Hypertension can be generated by a great number of mechanisms including elevated uric acid (UA) that contribute to the anion superoxide production. However, physical exercise is recommended to prevent and/or control high blood pressure (BP). The purpose of this study was to investigate the relationship between BP and UA and whether this relationship may be mediated by the functional fitness index.2max), AAHPERD Functional Fitness Battery Test to determine the general fitness functional index (GFFI), systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI) and blood sample collection to evaluate the total-cholesterol (CHOL), LDL-cholesterol (LDL-c), HDL-cholesterol (HDL-c), triglycerides (TG), uric acid (UA), nitrite (NO2) and thiobarbituric acid reactive substances (T-BARS). After the physical, hemodynamic and metabolic evaluations, all participants were allocated into three groups according to their GFFI: G1 (regular), G2 (good) and G3 (very good).All participants (n = 123) performed the following tests: indirect maximal oxygen uptake . As far as the lipid profile, participants in G3 presented better values of CHOL and TG when compared to those in G1.Baseline blood pressure was higher in G1 when compared to G3  and the subjects who had higher values of BP also presented higher values of UA. Although UA was not different among GFFI groups, it presented a significant correlation with GFFI and VOTaking together the findings that subjects with higher BP had elevated values of UA and lower values of nitrite, it can be suggested that the relationship between blood pressure and the oxidative stress produced by acid uric may be mediated by training status. The growing number of the elderly population and their complex health problems reveal the necessity of creating adequate health care programs. Among the elderly, the prevalence of hypertension reaches about 50% and has been considered the main risk factor for cardiovascular diseases. Therefore, the comprehension of the different mechanisms that generate hypertension is fundamental for creating strategies to control high blood pressure (BP).2-.) production [It has been shown that elevated uric acid (UA) can be one of the mechanisms responsible for hypertension. It is the final enzymatic and product of purine degradation in the human body and it is catalyzed by xanthine oxidase . Some auoduction ,4. Elevaoduction  and highoduction . Accordioduction  showed toduction ,9. Briefoduction , autonomoduction , nitric oduction  and otheoduction -15, espeoduction ,16.In addition, the current recommendation for elderly people has been recognized as a combination of different types of exercise for maintaining physical functional fitness . Both thFollowing these recommendations, some studies compared the effects of a multicomponent exercise program with a strength exercise program  and withAlthough it has been suggested that people with sedentary lifestyle exhibit lower mitochondrial capacity , there iAll the procedures were previously approved by Institutional Review Board of University of São Paulo / Brazil (CEP/FCFRP n°.172) and all the subjects provided written consent before the beginning of experiments.The sampling plan was probabilistic and obtained in two steps: the first one was obtained by random selection of clusters  that constitute and reflect the heterogeneous characteristics of the whole population. In the second, all individuals of each cluster were invited to participate in this study, with the same chance to be included once they met the following inclusion criteria: subjects should be non-smoking, non-alcoholic (<3 drinks/beers per day), age between 55–70 years old, non-diabetic (fasting glucose level < 100 mg/dL), should not have cardiovascular , peripheral, cerebrovascular, neurologic or psychiatric diseases, should have a body mass index <35, should not be under treatment with medications known to affect glucose metabolism or renal hemodynamics, not have maximal systolic blood pressure (SBP) > 160 mmHg and maximal diastolic blood pressure (DBP) > 100 mmHg or other medical or orthopedic conditions which could affect their ability to successfully participate in a physical exercise battery test. The subject medical history and all assessments were reviewed on their first visit.Blood samples were drawn after a 12-h overnight fasting for further analysis of lipid profile and uric acid content. All participants were informed to avoid fatty and hypercaloric food in the last meal before the 12-h fasting prior to blood collection.All subjects underwent a physical examination to assess the body mass index (BMI) and blood pressure (BP). After that, training status was evaluated by both indirect maximal oxygen uptake test (Baseline Testing (performed at least 24h after the last exercise session):a) Blood samples were used to evaluate the total-cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides (TG) and uric acid (UA) by enzymatic-colorimetric methods . Whole-blood nitrite concentration (NO2) was analyzed with ozone-based chemiluminescence , as previously described . Plasma b) Blood pressure (BP) was measured after 5 min of rest between 7–8 am on three separate days according to the VI Brazilian Hypertension Guidelines , using an aneroid sphygmomanometer adequate to the circumference of the arm and a stethoscope placed over the brachial artery. The average of the three separately recorded BP measurements was used as the outcome variable on data analysis.c) Training status: All participants performed two tests in order to determine the training status:2 max the following equation was used: VO2max = 6.9652 + (0.0091*weight) - (0.0257*age) + (0.5955*sex) - (0.2240*time) - . The one-mile walk test protocol provides a valid sub-maximum assessment for VO2 max estimation (r=0.93). The option to use this test was because walking on a running track is closer to the daily activities as compared to walking on the treadmill;(1.) The one-mile walk test as described previously . Briefly(1.) The AAHPERD functional fitness test battery was used to assess the functional fitness of the participants. The following tests were included: Coordination – time to complete a task requiring a manipulation of 12-oz soda cans in a precise fashion; Flexibility – sit-and-reach test; Muscular strength and endurance reported as the number of biceps-curl repetition performed during 30 s ; Agility dynamic test – time to complete tasks involving repeatedly standing from a chair, walking around cones, and returning to the chair; and cardiovascular endurance represented the time to complete an 880-yard walk. The AAHPERD battery test was completely described previously ,23. The The sample size was calculated taking into account that the prevalence of hypertension is around 30% in the Brazilian population . This caDescriptive statistics was calculated and Pearson’s correlation coefficient was performed to detect correlation among variables. One-way ANOVA with Scheffe post-hoc test was performed to assess statistically significant differences among groups. GFFI was considered as an independent variable.The general linear model was used in order to adjust for BMI and age in all variables, since they were considered as confounding factors. The data were analysed using SPSS 17.0 statistical package. All results are presented as means (SD). Differences were considered statistically significant if p<0.05.2max . All participants were separated according to the GFFI index (G1 = 207.3 ± 62.7 / G2 = 351.2 ± 28.6 / G3 = 437.2 ± 23.2). The groups were composed of both genders even though the number of men was very low. The option to use the GFFI as an independent variable was because it comprises a multicomponent assessment, had a good correlation with VOPearson’s correlation coefficient also showed moderate correlation between UA and SBP (r=0.3/p<0.001) and DBP r=0.29/p<0.001). Moreover, participants with elevated UA also exhibited high blood pressure values  and age (G1 = 60.9 ± 11.7 / G2 = 55.3 ± 8.1 / G3 = 53.9 ± 9.1) General Linear Model was performed to adjust for BMI and age. Subjects’ characteristics are presented in Table 2max was different among groups. As shown in table 2max in G3 were higher than those found in G1.As expected, the VOFor lipid profile, CHOL and TG values were significantly lower between G2 and G3 compared to G1 and no difference was found in LDL-c and HDL-c among groups Figures Nitrite concentration and oxidative stress are other important variables that can explain the relationship between BP and UA Figure Although the results indicate a relationship between the variables, the absence of differences in UA levels Figure  could raIt can be observed that only in G3 different levels of UA resulted in different values in BP. Therefore, this result suggests that very good levels of training status determine a reduction in BP values in the participants with low levels of UA.The present study was designed to investigate the potential effect of a good level of training status on blood pressure and UA concentration and the main results found were that patients with higher training status and low level of uric acid have low values of blood pressure.2-. production) and NO-scavenging. This mechanism can affect the vasodilatation thereby increasing BP. Although it has been reported that physical exercise contributes to an adequate maintenance of BP, there is limited evidence demonstrating the effect of physical exercise on UA concentration.Uric Acid has an important influence on vascular control by increasing oxidative stress (O2·) produced during the UA formation acts as a NO-scavenging thus reducing the NO bioavailability. NO is a potent vasodilator and has an important function in BP control [2O2) and 8-isoprostane activity when UA (200 μmol) was added. The increased production of these compounds suggests that UA stimulates the production of reactive oxygen species (ROS) which are associated with impaired endothelium-dependent vasodilatation. Therefore, UA seems to be associated with decreased NO bioavailability and consequently increased BP [Our results showed that subjects with elevated UA concentration demonstrated elevated BP. Also, we demonstrated that this result can be mediated by training status, since subjects with higher training status and lower levels of UA presented lower values of BP. The mechanisms that may explain the association between UA concentration and BP are still unknown. The anion superoxide  divided the participants with normal BP into two groups. The first group performed moderate-intensity exercise and the values of BP 40 min post-exercise were 147(6)/101(5) mmHg (SBP/DBP). The second group received oral administration of UA (0.5 g) before acute exercise and the values of BP 40 min post-exercise were 153(6)/103(6) mmHg (SBP/DBP). This study showed that an increased UA concentration might contribute to an increased BP after exercise. However, moderate-intensity exercise up-regulated the xanthine oxidase activity suggesting that a physiological level of UA might contribute to the BP control, especially because of the improvements in the antioxidative capacity .Although regular exercise has been considered the major stimulus to prevent high blood pressure, there is still no consensus of which is the best combination among type, intensity and frequency to achieve such benefits. Thus, our study leads us to the discussion of how training status, regardless of how physical exercise was previously performed, exerts an important role on this mechanism associated with BP control.The results presented in Table The present study found a relationship among SBP, DBP, UA, lipid profile and GFFI. Taking together the findings that subjects with elevated values of UA and lower values of nitrite had higher values of BP, this study suggests that the relationship between blood pressure and the oxidative stress produced by acid uric may be mediated by training status.AAHPERD: American Alliance for Health Physical Education, Recreation and Dance; ACSM: American College of Sports Medicine; ADP: adenosine diphosphate; AHA: American Heart Association; AMP: adenosine monophosphate; ATP: adenosine triphosphate; BMI: body mass index; BP: blood pressure; CHOL: total-cholesterol; DBP: diastolic blood pressure; GFFI: eneral fitness functional index; HDL-c: HDL-cholesterol; LDL-c: LDL-cholesterol; NO: nitric oxide; NO2: nitrite; O2-: anion superoxide; ONOO-: peroxinitrite; SBP: systolic blood pressure; T-BARS: thiobarbituric acid reactive substances; TG: triglycerides; UA: uric acid; “The authors declare that they have no competing interest”.AAT, AMJ, JJM and JTCS have made substantial contributions to acquisition, analysis and interpretation of data. All of them have been involved in drafting the manuscript. JETS, SLA and ASZ have made substantial contributions to analysis and interpretation of data and have been involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final manuscript.The authors understand that ambulatory BP measurements are more accurate than office BP measurements. However, we did not have this technique available at the time the data were collected; (b) although the authors are aware of the differences between genders, men and women were not analyzed separated in our study because no differences in all variables were found between male and female. We recognize the low number of men participating in the study; (c) the antihypertensive drugs were not interrupted during the study, however, participants were asked not to take the medicine before the blood pressure measurements; (d) some blood analysis such insulin levels were not performed; (e) no specific control of diet was performed, however, participants were requested to have a light meal before the test.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/44/prepub


There is some evidence suggesting that leptin and its negative regulator, soluble-leptinreceptor (SLR) may be able to influence inflammatory and autoimmune processes.In this study, several variables including socio-demographics, health-related habits, depression score, serum molecules and blood parameters besides the SLR level were evaluated in patients with SLE (SLE-patients) and healthy controls.The patients had significantly lower SLR level and higher depression score than the controls and both of these variables have a significant association with the occurrence of disease in logistic regression model. Moreover, the results of Pearson correlation analysis showed that patients’ SLR level was negatively correlated with their weights and BDI scores.For the first time, this study indicated a lower level of SLR in SLE-patients and suggested that lower concentrations of SLR in these patients may be implicated in the pathogenesis of SLE. It is revealed that leptin could promote inflammatory and autoimmune processes . SLR is There are several contradictory reports on leptin in rheumatic diseases. For example, although some authors have reported that leptin levels of SLE-patients  and rheuWe studied 34 unrelated SLE-patients which were not under therapy. Healthy sex and age matched controls were also randomly selected. Informed consent was obtained from all the participants.The presence of ANA and anti-dsDNA antibodies was determined by ELISA . Plasma concentrations of the Complement C3 and C4 component were quantified in nephelometry.The acute-phase inflammatory response was assessed by determining the serum level of CRP in a high-sensitive approach (HS-CRP). The serological status for RF was performed using a semi-quantitative kit.A complete blood count (CBC) with differential was done on the hematology counter (Coulter Sysmex K1000 machine).Depression score was measured using the Persian translated and validated version of the Beck's depression Inventory (BDI).7 The obtained BDI-scores were used for all statistical analysis.A team of interviewers, who received training, completed questionnaires consisting of variables, all of which were defined as quantitative values. These variables were contain socio-demographic and lifestyle parameters . All the discussed variables in the questionnaires along with all the measured factors and laboratory parameters were 50 variables which were classified into 2 set of main variables (blood factors and non-blood factors).The serum SLR levels were assessed in triplicate by a commercial human specific sandwich ELISA kit , according to the manufacturer’s guidelines. The minimum detectable dose (MDD) for this kit ranged from 0.020-0.128 ng/ml.The statistical significance of the differences between cases and controls was calculated by GLM multivariate analysis. Moreover, the impact of all main variables on the occurrence of disease was analyzed using binary logistic regression analysis, in order to assess odds ratio (OR) for the risk of systemic lupus erythematosus. Furthermore, the statistical correlation between variables was shown by Pearson correlation test. Data analysis was carried out using spss version 17 software and significant levels were considered 0.05. To illustrate differences between patients and controls and how the covariates were positively or negatively correlated we used a box plot and scotter plot with fitted regression lines respectively.However, by using a GLM multivariate analysis, there were no significant (P>0.05) differences for socio-demographic or lifestyle parameters  between groups, but patients had a higher depression score (P=0.009) than controls . We alsoOdds ratios and 95% confidence intervals were also calculated for 2 set of main variables (blood factors and non-blood factors) . DecreasPatients’ lower level of C3 and C4 complement component and their negative significant association (Odds Ratios) with the occurrence of disease which respectively were shown by GLM multivariate and logistic regression analysis could be as a result of more activation of complement in these patients. On the other hands higher level of other blood factors such as CRP, ESR1h, ESR2h and etc in patient group and their relative risk (Odds Ratios) for SLE disease can often be as a result of some inflammatory and autoimmune events during the diseases' process. For example in the presence of inflammation, the liver rapidly increases its synthesis of fibrinogen resulting in an elevated ESR in these patients. The significant lower of Hb or Hct level in our patient group in GLM multivariate analysis and their respective odds Ratios for disease is believed to be due to bone marrow depression resulting from kidney involvement. This is in harmony with the view of Bauer who reported that a mild to moderate normochromic microcytic anemia is seen in almost every patient with SLE -10.Laboni et al. reported a mild to moderate depression (mean BDI score=15.8+/-9.9) in lupus patients as their study group with disabling tiredness . It is aWe also found that patients had significantly lower SLR level than controls. Moreover, lower level of this blood marker was negatively associated with the occurrence of disease in logistic regression model. It means that SLR level may be a diagnostic or predictive factor in lupus patients. There are several contradictory reports on leptin in rheumatic diseases -6. LeptiWe also showed a negative correlation between weight and SLR level which was in line with most of the recent findings. For example, it is reported that the reduction of SLR concentrations in overweight and obese individuals may be the result of an increase in circulating leptin . HoweverWe also showed that higher weight is associated with higher anti-dsDNA titer in SLE-patients. There are some consistent results in this regard. For example, it was revealed that obese SLE-patients had worse functional capacity, more fatigue, and higher concentrations of inflammation markers . FinallyIndeed, as a new result, we found that serum level of SLR was significantly lower in SLE-patients than controls and may be a diagnostic or predictive risk factor in lupus patients. To our knowledge, this study is also relatively novel in that it simultaneously examines the relationship between serum SLR levels in SLE-patients and their autoantibody titers, socio-demographic, psychological, environmental, dietary, laboratory, smoking and lifestyle parameters all of which were intelligently defined as quantitative values.After putting together all the correlations, it could be expected that depression at any level can be harmful for SLE-patients, so that increasing the BDI score as a risk factor may be associated with the occurrence of lupus disease. Moreover, decreased serum concentration of SLR in these patients may be implicated in the pathogenesis of lupus.


There is a paucity of data on treatment adherence in patients with chronic heart failure (CHF) in Africa.n = 200) and pill count .We examined the pattern of treatment adherence, self-care behaviour and treatment knowledge in 200 consecutive patients with CHF attending the Chris Hani Baragwanath Hospital, Soweto, South Africa via a combination of questionnaire  and 109 (55%) were male. CHF-specific treatment included loop diuretics (93%), beta-blockers (84%), ACE inhibitors (74%), spironolactone (64%) and cardiac glycosides (24%); mean number of medications was 6 ± 2. Overall, 71% (58 of 82) adhered to their prescribed CHF regimen and individual medication adherence ranged from 64 to 79%. Behavioural adherence varied from 2.5 to 98%. Patient treatment knowledge was poor; 56% could not name medication effects or side effects. However, an average knowledge score of 69% was achieved on 10 questions concerning CHF management.As in other regions of the world, non-adherence to complex CHF treatment is a substantial problem in Soweto. Our data confirm the need for a dedicated CHF management programme to optimise CHF-related outcomes in a low-resource environment. Although the population burden and individual impact of chronic heart failure (CHF) has been well described in the western world,6Results from high-income countries have shown that poor adherence to medical recommendations remains a substantial problem among people with CHF who must follow a multicomponent treatment regimen that includes medications, dietary restrictions and exercise recommendations.12It is within the above context that we examined patterns of adherence to prescribed pharmacological and non-pharmacological therapy in a large cohort of black African patients in Soweto, diagnosed with CHF. We also examined their understanding of prescribed treatment and the overall purpose of CHF management.This represents a key substudy of the previously described Heart of Soweto study,Soweto, a township situated in the south west of Johannesburg, South Africa, has a population of 1.1 million, which has undergone economic development, enabling a large proportion of its population to achieve a more affluent lifestyle. The township comprises people from different ethnic backgrounds, however the black African population is predominant.As Chris Hani-Baragwanath Hospital is the only point of specialist cardiac care for the population of Soweto, the cardiology clinic probably attends to nearly every patient presenting with symptoms evolving from a cardiac condition. The population of the cardiology out-patient department consists of patients with a suspected cardiac disorder, seen and referred by 12 local Soweto primary-care clinics. Other patients are initially seen at the general medicine out-patient facilities, specialist medical registrar clinic, diabetes clinic or are in-patients admitted to any other ward of the Chris Hani-Baragwanath hospital and need a cardiac consultation.During November 2006 and April 2007, we recruited 200 consecutive patients with a confirmed diagnosis of CHF presenting at the cardiology clinic. For the purpose of this study, patients were included if they had a confirmed diagnosis of CHF by an attending cardiologist, based on typical clinical symptoms  and a documented left ventricular ejection fraction (LVEF) of ≤ 45% using echocardiography. Non-English-speaking patients were excluded only if a translator was unavailable. Patients were approached in the out-patient cardiology clinic and invited to participate. Data were collected after an informed consent form was signed.Prior to study commencement, the relevant local Ethics of Human Research Committee approved the study. The study conforms to the standard statements on ethics outlined by the Declaration of Helsinki.During a pilot study consisting of 20 participants, a ‘medication adherence and knowledge on heart failure’ survey specific to this predominantly black African community was developed in October 2006. The questionnaire was then applied to the above study population on a one-to-one basis in an interview of approximately 20 minutes. All interviews were executed by the same investigator (VR) and if needed, a translator assisted the applicant.A pill count of prescribed CHF treatment was conducted in those 82 patients (41%) who returned for a scheduled one-month post-interview appointment. If appropriate, a telephone reminder was made two days prior to this appointment; however, contact details were available for few patients.The medication adherence and knowledge on heart failure survey addresses the following sections: demographic and clinical data, medication adherence, self-care behaviour , knowledge concerning CHF medication and overall CHF management. Questionnaires in other studies included the same sections,In accordance with previous studies of this type,2 analyses for discrete variables and the Student’s t-test for continuous variables. Binary logistic regression models were performed in SPSS 11.5 to determine variables predicting adherence. Determinants for medication adherence were presented by odds ratio (OR) and 95% confidence intervals (CI), where an OR = 1 indicated no influence on medication adherence. Significance was accepted at the two-sided level of 0.05.Descriptive statistics and measures of frequency were conducted in Microsoft EXCEL® and were used to describe the study population and various adherences. Data are presented as means ± standard deviation or percentages. To compare groups we used χn = 157 (79%)] and there were more men [n = 109 (55%)] than women [n = 91 (45%)] with no difference in age profile (mean age 56 ± 13 vs 56 ± 15 years). Apart from black African patients there were Asian Indians (n = 10), coloureds (n = 8) and white Africans (n = 25), which we combined as ‘other races’. Almost half of the patients were retired and nearly all lived in a shared household. Black Africans were significantly more likely to have no or standard education than the other races combined .The overall demographic and clinical profile of the study cohort is presented in p = 0.038], however there was no major difference found in respect of reported emotional support.When questioned about their self-perceived level of social support, black Africans were less likely to report having ‘a lot of’ practical support than other races combined  and additionally, they were more likely to have been admitted to hospital before the point of investigation due to their CHF . However, that did not reach statistical significance.Overall, 90% of our study patients were classified as New York Heart Association functional class (NYHA) II and III at the point of being diagnosed with CHF. Overall, the mean left ventricular ejection fraction was 32 ± 8%. Black Africans were less likely to live longer than five years with CHF than the other races combined [61 (39%) vs 23 (53%), As represented in 2Standard CHF treatment included beta-blockers (84%), ACE inhibitors (74%), loop diuretics (93%), spironolactone (64%) and cardiac glycosides (24%). Other medications commonly prescribed in patients with CHF included potassium supplements (54%), aspirin (47%), lipid-lowering agents (33%), warfarin (19%), hypoglycaemic agents, thiamine supplements and calcium antagonists (14%), and the anti-arrhythmic agent amiodarone (7%). Study participants were prescribed a mean of 6 ± 2 individual medications.Overall, 82% of the study participants reported that they were compliant with their prescribed medication Although adherence to follow-up appointments given by the attending cardiologist was good p = 0.058) more likely to be designated as compliant, demonstrating the importance of treatment for symptom control and likely clinical benefit of prescribed treatment. At the same time, men tended to be more compliant than women  without approaching significance.There were no statistically significant factors linked to treatment non-adherence on the basis of multiple logistic regression analysis. However, those participants reporting less than three of the symptoms commonly found in patients with CHF were 4.5-fold , while avoiding alcohol intake was associated with the highest rate of adherence. From a dietary behaviour perspective, 87% of participating patients were non-compliant concerning daily intake of fruit. However, 64% of participants reported having difficulty affording fresh fruit. From a smoking perspective, there were 31 (16%) current smokers and 59 (30%) former smokers.The medication adherence and knowledge on heart failure survey contained questions in several sections on health education provided by a doctor or a nurse. According to the patient’s responses, the least amount of education was provided in relation to daily weight monitoring, with only 8% of participants remembering this component of education. Dietary management was also less memorable than education focusing on alcohol, smoking and CHF in general Overall, patient knowledge concerning their prescribed CHF medication was poor: 56% could not name the effect or any side effects of their medication. On average, only 10% of effects and side effects of pills taken could be named by all participating patients. However, in those patients who self-reported receiving health education on CHF 70%, , the aveTo our knowledge, this represents the largest report to date on the pattern of treatment adherence and knowledge in predominantly black African patients with CHF emanating from South Africa. Indeed, it is one of the largest overall reports relating to CHF from the continent.13How do our data compare with data derived from western cohorts? Our findings on medication adherence are generally lower than reports emanating from high-income countries.20et al. found that 18, 34 and 58% of patients had adherence rates of < 70%, < 85% and 100%, respectively, to prescribed ACE inhibitors.et al. found that only 10% of their study patients were fully compliant with prescribed digoxin therapy during one year of follow-up.22When looking at individual medication adherence to the five basic medications prescribed for CHF, our results ranged from 64 to 79%. In a UK study, Struthers et al. (23%)et al. (37%)With regard to adherence to appointment schedules, patients in this study were similar to most other reports (i.e. > 90% appointment adherence).et al. and Carlson et al. found less than 10% of their study patients to be non-compliant in this regard,et al. (46%) and also by Evangelista et al. (55%) in a study on veterans with CHF.27With 38% of participating patients performing some form of regular exercise , our results were lower than results from other studies .et al. where adherence to alcohol limitation varied between 64 and 94%,et al.18Overall, 98% of all study participants were compliant with regard to reduced alcohol intake. This result is higher than in studies led by Evangelista Our finding that men tended to be more compliant with prescribed medication is both supportedIt is now largely accepted that greater CHF-related knowledge has a positive impact on adherence behaviours.et al., the percentage of patients choosing the correct answer on eight questions concerning CHF management varied between 43 and 90% versus a range of 29 to 89% in our study.et al. found that only 38% of their study participants reported that they knew only a little or nothing about CHF.9In a study lead by Ni It is clear from this and other studies from the western world that poor adherence to treatment and CHF-related self-care behaviour exposes the patient to an increased risk of clinical instability and increased symptoms.In the western world, CHF management programmes have had a positive effect on outcomes of adherence, using various strategies.There are a number of study limitations that require comment. Although, pill counts are a fairly objective method to measure medication adherence, it is still prone to errors such as the assumption that a pill was truly taken if it is not in the medication box. Serum bioassays or electric monitoring advices may be more objective and thus more accurate.As we also based our adherence figures on the results from the pill counts, the findings may be biased, given that those patients who returned for the pill count were already more likely to be compliant in following instructions and were therefore more prone to follow advice concerning medication adherence. Similarly, as the interview took place before the pill count, patients might have paid more attention to taking their medication regularly during the following month. As a result, medication adherence may be overestimated in our study. In future studies, pill counts could be conducted at one, three and six months after the interview to obtain more accurate results.As self-reporting is always subjective and biased, adherence rates to self-care behaviour and the measured knowledge on CHF and its management may have been affected. We also defined behavioural adherence in accordance with the European Society of Cardiology guidelines, even though they might not be applicable to our study population, considering the different disease profiles, cultural and socio-economic profiles and financial backgrounds.Another limitation to our study was the diversity of languages in South Africa . A translator was used in various interviews.Finally, it is difficult to ascertain how representative these data are in relation to other African centres. For example, there was a relatively large number of patients with ischaemic CMO, a generally uncommon cause of CHF in Africa. However, we have recently reported a rise in such cases,Despite these limitations, our study is the first study of this dimension on medication adherence in South Africa. These data indicate the need for interventions that have already been established in the western world to improve health outcomes. These data therefore support the need for culturally sensitive and affordable CHF management programmes that can improve treatment adherence and optimise self-care behaviours and knowledge, in order to improve CHF-related health outcomes overall in South Africa.As in many other regions of the world, non-adherence to complex CHF treatment is a substantial problem in Soweto. Additionally, as education on heart failure is not optimal, knowledge on heart failure medication and management is poor. These data confirm the need for a dedicated heart-failure programme in a lowresource set up to optimise CHF management and outcomes.


A disturbed vitamin D–parathyroid hormone (PTH)–calcium axis may play a role in the pathogenesis of heart failure. Therefore, we investigated whether lower 25-hydroxyvitamin D (25(OH)D) and higher PTH are cross sectionally and after 8 years of follow-up associated with higher B-type natriuretic peptide (BNP) levels in older men and women.2) because of significant interaction.We measured baseline 25(OH)D, PTH, and BNP in 502 subjects in 2000–2001 in the Hoorn Study, a population-based cohort. Follow-up BNP was available in 2007–2009 in 278 subjects. Subjects were categorized according to season- and sex-specific quartiles of 25(OH)D and PTH at baseline. We studied the association of 25(OH)D and PTH quartiles with BNP using linear regression analyses adjusting for confounders. Analyses were stratified by kidney function estimated glomerular filtration rate D level was 52.2±19.5 nmol/l and mean PTH 6.1±2.4 pmol/l. Cross sectionally, 25(OH)D was associated with BNP in subjects with impaired kidney function (eGFR ≤60 ml/min) only. The association attenuated after adjustment for PTH. PTH was cross sectionally associated with BNP, also in subjects with impaired kidney function only: regression coefficient of highest quartile 9.9 pmol/l  with a significant trend across quartiles. Neither 25(OH)D nor PTH was associated with BNP in longitudinal analyses.This study showed overall no strong association between 25(OH)D and BNP. However, PTH was associated with BNP in subjects with impaired kidney function and may point to a potential role in myocardial function. Worldwide, vitamin D deficiency is highly prevalent among older people Loss of heart function or HF is a growing problem in our aging society, therefore determination of factors that can influence loss of heart function is of paramount importance. Recent evidence suggests a number of mechanisms where 25(OH)D and PTH may influence the pathophysiology of HF. These include actions on blood pressure via the renin–angiotensin system, calcium handling, reduction of proinflammatory cytokines, left ventricular mass, and improvements in endothelial function Plasma B-type natriuretic peptide (BNP) is a neurohormone that is primarily secreted in the cardiomyocytes in response to ventricular stretch and pressure overload, so the BNP level is determined by many aspects of cardiac function Patients with elevated BNP levels have often normal cardiac function when measured by conventional echocardiography but suffer from preclinical systolic and diastolic dysfunction as assessed by tissue Doppler imaging Observational data in patients with HF suggest that low 25(OH)D levels and high PTH levels are common and are both associated with higher BNP levels n=15) or 25(OH)D (n=26) were excluded. Subjects with no baseline BNP measurement were also excluded (n=105). This resulted in 502 subjects with vitamin D, PTH, and BNP measurements for cross-sectional analyses.The Hoorn Study started in 1989 and included 2483 men and women aged 50–75 years, from the Netherlands. Detailed descriptions of the study concept and baseline measurements have been published previously n=55). Our study sample consisted of 278 subjects for longitudinal analyses. The study complied with the Declaration of Helsinki, the local Ethics Committee approved the study, and all subjects provided written informed consent.In 2007–2009, ∼8 years after baseline, 169 subjects were not willing to participate for the follow-up examinations. We excluded subjects with no BNP measurement at follow-up (Vitamin D status was assessed by measuring serum 25(OH)D levels by a competitive binding protein assay  Plasma BNP was determined in spare frozen EDTA samples that had been stored at −80 °C for 4 years. At baseline, BNP was determined using an immunoradiometric assay . Inter- and intra-assay variability coefficients were analyzed within the normal range <10%. At follow-up, BNP was determined in spare frozen EDTA samples that had been stored at −80 °C for 2 years using a noncompetitive immunofluorometric assay . Intra-assay CV was 3.5% and the total CV was 12.3%.2). Waist circumference (cm) was measured at the level midway between the lowest rib and the iliac crest. Blood pressure (mmHg) was measured at the right-upper arm after 5 min at rest in a sitting position, using a random-zero sphygmomanometer , and the average of two consecutive measurements was used. Arterial hypertension was defined as systolic blood pressure (SBP) ≥140 mmHg, diastolic blood pressure (DBP) ≥90 mmHg and/or use of antihypertensive medication. As an estimate of kidney function, glomerular filtration rate (eGFR) was calculated using serum creatinine values – determined using the Jaffé method – according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation Fasting glucose, post-load glucose after an oral glucose tolerance test, high-density lipoprotein (HDL) and low-density lipoprotein cholesterol, and triglycerides were measured as described elsewhere Subjects filled out questionnaires to obtain self-reported information on medication use, smoking status, education level, and physical activity. Current smoking was classified as yes/no. High education level was defined as higher vocational education or university, medium level as secondary education, and low level as elementary school, lower vocational training, or less. Physical activity (h/day), including commuting activities, leisure time activities, and occupational activities, was assessed by a validated questionnaire Baseline characteristics and BNP levels are presented according to sex- and season-specific 25(OH)D quartiles and PTH quartiles. Sex- and season-specific quartiles were used because of the described sex difference in 25(OH)D levels in our study χ2-test was performed to test for trend for categorical variables across the 25(OH)D and PTH quartiles.Season classification was based on the date of blood sampling: winter (December–February), spring (March–May), summer (June–August), and autumn (September–November). We used linear regression analyses to examine linear trends in the continuous variables across the quartiles of 25(OH)D and PTH using the categorical quartile variable as a continuous variable. A P value for trend by adding the 25(OH)D quartiles and PTH quartiles as a continuous variable to the regression models.We used multiple linear regression analyses to study the cross-sectional associations between baseline 25(OH)D quartiles and PTH quartiles in relation to baseline BNP levels. In the case of 25(OH)D, we considered the highest 25(OH)D quartile as the reference group, in the case of PTH we considered the lowest quartile as the reference group. We calculated a et al. BNP values at baseline and at follow-up were determined by different methodologies. We added 9.2 ng/ml  to the baseline values of BNP as suggested by Hammerer–Lercher Multiple linear regression analyses were used to study the association between baseline 25(OH)D quartiles and PTH quartiles and BNP levels after 8 years of follow-up. We adjusted for the baseline value by adding the baseline BNP as an independent variable to the regression models.We adjusted for potential confounding in the regression models by adding potential confounders one by one to the regression models. Potential confounders considered were: waist circumference, BMI, outdoor activities, blood pressure, cholesterol, triglycerides, glucose levels, antihypertensive or lipid lowering medication use and eGFR. Variables that changed the regression coefficients of 25(OH)D or PTH quartiles more than 10% were included in the models. eGFR was added to describe separately the influence of adjustment for kidney function. In the case of PTH, we also adjusted for total 25(OH)D, because vitamin D deficiency is a known risk factor for hyperparathyroidism.2) because lower kidney function may result in lower conversion of calcitriol (active form of vitamin D) and may increase PTH P value interaction term <0.10), analyses were stratified accordingly.We tested for effect modification by presence of prior cardiovascular disease (CVD) because CVD treatment and self-care could change BNP. We also tested for effect modification by the presence of type 2 diabetes because subjects were invited according to their glucose tolerance status. Furthermore, we tested for interaction by presence of impaired kidney function .All reported Baseline serum 25(OH)D, PTH, and BNP were available for 502 subjects. Mean 25(OH)D level was 52.2±19.5 nmol/l and mean PTH was 6.1±2.4 pmol/l. Plasma BNP showed a distribution skewed to the right, median BNP was 7.7 pmol/l and interquartile range was 4.0, 11.3 pmol/l. The BNP residuals were normally distributed and therefore BNP is treated in its natural scale.Baseline characteristics according to sex- and season-specific 25(OH)D quartiles showed that subjects with lower 25(OH)D levels were significantly older, were more often hypertensive, had less physical activities and outdoor activities, had higher BMI, larger waist circumference, higher blood pressure (SBP and DBP), higher post-load glucose levels, higher triglycerides, lower HDL cholesterol, higher PTH levels, and higher BNP levels with significant trends across the 25(OH)D quartiles . SubjectP<0.001) and not by prior CVD (P=0.162) or by the presence of type 2 diabetes (P=0.100). Therefore, we stratified the analyses based on kidney function: impaired kidney function (eGFR ≤60 ml/min per 1.73 m2) and normal kidney function (eGFR >60 ml/min per 1.73 m2). Stratification based on CKD stage is not possible because of too few subjects in the more severe stages of kidney function. Results of the linear regression analyses showed that in subjects with impaired kidney function the lowest 25(OH)D quartile was associated with higher BNP with a significant trend (P=0.031) across the 25(OH)D quartiles (P trend 0.013). In subjects with normal kidney function (eGFR >60 ml/min), no association was observed between 25(OH)D and BNP D with BNP  but not by prior CVD (P=0.151) or by the presence of type 2 diabetes (P=0.171). In subjects with impaired kidney function (eGFR ≤60 ml/min), the highest PTH quartile was associated with higher BNP with a significant trend across the categories . The results attenuated only marginally and remained statistically significant when additionally adjusted for 25(OH)D with a significant trend across the PTH quartiles: regression coefficients were first quartile −1.5 , second quartile 4.0 , and third quartile 7.8 . Similar results were seen when PTH was treated as a continuous variable: regression coefficient was 2.1  and changed slightly after adjusting for 25(OH)D, 1.9 .We also found effect modification by eGFR for the cross-sectional association between PTH and BNP .In subjects with normal kidney function, the association of PTH with BNP was in the same direction as for impaired kidney function although the association was less pronounced . RegressBaseline serum 25(OH)D, PTH, and baseline and follow-up BNP were available for 278 subjects. Mean 25(OH)D level was 54.7±18.4 nmol/l and mean PTH was 6.0±2.1 pmol/l. Median baseline BNP was 7.3  and median follow-up BNP was 14.5  pmol/l.Also in this subsample, subjects in the lowest 25(OH)D quartile were significantly older, were more hypertensive, had less outdoor activities, larger waist circumference, higher blood pressure (SBP and DBP), and higher eGFR (data not shown). Subjects in the lowest 25(OH)D quartile had a significantly larger increase in BNP levels . SubjectResults of the longitudinal analyses in which follow-up BNP was adjusted for baseline BNP showed no association of 25(OH)D quartiles or PTH quartiles with BNP  and 3. WIn our study sample of older subjects, 25(OH)D was cross sectionally associated with higher BNP, only in subjects with impaired kidney function (eGFR ≤60 ml/min). The association was not independent of PTH, because adjusting for PTH attenuated the association. PTH was associated with higher BNP levels independent of 25(OH)D in subjects with impaired kidney function. In the longitudinal analyses, 25(OH)D and PTH were not associated with BNP levels after 8 years of follow-up.The association between 25(OH)D and PTH in relation to cardiac markers such as BNP has not been studied extensively. In line with our study, cross-sectional studies showed that 25(OH)D was inversely associated with BNP levels in patients referred for coronary angiography Our study is the first to investigate the association of 25(OH)D and PTH in relation to BNP in a general population. There were several reasons that could possibly explain why we were not able to show longitudinal associations. First, follow-up BNP measurements were determined using a different methodology than the baseline measurements. We applied a literature-based correction factor for baseline BNP, however, this may also introduce some bias. A second limitation is that missing data on follow-up BNP may not be missed at random but be related to conditions such as obesity or underlying cardiac abnormalities. Included subjects with a baseline and follow-up measurement were significantly younger (67.4 vs 69.7 years), had less hypertension (62 vs 67%), and lower waist circumference (93.1 vs 94.1 cm) than subjects who had no follow-up measurement. Therefore, the associations of 25(OH)D and PTH with BNP are possibly obscured because subjects with more cardiac abnormalities were lost to follow-up. Third, as an estimate of kidney function, eGFR was calculated with serum creatinine using the Jaffé method. Nowadays, the use of standardized creatinine measures is the standard for estimating GFR Fourth, the subjects for longitudinal analyses had more homogenous values for 25(OH)D, PTH, and BNP than the subjects for cross-sectional analyses which make it difficult to show associations; i.e. PTH range  decreased from  to  (pmol/l). The smaller sample size and range of 25(OH)D and PTH could have contributed to the lack of longitudinal associations. Another explanation could be that the findings for low 25(OH)D and high PTH observed in HF patients may not be translatable to a population with nonHF subjects. Future studies could benefit from a larger sample size and a wider range of vitamin D and PTH to show potential longitudinal associations.In our study, we observed effect modification by kidney function (eGFR) in the cross-sectional association of 25(OH)D and BNP. Subjects with low eGFR have lower kidney-specific 1α-hydroxylase activity D to calcitriol, the active form of vitamin D). Decreased synthesis of calcitriol occurs already at eGFR values <90 ml/min Higher BNP levels could also be affected by impaired kidney function given the important inter-relationship between cardiac and renal dysfunction. There is uncertainty about the effect of declining eGFR and accumulation of BNP concentrations. Nevertheless, recent evidence suggests that BNP does not accumulate because of moderate renal impairment but reflects cardiac production rather than impaired clearance Effect modification by kidney function (eGFR) was also observed for the association between PTH and BNP. Impaired kidney function results in decreased calcitriol production and increased PTH levels. If kidneys are not able to reabsorb calcium, blood calcium levels will fall which stimulates continual secretion of PTH to maintain blood calcium levels There are potential mechanisms through which low vitamin D and high PTH could harm the cardiac system. The underlying pathways are still unclear as the interdependency of vitamin D, PTH, and calcium makes it hard to study individual factors. Low 25(OH)D is associated with cardiac cell growth and hypertrophy and can thereby stimulate BNP secretion in vitro PTH induces hypertrophy of cardiomyocytes PTH may influence intracellular signaling by an increase of intracellular calcium in the cardiomyocytes. PTH receptors have been demonstrated in the heart, and Strength of this study is the use of BNP as an easily obtainable and sensitive marker of early myocardial deterioration in subjects not suffering from HF. An early diagnosis of HF could be beneficial to prevent or postpone HF and cardiac diseases, if modifiable determinants are known. Our study allowed us to investigate subjects with moderately increased BNP which already indicates a higher future risk of developing cardiac diseases In conclusion, lower 25(OH)D was cross sectionally associated with higher BNP in subjects with impaired kidney function only (eGFR ≤60 ml/min). The association was not independent of PTH because adjusting for PTH attenuated the association. Higher PTH was cross sectionally associated with higher BNP levels in subjects with impaired kidney function, independent of 25(OH)D. These findings may point to a potential role for PTH in myocardial function, although the results should be interpreted with caution because of the design, sample size, and missing values. Confirmation by larger prospective studies is needed. No longitudinal associations of 25(OH)D and PTH were observed with BNP, which may have been due to small sample size and/or healthy selection, or the study population.


ScvO2 is an indirect index of the balance between oxygen supply and demand, thus in critically ill patients a fall in ScvO2 reflects a decrease in tissue oxygenation. ScvO2 depends on arterial oxygen saturation, oxygen consumption, cardiac output and hemoglobin. The aim of the study was to evaluate events of tissue oxygenation impairment that could be unrecognized by simple blood gas analysis, by continuously monitoring ScvO2 and to establish whether peripheral oxygen saturation (SpO2), mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) could predict LowScvO2 events.Central venous oxygen saturation  for clinical use were enrolled. Continuous ScvO2, SAPS II 40 ± 13 (on 33 patients), PaO2/FiO2 206 ± 79, MAP 80 ± 13 mmHg, HR 92 ± 21 bpm, CVP 12 ± 3 mmHg, Hb 10.6 ± 1.9 g/dl. Continuous monitoring analysis detected 147 LowScvO2 events in 15 patients; while central venous blood gas analysis identified only nine LowScvO2 events in eight patients (6%). Table 2 ranges. SpO2, HR, MAP and CVP were not correlated with LowScvO2 events. Most patients had long periods of ScvO2 > 75 .Thirty-seven patients  were enrolled. The mean clinical characteristics at admission to intensive care were: age 59 ± 16 years, BMI 26.1 ± 4.5 kg/m2 monitoring showed that most events of poor tissue oxygenation are relatively common, are not recognized by extemporary central venous blood gas analysis and are not mirrored by changes in SpO2, HR, MAP or CVP.Continuous ScvO


Evidence indicates that rheumatoid arthritis (RA) patients have increased susceptibility to myocardial ischaemia that contributes to myocardial infarction. The subendocardial viability ratio (SEVR) can be measured using pulse wave analysis and reflects myocardial oxygen supply and demand. The objective of the present study was to examine specific predictors of SEVR in RA patients, with a specific focus on inflammation and classical cardiovascular disease (CVD) risk factors.Two patient cohorts were included in the study; a primary cohort consisting of 220 RA patients and a validation cohort of 127 RA patients. All patients underwent assessment of SEVR using pulse wave analysis. Thirty-one patients from the primary cohort who were about to start anti-inflammatory treatment were prospectively examined for SEVR at pretreatment baseline and 2 weeks, 3 months and 1 year following treatment. Systemic markers of disease activity and classical CVD risk factors were assessed in all patients.P < 0.001), erythrocyte sedimentation rate (P < 0.005), Disease Activity Score in 28 joints (P < 0.001), mean blood pressure (P < 0.005) and augmentation index (P < 0.001) were significantly reduced after commencing anti-TNFα treatment. Increasing C-reactive protein was found to be associated with a reduction in SEVR (P = 0.02) and an increase in augmentation index (P = 0.001).The SEVR (mean ± standard deviation) for RA in the primary cohort was 148 ± 27 and in the validation cohort was 142 ± 25. Regression analyses revealed that all parameters of RA disease activity were associated with SEVR, along with gender, blood pressure and heart rate. These findings were the same in the validation cohort. Analysis of longitudinal data showed that C-reactive protein (The present findings reveal that the SEVR is associated with markers of disease activity as well as highly prevalent classical CVD risk factors in RA, such as high blood pressure and diabetes. Further prospective studies are required to determine whether the SEVR predicts future cardiac events in RA. Rheumatoid arthritis (RA) is a chronic inflammatory musculoskeletal disease that affects ~0.8% of the adult population. RA also associates with an increased risk for cardiovascular disease (CVD) , which iThe leading cause of cardiac death in RA is myocardial infarction . A studyThe current gold standard measure of microvascular coronary perfusion is coronary angiography; however, this procedure is invasive, carries considerable risk to the patient and cannot be repeated at regular intervals. Arterial tonometry using pulse wave analysis has recently gained interest in clinical research as it can non-invasively measure the central aortic pressure waveform and yield information on the augmentation index (AIx) , ejection duration (duration of ventricular contraction), pulse pressure , mean blood pressure , tension time index , diastolic time index  and subendocardial viability ratio  .In particular, the SEVR reflects myocardial oxygen supply and demand, with low values representing a lesser degree of myocardial perfusion . The ratTo our knowledge only two studies have examined the SEVR in patients with RA ,18; one The aims of the present study were: to examine associations between disease-related inflammation and classical CVD risk factors with SEVR in two separate cohorts of RA patients; and to prospectively assess the long-term effects of anti-inflammatory treatment on SEVR.Two hundred and twenty consecutive RA patients were recruited from the rheumatology outpatient clinics of the Dudley Group of Hospitals NHS Trust, UK and formed the primary cohort. A separate validation cohort consisting of 127 consecutive RA patients were recruited from the rheumatology outpatient clinics of the First Department of Propaedeutic and Internal Medicine, Laikon Hospital, Greece. All patients met the retrospective application of the 1987 revised RA criteria of the American College of Rheumatism [Patients reported to a temperature-controlled vascular laboratory (22 to 24°C) after a 12-hour overnight fast. Patients from both cohorts underwent a detailed clinical examination, which included evaluation of their medical history and hospital records, and assessment of their height and weight, as well as calculation of their body mass index. In addition, demographic information was collected from all patients by questionnaire. The Disease Activity Score in 28 joints (DAS28)  and the ® 5.1 FS Chemistry system . The Westergren erythrocyte sedimentation rate (ESR) was measured using the Starrsed Compact . All tests were carried out in the routine and research laboratories of Russells Hall Hospital, Dudley Group NHS Foundation Trust, UK. In the validation cohort, only CRP was measured using a Vitros® 5.1 FS Chemistry system in the routine laboratory of Laikon Hospital, Greece.Serum from patients in the primary cohort was analysed for total cholesterol, high-density lipoprotein cholesterol, triglycerides, C-reactive protein (CRP) and glucose using a VitrosPulse wave analysis  was used to determine the SEVR, AIx, PP, MBP, TTI, and DTI. After recording the brachial blood pressure, the left radial artery was palpated to identify a suitable pulse. The applanation tonometer was positioned over the artery with enough pressure to flatten (but not occlude) the patient's radial artery. The applanation tonometer detects the PP wave, which is calibrated against the standard brachial blood pressure and gives the maximum (systolic) and minimum (diastolic) points of the pressure wave. The pressure waveform is then mathematically transformed into a central aortic waveform that contains the first (peak flow) and second (peak pressure) systolic peaks and displays information on ejection duration.The SEVR is calculated by utilising the ejection duration that is automatically measured by the Sphygmocor system and dividing the area under the diastolic curve (coronary perfusion) by the area under the systolic curve (cardiac workload). In normal conditions, the SEVR can be anywhere between 130 and 200%. Values that are below unity (100%) reflect poor perfusion of the subendocardium . The AIxn = 21), intravenous glucocorticoids (n = 6), and rituximab (n = 4) on clinical indication (UK guidelines) were recruited into a 1-year prospective study. All of the assessments described above were conducted before patients started treatment (pretreatment baseline), and repeated at 2 weeks, 3 months and 1 year after initiation of treatment. For patients starting on anti-TNFα, assessments at 2 weeks and 3 months were performed before receiving the next dose of their anti-TNFα drug.Thirty-one patients from the primary cohort who were about to start anti-inflammatory treatment . Variables were tested for normality by the Kolmogorov-Smirnov test. Log transformation was performed for positively skewed variables as appropriate. Values are expressed as the mean (standard error), geometric mean , median  or percentages, as appropriate. Univariate analysis of variance was used to assess differences in the SEVR (dependent variable) according to gender, presence of CVD risk factors, medication use and rheumatoid factor positivity (fixed factors). To identify specific determinants of the SEVR in RA, linear regression (continuous variables) and logistic regression (discontinuous variables) were used. The SEVR was entered as the dependent variable, and demographic, CVD risk factors and inflammatory variables were entered separately as independent variables.10-transformed prior to the analysis, where applicable. The measurement time was entered as a factor in each model, with the baseline value set as the reference category. An unstructured correlation structure was used where possible, since this is the most general option, with exchangeable structures used where convergence was not achieved.The longitudinal data were analysed using generalised estimating equations. This allowed for the potential correlations between repeated measurements made on the same patients to be adjusted for. To consider the effect of the anti-inflammatory treatment, separate models were produced for each of the outcomes considered, which were logCRP and the ESR were then included separately as factors in these models. This separate inclusion allowed for the effect each of these factors on the other outcomes to be considered, whilst adjusting for the changes over time.The patient characteristics for both cohorts are presented in Table P < 0.01).Univariate analysis of variance showed that the SEVR did not differ between patients receiving or not receiving steroid treatment in both the primary and validation cohorts. This was a similar finding for disease-modifying anti-rheumatic drug use, biologic agents, antihypertensives, anti-hypercholesterolemics, nonsteroidal anti-inflammatory drugs, and cyclooxygenase II inhibitors. However, the SEVR was higher in patients receiving β-blockers in the primary cohort only . There was no difference in SEVR for any of the other CVD risk factors. Similar findings were also apparent in the validation cohort, except that the SEVR between diabetic and nondiabetic patients did not reach statistical significance .Univariate analysis of variance was used to compare SEVR levels in patients with and without classical CVD risk factors. This analysis revealed that patients with diabetes had significantly lower SEVR than nondiabetic patients . Similarly, gender was also associated with the SEVR in the validation cohort; with females having a lower SEVR than males . From the disease-related variables, log ESR and log CRP were inversely associated with the SEVR, and a positive association was found with log disease duration in patients in the primary cohort  of the SEVR (dependent variable) in patients with RA . Significant variables within the model included heart rate , PP , log ESR  and log CRP .Stepwise multivariate regression was performed to examine the relationship between significant univariate predictors presented in the analysis above (independent variables) and the SEVR (dependent variables). The individual components that were entered into the model were gender, log disease duration, log ESR, log CRP, PP and heart rate. The entry probability was 0.05 and none of the variables were forced back into the model. From this analysis a significant model emerged . Significant variables within the model included heart rate , PP , and gender . In an alternative model without heart rate, log CRP was, independently of gender and PP, associated with the SEVR .Similar multivariate regression as above was performed in the validation cohort. The individual components that were entered into the model as independent variables were gender, log CRP, PP and heart rate, with the SEVR entered as the dependent variable. From this analysis a significant model was apparent  while heart rate was inversely associated with log CRP   Table .P < 0.001), ESR (P = 0.004), DAS28 (P < 0.001), MBP (P = 0.002) and AIx (P < 0.001), with the only nonsignificant outcome being the SEVR (P = 0.30). Hence, for those outcomes that were significant, it can be concluded that the average measurements changed over time.The effect of anti-inflammatory treatment on a range of outcomes was considered using generalised estimating equations Table . Each ouTo detect where these changes occurred, pairwise comparisons were made between the baseline and all of the subsequent measurement times. Where this was significant, it implied that the outcome considered changed significantly after the treatment began. As can be seen in Table P value then represented the strength of the relationship between the two variables in the model. The coefficient demonstrated the increase in the dependent variable that would be expected for each increase in the predictor variable. Owing to the necessity of log transformations, this relationship was not necessarily linear.A secondary analysis considered the effect of CRP and ESR on the other factors considered above Table . GeneralP < 0.001) and the SEVR (P = 0.02). For the former, the resulting coefficient implied that a 10-fold increase in CRP increases the AIx by 5.4 . Because both of these variables are log10 transformed, the relationship between CRP and the SEVR is more complex. The model showed that a 10-fold increase in CRP reduces the log10 of the SEVR by 0.03 . Applying this to a real-world example, an increase of CRP from 1 to 10 would be expected to reduce the SEVR from 174 to 162. A 10-fold increase in CRP hence reduces the SEVR by approximately 12.The ESR was not found to be a significant predictor of any of these outcomes, whilst CRP was found to have significant effects on both the AIx . The results of the model showed that a 10-fold increase in CRP is associated in a reduction of 0.031 in the log10 SEVR. To our knowledge only one other study, with a small sample size of RA patients (n = 17), has assessed the effects of inflammation on the SEVR in RA, and revealed that the SEVR was worse following 7 weeks of treatment with anti-TNFα despite a reduction in disease activity and inflammation [The inflammatory nature of RA and CVD is strikingly similar , and on ammation . Howeverammation .Studies assessing coronary microvascular function consistently demonstrate inflammation to be an important contributor to myocardial ischaemia. For example, Kobayashi and colleagues demonstrated myocardial perfusion defects in RA patients using cMRI . FurtherIn the present work, inflammation was inversely associated with DTI and positively associated with heart rate. These findings suggest that inflammation may lower the time for diastolic filling of the heart while simultaneously increasing cardiac workload due to an elevated heart rate. Both of these actions would have a negative impact on cardiac perfusion and contribute to myocardial ischaemia, especially as the heart rate was inversely associated with the SEVR in multivariate analysis. Inflammation therefore appears to have a detrimental association with myocardial ischaemia, possibly due to negative actions on cardiac perfusion and workload. Alternatively, as shown in the validation cohort, higher CRP levels may be associated with lower SEVR due to increased TTI ), presumably induced by the described effect of inflammation and heart rate acceleration on aortic stiffness.Another important finding in the current study was that the SEVR was positively associated with disease duration. Patients with greater disease duration therefore had better myocardial perfusion. This finding appears to contradict the general hypothesis that longer disease duration is associated with greater CVD risk . HoweverThe SEVR was found to inversely associate with PP in the present cohort, but not with MBP. This finding supports the results of a meta-analysis which revealed that PP but not MBP was an independent predictor of cardiovascular complications and all-cause mortality in older hypertensive patients . PP is gRA patients with diabetes had lower SEVR than nondiabetic patients, in line with findings from another study in type 1 diabetics . A numbeThe strength of the present study is the inclusion of two separate cohorts of well-characterised RA patients along with the assessment of a novel and non-invasive measure of myocardial ischaemia. In addition, the 1-year prospective study allowed observation of the effect of anti-inflammatory treatment on the SEVR. Importantly, the findings were replicated in both cohorts, demonstrating the strength of the findings. The limitations of the study include the prospective assessment of the SEVR following administration of three different types of anti-inflammatory treatment  whose mode of action could differentially affect the vasculature. However, there was no difference in parameters of pulse wave analysis between treatment types at any time point (data not shown). Another limitation in the prospective arm of the study was that it was not possible to determine whether parameters of pulse wave analysis were already impaired at baseline due to an absence of a healthy control group. Nevertheless, the average AIx relative to the age of the prospective cohort would be considered normal, and the AIx did improve with treatment at 1 year - which tends to suggest that irreversible vascular alterations were not evident in this cohort. Finally, the prospective arm of the study was possibly underpowered to detect a change in SEVR following treatment; further prospective studies with a large sample size as well as including a more thorough examination of the factors that affect the ventricular-vascular coupling are therefore warranted.In summary, the present study reveals that systemic markers of inflammation and some classical CVD risk factors associate with myocardial ischaemia, but further prospective studies that assess whether the SEVR predicts future cardiac events in RA and other populations are warranted.AIx: augmentation index; CRP: C-reactive protein; CVD: cardiovascular disease; cMRI: contrast-enhanced magnetic resonance imaging; DAS28: Disease Activity Score in 28 joints; DTI: diastolic time index; ESR: erythrocyte sedimentation rate; MBP: mean blood pressure; PP: pulse pressure; RA: rheumatoid arthritis; SEVR: subendocardial viability ratio; TTI: tension time index; TNF: tumor necrosis factor.The authors declare that they have no competing interests.AS and ADP participated in the design of the study, recruited patients, performed assessments of pulse wave analysis, conducted data analysis and drafted the manuscript. JH performed statistical analysis of longitudinal data. JPS conducted laboratory analysis. EZ, PPS and GK participated in the design of the study and helped with writing the manuscript. All authors read and approved the final manuscript.


Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions.Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013.The “The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. Arterial hypertension is a highly prevalent disease, substantially impacting cardiovascular prognosis. Despite1 receptor may contribute to its potent and long-lasting antihypertensive activity.Azilsartan medoxomil AZM, TAK-491) is a recently developed angiotensin receptor blocker (ARB) that has a number of specific characteristics. It is s91 is a rFour studies compared the clinical efficacy of AZM with other ARBs. The studies included patients with primary hypertension and used ambulatory BP monitoring (ABPM) to determine BP lowering efficacy. AZM at a dose of 80 mg once daily provided superior BP lowering compared to the highest approved doses of olmesartan (40 mg), valsartan (320 mg) and candesartan (32 mg)-9 Table.Treatment was generally well-tolerated with a similar rate of adverse events between AZM and placebo and low rates of 2% to 3% for the withdrawal due to adverse events. The mosRecently, a randomized trial compared the antihypertensive efficacy and safety of AZM to ramipril. This coBased on these data, a considerable improvement of BP control might be expected from using AZM in clinical practice. The prospective observational registry (EARLY) aims at documenting BP control and its impact on cardiovascular and renal events during 12 months of follow-up in patients with either AZM or ACE-inhibitor treatment.Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of 12 months. The registry will enroll up to 5000 patients with arterial hypertension starting treatment on either AZM or any ACE inhibitor monotherapy in up to 1000 sites in Germany in a ratio of 7 (AZM) to 3 (ACE-inhibitors) , and applicable regulatory requirements. The protocol was approved by the independent ethics committee in Freiburg and the ethics committee of the State Medical Council of Rheinland-Pfalz, Germany. EARLY has further been registered with the database of the Verband forschender Arzneimittelhersteller (VFA). Patients being enrolled into this registry have to provide written informed consent.co-primary objectives: 1) Description of the safety profile of AZM. 2) Achievement of BP targets based on recent national and international guidelines for patients treated with AZM in comparison to those treated with ACE-inhibitors.EARLY has two Secondary objectives are as follows: 1) Absolute and relative BP reduction with antihypertensive treatment over the duration of one year. 2) Documentation of the adherence to guidelines for the diagnosis and treatment of hypertension in ambulatory care. 3) Persistence understood as the mean duration of monotherapy and / or AZM based combination therapy during follow-up. 4) Documentation of adverse events. 5) Prospective documentation of cardiovascular and renal events. 6) A pharmaco-economic evaluation of AZM use.Additional objectives in a subgroup of patients with ABPM are to document BP lowering and pulse pressure reduction over the 1 year follow-up considering prior and concomitant antihypertensive pharmacotherapy as well as BP at baseline, and BP control with AZM in comparison to ACE-inhibitors (specific ACE inhibitors will be considered given their sample size is sufficient). Second, BP values obtained from ABPM will be compared to corresponding office BP values. Finally, central systolic and diastolic blood pressure, cardiac output (per minute), peripheral resistance, augmentation index, and pulse wave velocity will be determined and compared between patients receiving AZM or ACE-inhibitor treatment.The registry is performed in primary care offices in Germany, with a planned participation of up to 1000 sites. Centers will be selected from a database maintained at the Institut für Herzinfarktforschung, Ludwigshafen, in order to be representative for the ambulatory treatment of hypertension in Germany. The recruitment per physician is limited to a maximum of 30 patients.Adult patients (≥ 18 years) with essential arterial hypertension are included on a consecutive basis, given they have provide written informed consent and fulfill the following two criteria: 1) Participants have either no anti-hypertensive treatment prior to inclusion or a prior non-RAS based antihypertensive monotherapy. 2) A monotherapy using AZM or any ACE-inhibitor is initiated at baseline.th 2013 at the latest or as soon as the recruitment target of 5000 patients is met.Patients are excluded from participation if they 1) receive antihypertensive drugs for an indication other than hypertension (e.g. beta blockers or diuretics for heart failure), 2) have a history of alcohol, drug abuse or illegal drug addiction, 3) have a life expectancy of less than one year, 4) are pregnant or breast feeding, or 5) are participating in other trials or registries. Further to this, patients with contraindications as to the summary of product characteristics of AZM or the ACE inhibitors will not be permitted. Patient recruitment started in January 2012 and will end on February 28Table There are three strategies for data quality checks: validations that occur at the time of data entry , a second, more sophisticated quality control program that runs as a prelude to the creation of the analysis data set and on-site data monitoring. Front-end data checks are advantageous because mistakes are caught and corrected at the time of entry – a system that is efficient for data collectors. Certain data elements can be required, while other variables may allow for missing values. Additionally, parameters will be defined to allow entry of only those records that meet inclusion criteria. Prior to the creation of the analytic dataset, more extensive quality control processes are performed. These checks, programmed in SAS, include parent–child edits, consistency edits, and data transformations that will facilitate analyses. Source documentation and data accuracy will be verified by site visits in randomly selected 5% of the sites.Data entry is performed by the physician or study nurse via a secure website directly into an electronic database. This approach allows online checks for plausibility and integrity.th 2013. In case the recruitment target of 5000 patients is not met, a reduced precision of the primary objective will be accepted.The sample size for this registry was determined aiming to provide a sufficient precision of the primary endpoint, e.g. BP target achievement of <140/90 mmHg with a monotherapy of AZM or an ACE-inhibitor. Based on the aforementioned trial published by Bönner et al. comparinAll variables collected in the eCRF as well as the data obtained from the quality of life assessments and all derived parameters will be used in the statistical analysis. Binary, categorical, and ordinal parameters will be summarized by means of absolute and percentage numbers within the various categories . Numerical data will be summarized by means of standard statistics . In addition, adequate graphs  may be presented to summarize the results for some parameters. Time-to-event variables will be analyzed via a Cox proportional hazard regression model presenting hazard ratios and the corresponding 95% confidence intervals (CI). In addition Kaplan-Meier curves will be presented for these variables. Two-sided 95%-CI will be presented for important parameters, but should be interpreted in an exploratory descriptive way. Further multivariable analyses will be performed according to the statistical analysis plan (SAP). Formal statistical tests will not be performed within the statistical analysis. A report including descriptive statistics of all documented parameters will be generated for the overall patient population. Depending on the variable(s) of interest, additional selection criteria for patients  considered in specific analyses may be used, if considered useful during the statistical analysis. Details on the selection criteria used will be given in the SAP and in the statistical section of the report. The statistical analysis will be performed using SAS .“Global Registry of Acute Coronary Events” (GRACE registry)[Non-interventional studies supplement the results from randomized clinical trials (RCT) because they include patients that are frequently excluded from clinical trials because of stringent in- and exclusion criteria, thus representing clinical practice. This has been exemplified based on the egistry). For thiSimilar observations were made in the recent non-interventional study SERVE. Out of For the particular comparison of ARB with ACE-inhibitor treatment the EARLY registry is pursuing, available data is limited. This is mostly because non-interventional studies usually have no control group and are single-armed studies. If the results of a comparison are presented these mostly relate to differences between ARB treatment versus a stopped ACE-inhibitor at baseline. A more recent retrospective analysis by Roy and colleagues used proThere is a substudy in EARLY utilizing ABPM to verify and enhance diagnostic accuracy and add values not regularly obtained during office BP measurement. This is of particular importance since it has been shown that reductions in office-based BP values cannot to be translated 1:1 to 24-hour BP values. This was shown in a recent study in which lercanidipine was compared with enalapril in daily practice using ofIn addition to the brachial blood pressure measurements, the use of the mobilograph device allows to analyze the treatment induced changes of the central systolic blood pressure and pulse pressure as well as the augmentation index. Thus, we are able to examine the effects of AZM on central hemodynamic and vascular stiffness of large arteries.There are a number of potential limitations to the design of the EARLY registry. Although we have a control group of patients receiving ACE-inhibitors, allowing to compare effectiveness and tolerability between AZM and ACE-inhibitors we have an 1) imbalance in group size, that will allow to determine control rates with AZM more precisely than in the control group. 2) The assignment to AZM or ACE-inhibitor treatment is performed by the treating physician and not the result of randomization. 3) Only a limited number of the available ACE inhibitors (e.g. ramipril) will be allowed because prescription rates of some of the other ACE inhibitors may be low. 4) Patients selected for AZM treatment may differ for known or unknown reasons from those receiving ACE inhibitor treatment. These limitations have to be weighed against the potential implications of EARLY findings: the registry includes a large group of unselected patients in primary care without the limitation given by stringent in- and exclusion criteria and has a 1 year follow-up that will allow to determine whether differences in BP lowering efficacy, persistence with treatment and tolerability might translate into a reduction of events throughout follow-up.The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE inhibitor treatment for target BP achievement.ABPM: Ambulatory blood pressure monitoring; ACE: Angiotensin converting enzyme; ARB: Angiotensin receptor blocker; AZM: Azilsartan medoxomil; BP: Blood pressure; CI: Confidence interval; DBP: Diastolic blood pressure; eCRF: Electronic case report form; GEP: Good epidemiology practice; OBPM: Office blood pressure measurement; SAP: Statistical analyses plan; SBP: Systolic blood pressure; SBPM: Self blood pressure measurement.Roland E. Schmieder (RES), Peter Baumgart (PBau), Peter Bramlage (PBra), Felix Mahfoud (FM), Sebastian A. Potthoff (SAP), Steffen Schneider (StS), and Anselm K. Gitt (AKG), have received research support and/or honoraria for lectures from a number of pharmaceutical companies producing anti-hypertensive drugs including Takeda the sponsor of this study. Hartmut Buhck (HB) is freelance consultant to the sponsor Takeda.AKG, PBau, PBra, FM, SAP, JS, StS and RES have designed the registry. StS is responsible for the analysis of data. AKG, PB and HB drafted the manuscript based on the protocol and all other authors revised the article for important intellectual content. All authors have finally approved the version to be published.EARLY Registry Group: Anselm K. Gitt , Peter Baumgart (Münster), Peter Bramlage (Mahlow), Felix Mahfoud (Homburg/Saar), Sebastian A. Potthoff (Düsseldorf), Jochen Senges (Ludwigshafen), Steffen Schneider (Ludwigshafen), Hartmut Buhck (Hanover), Roland E. Schmieder , Georg Lübben (previously Takeda), Claus Jünger (Ludwigshafen), Alexander Neumer (Ludwigshafen), Karin Vonderschmitt (Ludwigshafen), Reinhold Hübner (Berlin).The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/46/prepub