derived from amplitudes computed using the frequency domain method ,12, we pIt can be discussed how many data points that should be used for computation of RAP. Most recent studies have determined RAP from 40 data points separated by 6 seconds over 4 min periods ,7-9,11. Combining the present RAP findings with those of an earlier study , differeThe present findings extend our previous observations of marked differences in 4-min RAP when monitored simultaneously from two separate ICP sensors . A diffeDetermining the RAP every 4 min period (presently referred to as method 1) carries the potential risk of introducing high variability in the recorded value. In an attempt to reduce the variation in calculated RAP, some clinicians chose to use a moving window with updates every 5-10 seconds . IncorpoAnother approach to reduce the variability in RAP is to average scores over a long time period, e.g. 20-30 min. However, averaging scores works as filtering of the calculated values, and has the drawback of hiding information. Averaging over long time periods will thus extensively mask differences in RAP. This can be seen in Table Obviously, it can be disputed which differences in RAP that have clinical significance. In this context, it should be remembered that ICP and ICP-derived indices such as RAP are used in the surveillance of critically ill patients. An erroneous measurement revealed to the physician/nurse may represent potential harm to the patient. In this present study cohort, one ICP sensor showed RAP >0.6 while the other showed RAP <0.6 in about 1/10 observations (9-14%) in 8/16 patients. Given the diagnostic importance of such an index in patient management, we consider such a difference of clinical significance.In the present patients, ICP monitoring was done as part of patient surveillance. Therefore, monitoring was independent whether the EVD was open or closed, and independent the opening pressure of the EVD. Since the ICP sensors were placed close by within the brain, both ICP sensors would be similarly impacted independent of drainage through the EVD.The RAP should be considered together with the mean ICP since RAP may become de-coupled from the mean ICP when mean ICP is very high (>20-40 mmHg) . It shouIn 2006 Eide  describeIn an experimental study, Eide and Bakken , showed As illustrated in Figure Given that BPEs cause alterations in mean ICP, it is to be expected that every pressure index wherein the mean ICP is incorporated also becomes affected. However, the differences in RAP are less pronounced than the differences in mean ICP. This is because the RAP also incorporates the ICP amplitude, which is resistant to BPEs. For this reason, indices solely based on static pressure measures such as the pressure reactivity index (PRx), which is the moving correlation between mean ICP and mean arterial blood pressure (mean ABP) , can be Due to the effect of BPEs on the RAP indices, its feasibility as a guide in the management of neurosurgical patients will be hampered. In our opinion, the divergence in RAP from the two sensors is of such an extent that we do not advocate the use of RAP in clinical practice. In contrast, since the ICP wave amplitude is unaffected by BPEs, the ICP wave amplitude is a robust parameter. Thus, in a recent study comparing the ICP wave amplitude, ICP wave slope, and RAP as measures of intracranial compliance in head injury patients, the ICP wave amplitude was found to be superior to the other parameters .Simultaneous monitoring from two separate, close-by ICP sensors reveals significant differences in RAP that correspond to the occurrence of BPEs. As differences in RAP are of magnitudes that may alter patient management, we do not advocate the use of RAP as a guide in the management of neurosurgical patients.BPE: Baseline Pressure Error; dP: Amplitude; dT: Rise time; dP/dT: Rise time coefficient; ESD: Electrostatic discharge; ICP: Intracranial pressure; MWA: Mean ICP wave amplitude; RAP: Correlation coefficient (R) between ICP wave amplitude (A) and ICP level (P); SAH: Subarachnoid haemorrhage; SW: Single wave; TBI: Traumatic brain injury.AS, TRM and WSO report no conflicts of interest. PKE has financial interest in the software company (dPCom A/S) that manufactures the software (Sensometrics® Software), which was used for digital recording of the continuous pressure signals in this study.All authors contributed to conception and design, acquisition and interpretation of data. PKE contributed the bulk of the drafting of the manuscript and AS, TRM and WSO contributed with thorough editing of the manuscript. All authors have read and approved the final manuscript.


Introduction. High blood pressure (BP) is one of the most important modifiable risk factors for cardiovascular diseases, which accounts for one in every eight deaths worldwide. It has been predicted that, by 2020, there would be 111% increase in cardiovascular deaths in India. Aerobic exercise in the form of brisk walking, jogging, running, and cycling would result in reduction in BP. Many meta-analytical studies from western world confirm this. However, there is no such review from Indian subcontinent. Objective. Our objective is to systematically review and report the articles from India in aerobic exercise on blood pressure. Methodology. Study was done in March 2016 in Google Scholar using search terms “Aerobic exercise” AND “Training” AND “Blood pressure” AND “India.” This search produced 3210 titles. Results. 24 articles were identified for this review based on inclusion and exclusion criteria. Total of 1107 subjects participated with median of 25 subjects. Studies vary in duration from +3 weeks to 12 months with each session lasting 15–60 minutes and frequency varies from 3 to 8 times/week. The results suggest that there was mean reduction of −05.00 mmHg in SBP and −03.09 mmHg in DBP after aerobic training. Conclusion. Aerobic training reduces the blood pressure in Indians. Elevated blood pressure, also known as hypertension, is one of the most important modifiable risk factors for cardiovascular disease and is accounting for 10% of overall deaths in India  and is mAerobic exercises are advised for health promotion and prophylaxis for many cardiovascular diseases. They refer to all exercises that involve major muscle groups and improve oxygen consumption by the body. Many methods of aerobic exercise are available like walking, jogging, running, cycling, and others. Recent meta-analytical study from western world confirms that aerobic exercise would result in clinically significant reduction in blood pressure . AerobicEven though it is confirmed from western world that exercises are helpful, there is little available evidence from India. Many of Indian literatures are grey in nature, that is, short studies done for postdoctoral dissertation or doctoral thesis which are not available in standard electronic database, namely, Pubmed, CINHAL, and EMBASE. However, recent rise in electronic journals with or without print copy encourages young researchers from India to publish their research in them. But these journals are not indexed in major databases and hence are not noticed and reported by other authors. Thus the objective of this paper is to collect the available literature from India using secondary search engine “Google Scholar” and derive the conclusion whether aerobic exercise is reducing blood pressure in normal and pathological conditions or not in Indians.Computerized literature search was performed using “Google Scholar” search engine during March 2016. Keywords or search protocol used for this review is “Aerobic Exercise” AND “Training” AND “Blood Pressure” AND “India.” Inclusion criteria for this review were as follows: (i) experimental study with post-premeasurement of BP, (ii) aerobic exercise as the exercise intervention with minimal duration of 3 weeks, (iii) full-text articles in English published in journals with ISSN number, (iv) study done in any part of India without any time limitation, and (v) subjects being either normal or with following clinical conditions: obesity, hypertension, and diabetes. A main exclusion criterion was other clinical conditions (2 articles were excluded based on this criterion). Search protocol resulted in 3210 articles. Authors Sonu Punia and Sivachidambaram Kulandaivelan reviewed 3210 titles individually and selected articles based on inclusion and exclusion criteria. Sonu Punia selected 19 articles and Sivachidambaram Kulandaivelan selected 24 articles. Authors Vandana Punia and Varun Singh studied 43 articles and selected 25 articles (18 were duplicates). Results were prepared by Varun Singh. During this, we found two articles which used the same results in their papers [Mean difference with 95% CI  for individual studies was calculated using mean, standard deviation (SD), and sample size (this was not possible in –15 due t−1 (median: 5) and total duration of 12.5 weeks (median: 12) (We selected 24 articles –33 with ian: 12) .A total of 5 articles , 19–21 wA total of 4 articles , 27, 28 Out of 24 included articles , 10 studies used control group  , 32, 33.Primary objective of this review is to collect and present the literature from India of aerobic exercise on blood pressure. We found 24 articles from different parts of India . Results show 5.00 mmHg reduction in SBP and 3.09 mmHg reduction in DBP. This result is supported by several meta-analyses from western population –36. CornAs compared to control group, aerobic training reduced 4.16 mmHg in SBP and 2.43 mmHg in DBP in experimental group of Indians which is lower end of 95% CI in post-premean MD of present study. This is in agreement with western meta-analysis , 36. We Hypertension is a growing problem in India with every third to fifth Indian as hypertensive , 37, 38.There are some limitations observed in this review. We used improvement in BP using after minus before values, except one study , and oneAerobic training of 4-week duration would reduce BP to a clinically significant level in Indian population. This reduction is more pronounced in clinical conditions like hypertension and diabetes. So this type of training should be used as primary prevention in high risk population and as secondary prevention in hypertension, diabetes, and so forth.


Cross-sectional studies show a strong association between chronic kidney disease and apparent treatment-resistant hypertension, but the longitudinal association of the rate of kidney function decline with the risk of resistant hypertension is unknown.The population-based Three-City included 8,695 participants older than 65 years, 4265 of them treated for hypertension. We estimated the odds ratios (OR) of new-onset apparent treatment-resistant hypertension, defined as blood pressure ≥ 140/90 mmHg despite use of 3 antihypertensive drug classes or ≥ 4 classes regardless of blood pressure, associated with the mean estimated glomerular filtration rate (eGFR) level and its rate of decline over 4 years, compared with both controlled hypertension and uncontrolled nonresistant hypertension with ≤ 2 drugs. GFR was estimated with three different equations.Baseline prevalence of apparent treatment-resistant hypertension and of controlled and uncontrolled nonresistant hypertension, were 6.5%, 62.3% and 31.2%, respectively. During follow-up, 162 participants developed apparent treatment-resistant hypertension. Mean eGFR decline with the MDRD equation was 1.5±2.9 mL/min/1.73 m² per year: 27.7% of the participants had an eGFR ≥3 and 10.1% ≥ 5 mL/min/1.73 m² per year. After adjusting for age, sex, obesity, diabetes, and cardiovascular history, the ORs for new-onset apparent treatment-resistant hypertension associated with a mean eGFR level, per 15 mL/min/1.73m² drop, were 1.23 [95% confidence interval 0.91–1.64] compared to controlled hypertension and 1.10 [0.83–1.45] compared to uncontrolled nonresistant hypertension; ORs associated with a decline rate ≥ 3 mL/min/1.73m² per year were 1.89 [1.09–3.29] and 1.99 [1.19–3.35], respectively. Similar results were obtained when we estimated GFR with the CKDEPI and the BIS1 equations. ORs tended to be higher for an eGFR decline rate ≥ 5 mL/min/1.73m² per year.The speed of kidney function decline is associated more strongly than kidney function itself with the risk of apparent treatment-resistant hypertension in the elderly. Despite use of an increasing number of antihypertensive medications, uncontrolled hypertension remains common and one of the most important risk factors for end-stage renal disease and cardiovascular mortality in persons with chronic kidney disease (CKD)–7. UnconMost studies reporting associations between CKD and aTRH have been cross-sectional ,15,17,18We therefore studied the association of kidney function and its rate of decline with both the prevalence of and new-onset aTRH in the elderly population of the Three-City study.The Three-City study is a population-based prospective cohort that included 9,294 non-institutionalized individuals aged 65 years or older randomly selected from electoral rolls of three French cities from March 1999 through March 2001—Bordeaux , Dijon , and Montpellier . Details of the study protocol have been published elsewhere [Trained staff administered standardized questionnaires and performed clinical examination at baseline and at the 4-year follow-up. Socio-demographic data, education level, monthly income, smoking status, and medical history were recorded. History of CVD included coronary heart disease, myocardial infarction, heart failure, stroke, peripheral artery disease, and artery surgery or angioplasty. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m². Medication use was collected and coded according to the World Health Organization’s Anatomical Therapeutic Chemical classification system. All three centers collected blood at baseline. For financial reasons and because of the specific objectives in each center, only two centers (Bordeaux and Dijon) collected blood at 4 years and only one (Bordeaux) urine. Hypercholesterolemia was defined as use of statins or fasting cholesterolemia ≥ 6.2 mmol/L. Diabetes was defined as the current use of antidiabetic drugs or fasting glycemia ≥7.2 mmol/L or non-fasting glycemia ≥ 11 mmol/L.At baseline, creatinine was measured in a single laboratory with the Jaffé assay and further standardized to isotope dilution mass spectrometry (IDMS) traceable enzymatic creatinine as described elsewhere . We used2 per year as the difference between 4-year and baseline eGFR divided by the absolute follow-up time.At the 4-year follow-up, 1,629 of 3,865 participants with treated hypertension had a second creatinine measurement, similarly standardized; 739 also had urine measurements taken to assess protein-to-creatinine ratio (PCR) and ACR when proteinuria was <300 mg/L. Albuminuria was defined as ACR ≥ 3 mg/mmol or PCR ≥ 30 mg/mmol when ACR was missing (n = 23). For each participant, we calculated eGFR slope in mL/min/1.73 mDuring both examinations, trained staff using a validated digital electronic sphygmomanometer with an appropriately sized cuff on the right arm  measured BP twice at the participant’s home, after at least five minutes at rest in seated position . The anaWe classified participants into 3 groups according to hypertension control status and used cHT and ucHT as references for aTRH. We first compared baseline characteristics between the group with aTRH and the other two, with Student’s t-test or the Wilcoxon or chi-square test, as appropriate. We also compared the distribution of the 3 groups according to the presence or absence of CKD.2 drop, which is equivalent to the GFR drop between two CKD stages, and adjusted for age, gender, smoking, obesity, diabetes, history of cardiovascular disease, and center. In the subsample of 1,629 participants with two eGFR measurements, we then estimated ORs of prevalent aTRH at the 4-years follow-up associated with an eGFR decline rate ≥ 3 mL/min/1.73 m2 per year and adjusted for the same covariates, with comorbidities updated at 4 years. This cutoff was chosen because it is about 3 times greater than the annual physiological kidney function decline due to aging. To account for the phenomenon of regression to the mean [2 drop, computed as the average of the baseline and 4-year eGFR values. As a sensitivity analysis, we also estimated ORs for an eGFR decline rate ≥ 5 mL/min/1.73 m2 per year, which defines fast progression according to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 [Second, we used multinomial regression models to estimate odds ratios (OR) of prevalent aTRH at baseline, compared with the two reference groups, associated with eGFR treated continuously per 15 mL/min/1.73 mthe mean , we adju2 drop, compared with both reference groups. To assess the impact of the rate of kidney function decline, we finally estimated the OR of new-onset aTRH associated with an eGFR decline ≥3 (or ≥5) mL/min/1.73m² per year over the period, adjusted for age, gender, center, mean eGFR per 15 mL/min/1.73m² drop, and comorbidities in the subsample of participants with two eGFR measurements ; all probabilities were two-tailed, and a p-value ≤ .05 was defined as statistically significant.The prevalence of aTRH was 6.5%, that of cHT 31.2%, and that of ucHT 62.3%. When we applied the JNC8 BP cutoffs (≥ 150/90 mm Hg) for participants older than 60 years, these percentages were 5.4%, 46.7%, and 47.9%. The overall mean MDRD-eGFR was 74±17.0 mL/min/1.73m², the mean BIS1-eGFR 63.2±12.1, and the median CKD-EPI-eGFR (quartiles) 75.2(63.9–84.6). The overall prevalence of CKD was twice as high with the BIS1 than with the other two equations. Among participants with aTRH, approximately 2% had controlled BP while taking ≥ 4 drugs. Participants with aTRH were significantly older than those in the other two groups and more often obese; they also had diabetes and CVD more often, as well as higher pulse pressure and social factors that were lower, but not significantly so .They were also more likely to be men and current or past smokers than those with cHT. The prevalence of aTRH increases with the reduction of the level of eGFR and it is 3 to 4 times higher in participants with an eGFR below 45 mL/min per 1.73m² regardless of the equation used .Around 75% of the participants with aTRH reported taking diuretics and renin angiotensin system inhibitors (RASi), while less than 66% reported calcium channel blockers and betablockers.At baseline, lower MDRD-eGFR values were associated with higher ORs of aTRH, compared to both reference groups , part I,In the subsample of participants with a second eGFR assessment at four years, the percentage with a decline rate ≥ 3 mL/min per 1.73 m² was 27.7% with the MDRD, 24.3% with the CKDEPI, and 21.1% with the BIS1 equation; these percentages were 10.1%, 8.6%, and 4.4%, respectively for an eGFR decline rate ≥ 5 mL/min per 1.73 m². An MDRD-eGFR decline rate ≥ 3 mL/min per 1.73 m² was associated with a higher OR of aTRH, independent of mean MDRD-eGFR over the period and other covariates , part IIOf the 8,695 participants at baseline, 78% had BP measured at the 4 years follow-up; 15.1% declined participation, BP was missing at examination for 0.8%, and 6% had died . At 4 yeUnlike obesity and diabetes, baseline MDRD-eGFR level was not related to new-onset aTRH, compared to either persistent cHT or ucHT , Part I.In this community-dwelling elderly population, ucHT affected 62% of those treated for hypertension, while only 6.5% had aTRH. The novelty of this study lies in the finding that a rapid decline in kidney function was associated with a higher OR of aTRH independent of eGFR level and other major risk factors for resistant hypertension. Another new element is that kidney function, measured once at baseline, seems to lack predictive value for new-onset aTRH in this population. These findings provide insight about the relation between CKD and resistant hypertension and about the clinical perspectives for managing hypertension in the elderly.It is difficult to compare our prevalence estimate of aTRH with others, because with few exceptions , previouRisk factors most commonly related to aTRH in previous cross-sectional surveys include age, gender, obesity, diabetes, and CKD. We confirm the strong association with diabetes and obesity ,15,17 anNote that all three equations yielded similar findings about the associations of CKD with resistant hypertension. However, while using the MDRD and the CKDEPI equations provided similar estimates of CKD prevalence, the estimates with the BIS1 were twice as high. Two studies have assessed the performance of these equations in the elderly population in France ,33. AlthThe major importance of this study is that it provides additional evidence about the longitudinal association between kidney function decline and aTRH. First, it shows that a fast rate of eGFR decline is strongly associated with new-onset aTRH over a 4-year period, independent of mean eGFR level over that period and other comorbidities. Although it was not possible to adjust for albuminuria, which was lacking at baseline, we were able to show that, in the subgroup of participants with measurements at 4 years, past eGFR decline remained strongly associated with prevalent aTRH after adjusting for albuminuria at 4 years as well as other covariates. This is consistent with the study by Tanner et al  showing This study also shows that, unlike diabetes and obesity, kidney function measured once at baseline may not predict new-onset aTRH in the elderly. This finding may argue against a causal role of kidney function in resistant hypertension. Alternatively, however, it suggests that the speed of the decline in kidney function is a better indicator of the severity of kidney impairment in the elderly than a single kidney function measurement. We have previously shown that low eGFR without specific markers of kidney damage is common in this population, particularly among women and is likely to reflect normal aging rather than true CKD ,39. OtheThe large sample size of this community-based elderly population and the low rate of attrition over 4-year follow-up are major strengths of this study. Other strengths include standardized in-home BP measurements over four years and careful record of drug use, as well as standardized serum creatinine measures in a single laboratory.This study also has limitations. First, despite its longitudinal design, it does not allow us to conclude that kidney function decline is causally related to resistant hypertension. Unidentified confounders, other than those we accounted for, may cause both kidney function decline and resistant hypertension. Second, the construction of the slope on only two points is another limitation of this study. Third, because information about adherence and drug doses was not available, pseudo-resistance could not be assessed. Similarly self-measured BP at home or ambulatory BP monitoring would have been preferable to staff-assisted BP measurements. Fourth, the absence of serum creatinine measurements in some participants at the 4-year follow-up reduced the power of the longitudinal analysis. Finally, the failure to measure albuminuria at baseline prevented us from studying its impact on new-onset aTRH. However, we were able to show that it did not confound the relation with kidney function decline, an association that is the main finding of this study.In this elderly white population, aTRH was uncommon, but likely to have been underestimated due to treatment inertia. In addition to obesity and diabetes, this study points to rapid decline in kidney function as a major risk factor for resistant hypertension. These findings are limited to elderly, white individuals with individuals with CKD and may not apply to younger patients or to ethnic minorities. They do, however, call for increased awareness of the importance of resistant hypertension in the elderly. Identifying those who may need further investigations for secondary hypertension and enhanced treatment should be a priority to reduce adverse outcomes.S1 FileTable A: Association of kidney function estimated with MDRD, CKDEPI or BIS1 equations with the prevalence of apparent treatment-resistant hypertension at baseline. Table B: Association of kidney function decline rate with the prevalence of apparent treatment-resistant hypertension at 4-years. Table C: Association of kidney function decline rate with the prevalence of apparent treatment-resistant hypertension at 4-years in the subgroup with albuminuria. Table D: Association of kidney function decline rate with new-onset apparent treatment-resistant hypertension at 4-years. Table E: Association of kidney function decline rate (≥ 5 mL/min/1.73m²) with apparent treatment-resistant hypertension at 4-years. Table F: Association of kidney function decline rate (≥ 5 mL/min/1.73m² per year) with apparent treatment-resistant hypertension at 4-years in the subgroup with albuminuria. Table G: Association of kidney function decline rate (≥ 5 mL/min/1.73m² per year) with new-onset of apparent treatment-resistant hypertension at 4-years. Table H: Characteristics of participants according to hypertension control status at 4 years.(TIFF)Click here for additional data file.