Hypertension. The results of the new study further hint that this control may become worse as exposure to secondhand smoke continues, perhaps increasing the risk of developing hypertension in later life.Babies born to mothers who smoke cigarettes may be at risk for abnormal blood pressure and heart rate control at birth, suggests research published in the March 2010 issue of The study compared the heart rate and blood pressure control of 19 infants born to nonsmokers with those of 17 infants whose mothers reported smoking an average of 15 cigarettes per day before and after giving birth. The resting blood pressure of the infants in both groups followed essentially the same developmental trend over the first year of life, although the smoke-exposed infants had higher diastolic blood pressure at age 3 months. The resting heart rate of both groups also was similar and followed the same trend up to age 3 months. But by 1 year the resting heart rate of the smoke-exposed infants averaged 20% slower than that of their unexposed counterparts.The researchers also monitored changes in heart rate and blood pressure over a span of 40 beats as the infants, sleeping soundly on tilt tables, were raised from a supine position to an inclination of 60º over 5 seconds and held in that position for 1 minute. “As the body becomes more upright, the heart rate should rise temporarily, and different blood vessels should constrict to increase the blood pressure and ensure enough blood gets to the brain,” explains first author Gary Cohen, a senior research scientist in the Department of Women’s and Children’s Health at the Karolinska Institute, Stockholm. Sure enough, that is what the authors observed for the nonexposed infants, with peak values becoming somewhat higher between 1 week and 1 year as expected.The exposed infants showed a similar trend over time. However, between 3 months and 1 year their responses became exaggerated, with their heart rate rising faster (and increasing by an average of 11.5% instead of the 6.5% seen in the nonexposed babies) before falling more quickly. Their diastolic blood pressure followed suit.When the nonexposed infants were tilted and maintained upright, sustained rises in systolic, diastolic, and mean blood pressure of 2–3% were seen at age 1 week, rising to 8–10% by 1 year as expected. In contrast, in the exposed infants the increases in blood pressure were nearly double at age 1 week but failed to increase over time.“Thus, the newborns of smokers hyperreact to positional change, but by the time they are one year old and want to stand up they are underreacting; their routine blood pressure compensation systems just don’t work properly,” says Cohen. “It would appear that neither their heart rate nor sympathetic constrictor tone [impulses from the sympathetic nervous system that help control blood vessel constriction] are properly ‘programmed’ even at birth, with things getting worse over time.”This programming problem could lie in an overly strong sympathetic tone caused by exposure to some compound in cigarette smoke in the womb and after birth, the researchers say. This might slowly increase vascular resistance, leading to the increased diastolic blood pressure seen at rest at 3 months, and the eventual loss of sympathetic reactivity.The authors further hypothesize that the fall in heart rate observed in exposed infants at age 1 year was an attempt to restore some kind of equilibrium. Unfortunately, this reprogramming solution appears to hinder proper positional blood pressure control, “and there is evidence this could increase the chances of hypertension later on,” explains Cohen.In adults, cardiovascular pathophysiology can involve chronic sympathetic overactivity leading to increased blood pressure. The authors suggest something similar may be happening in the children they studied.“[Whether these observations can be] explained by alterations in central sympathetic outflow requires further investigation as this was not directly assessed in this study,” remarks James Fisher, a lecturer in exercise physiology in the School of Sport and Exercise Sciences, University of Birmingham who was not involved in the study. “As is often the case with good research, we are left with more questions than answers. Is the altered cardiovascular reactivity specific to postural stress, or is it more generalized? What is the biological significance of the magnitude of the alteration in cardiovascular reactivity? How permanent is the ‘reprogramming,’ and is it reversible if smoke exposure is withdrawn?”Although interesting, the study is rather small. “I would like to see confirmation in a larger study,” says Mark Caulfield, director of the William Harvey Research Institute at Barts and The London School of Medicine and Dentistry, “with formal proof of cigarette consumption status in each of the study groups before drawing a firm conclusion.”


Healthy lifestyles may help to delay arterial aging. The purpose of this study is to analyze the relationship of physical activity and dietary pattern to the circadian pattern of blood pressure, central and peripheral blood pressure, pulse wave velocity, carotid intima-media thickness and biological markers of endothelial dysfunction in active and sedentary individuals without arteriosclerotic disease.Design: A cross-sectional multicenter study with six research groups.Subjects: From subjects of the PEPAF project cohort, in which 1,163 who were sedentary became active, 1,942 were sedentary and 2,346 were active. By stratified random sampling, 1,500 subjects will be included, 250 in each group.Primary measurements: We will evaluate height, weight, abdominal circumference, clinical and ambulatory blood pressure with the Radial Pulse Wave Acquisition Device (BPro), central blood pressure and augmentation index with Pulse Wave Application Software (A-Pulse) and SphymgoCor System Px , pulse wave velocity (PWV) with SphymgoCor System Px (Pulse Wave Velocity), nutritional pattern with a food intake frequency questionnaire, physical activity with the 7-day PAR questionnaire and accelerometer (Actigraph GT3X), physical fitness with the cycle ergometer (PWC-170), carotid intima-media thickness by ultrasound (Micromax), and endothelial dysfunction biological markers (endoglin and osteoprotegerin).Determining that sustained physical activity and the change from sedentary to active as well as a healthy diet improve circadian pattern, arterial elasticity and carotid intima-media thickness may help to propose lifestyle intervention programs. These interventions could improve the cardiovascular risk profile in some parameters not routinely assessed with traditional risk scales. From the results of this study, interventional approaches could be obtained to delay vascular aging that combine physical exercise and diet.Clinical Trials.gov Identifier: NCT01083082 Aging is associated with an increase in arterial stiffness that can be assessed using different tools, such as the increase in pulse pressure, both clinical and ambulatory, changes in circadian pattern of blood pressure, increased pulse wave velocity and central blood pressure, as well as certain biological markers of endothelial dysfunction-3.Blood pressure measurement at the clinic is still currently the standard of reference, but there is increasing evidence that the values obtained after home blood pressure measurement by the patient and particularly 24-hour ambulatory blood pressure monitoring (ABPM) show a better correlation with target organ damage,6. It haThe accepted gold standard to assess arterial stiffness is currently femoral carotid pulse wave velocity (PWV)  and it hSerum levels of osteoprotegerin (OPG) are elevated in patients with type 1 and 2 diabetes ,17 from The potential benefits enjoyed by active people, both at the biological and psychological level, range from a better quality of life to a reduction in the risks associated with hypertension, diabetes, cardiovascular diseases and all causes of mortality-22. SomeTherefore, there are still some unresolved issues, such as the effect on vascular structure and function of endurance exercise, alone or combined with aerobic exercise, recommended for maintenance of muscular strength in the elderly. The effThere is evidence that the Mediterranean diet (Mediterranean/DASH diet) with high consumption of fruit and vegetables, fish and olive oil may have a positive effect on endothelial function-37, as wTherefore, the purpose of this study is to analyze the relationship of different doses of physical activity, fitness and dietary pattern to the circadian pattern of blood pressure, vascular structure and function analyzed by PWV and AIx, carotid intima-media thickness and biological markers of endothelial dysfunction (OPG and endoglin). This study continues the research line of the project "Multicenter Assessment of Experimental Program Promoting Physical Activity (PEPAF)" ,43, focu1. To analyze the relationship of physical activity and fitness to circadian pattern of blood pressure, central and peripheral blood pressure, PWV, AIx, and carotid intima-media thickness in active and sedentary individuals without arteriosclerotic disease.2. To analyze the relationship of caloric intake and food pattern to circadian pattern of blood pressure, central and peripheral blood pressure, PWV, AIx and carotid intima-media thickness in active and sedentary individuals without arteriosclerotic disease.3. To study the correlation of OPG and endoglin levels with arterial stiffness assessed by PWV and AIx, as well as with circadian pattern of blood pressure and carotid intima-media thickness in subjects with different level of physical activity and different nutritional patterns.A cross-sectional study, to evaluate the association of lifestyles (diet and exercise) with circadian pattern of blood pressure, arterial stiffness and endothelial function in a previously established cohort of healthy subjects with different levels of physical activity. This is a multi-center study with the participation of six groups distributed throughout Spain with the purpose of increasing the sample size to test the proposed hypotheses and to increase the external validity of the study.Subjects will be selected from the PEPAF project cohort,40. ThisSample size was estimated using AIx as a indicator of central arterial stiffness. The CAFE study  will be calculated. Waist circumference will be measured using a flexible graduated measuring tape with the patient in the standing position without clothing. The upper border of the iliac crests are located, and the tape is wrapped around above this point, parallel to the floor, ensuring that it is adjusted without compressing the skin.Body weight will be determined on two occasions using a homologated electronic scale (Seca 770) following due calibration (precision ± 0.1 kg), with the patient wearing light clothing and no shoes. These readings will be rounded to 100 g. Height in turn will be measured with a portable system (Seca 222), recording the average of two readings, and with the patient shoeless in the standing position. The values will be rounded to the closest centimetre. Body mass index (BMI)(kg/mOffice blood pressure measurement involves three measurements of systolic (SBP) and diastolic blood pressure (DBP), using the average of the last two, with a validated OMRON model M7 sphygmomanometer , by following the recommendations of the European Society of Hypertension. Pulse p(ABPM): The ABPM will be performed on a day of standard activity, with a radial tonometer. Radial pulse wave acquisition device (BPro)  validated according to the protocol of the European Society of Hypertension (ESH), Association for Advancement of medical Instrumentation (AAMI) and British Hypertension society will be Central blood pressure will be measured with Pulse Wave Application Software (A-Pulse)  using tonometry to capture the radial pulse and by equation patented estimate central blood pressure. The increase in central blood pressure, mean blood pressure and radial Augmentation index will be estimated. Radial AI will be calculated as follows: (Second peak systolic blood pressure [SBP2] - diastolic blood pressure [DBP])/(first peak SBP - DBP) × 100 (%).It is the same instrument that performs the 24 ABPM (BPro), with an specific software to determine the central blood pressure and estimation of the parameters derived from it.In the Salamanca cohort, AIx and PWV will also be estimated using the SphymgoCor System , currently the gold standard for measuring arterial stiffness, and wilSonosite Inc., Bothell, Washington, USA) device paired with a 5-10 Mhz multifrequency high-resolution linear transducer with Sonocal software will be for performing automatic measurements of IMT for optimising reproducibility. Measurements will be made of the primitive carotid after the examination of a longitudinal section of 10 mm at a distance of 1 cm from the bifurcation, performing measurements in the anterior or proximal wall, and in the posterior or distal wall in the lateral, anterior and posterior projections, following an axis perpendicular to the artery to discriminate two lines, one for the intima-blood interface and the other to the media-adventitious interface. A total of 6 measurements will be obtained of the right carotid and other 6 of the left carotid, using average values (average IMT) and maximum values (maximum IMT) calculated by the software automatically. The measurements will be obtained with the subject lying down, with the head extended and slightly turned opposite to the carotid examined, following the recommendations of the Manheim Carotid Intima-Media Thickness Consensus[Carotid ultrasonography to assess IMT will be performed by two investigators specifically trained for this before starting the study. A Sonosite Micromax ultrasound  applying the probe at the anterior or posterior tibial artery at an angle of approximately 60° to the direction of blood flow. The transducer's cuff will be quickly inflated in each ankle about 30 mmHg above the systolic pressure and the pressure will be allowed to descend (by about 2 mmHg per second) until the first sound corresponding to the systolic pressure was heard. The blood pressure will be also measured in both arms . The ABI will be calculated separately for each foot by dividing the higher of the two systolic pressures in the ankle by the highest measurement of the two systolic pressures in the arm [This will be evaluated using the ankle-brachial index (ABI), performed in the morning without having consumed coffee or tobacco for at least 8 hours prior to measuring and an ambient temperature of 22-24°C. With the feet uncovered, in a supine decubitus position after 20 minutes of rest, the pressure in the lower extremities was measured using a portable Doppler system Minidop Es-100Vx  and accelerometer. The PAR is a general measure of physical activity, which has been recognized as valid and reliable tool in recent years and is widely used in epidemiological, clinical and behavior change studies. It consists of a semi-structured interview (10-15 minutes) in which participants provide an estimate of the number of hours dedicated to physical or occupational activities requiring at least a moderate effort in the past seven days. The categories collected are: moderate, vigorous, and very vigorous physical activity. The amount of time dedicated to each activity is multiplied by the mean metabolic equivalents (METs) of each category: light activity 1.5, moderate 4, vigorous 6, and very vigorous 10. The sum of the products of the hours dedicated to each activity and its estimated mean energy expenditure (MET) provides an estimation of the kilocalories per kilogram used per day . The dose of physical exercise will be estimated in METs/hour/week and active persons were considered as those doing at least 30 minutes of moderate activity, five days a week, or at least 20 minutes of vigorous activity, 3 days a week. Persons not reaching this level of physical activity were considered sedentary.Actigraph GT3X accelerometers  will be used, which have been previously validated. Subject2 max) and physical work capacity using a submaximal test. Evaluation of physical fitness or maximal oxygen consumption will be made using indirect exercise tests (which are simpler and safer), extrapolating the data obtained from the work load performed (watts) and heart rate using the PWC-170 or physical work capacity at 170 beats per minute.Measurement of physical fitness will focus on estimating cardiorespiratory fitness, defined as maximal oxygen consumption  and cardiovascular diseases and drug use. A blood sampling will be drawn to assess lipids, blood glucose, HbA1c, blood insulin, and renal function, and a urine sample will be collected to assess index albumin/creatinine. A blood sample will be frozen for subsequent determination in the laboratory of the physiology department of the University of Salamanca of biological markers of endothelial dysfunction, OPG and endoglin in plasma by ELISA using specific commercial kits and following the manufacturer's instructions.Data input will be made using the Teleform system , with a questionnaire previously designed for the project. Results will be expressed as mean ± standard deviation for quantitative variables or by frequency distribution for qualitative variables. The Pearson chi-square test will be used to analyze associations between qualitative variables. Student's t test for independent samples will be used to compare the means of the two groups and an ANOVA will be performed if the number of groups is increased. Post hoc comparisons will then be performed using the LSD method, with alpha < 0.05. The relationship between quantitative variables will be analyzed using Pearson's correlation coefficient. Finally, a multivariate analysis of multiple linear regression and logistic regression will be made to analyze the most significant variables  circadian pattern, arterial stiffness (PWV and AIx), and endothelial dysfunction (endoglin and OPG). Physical exercise will be analyzed to determine changes in cardiovascular parameters according to the dose of physical exercise performed. For hypothesis testing, an alpha risk of 0.05 will be set as the limit of statistical significance. SPSS/PC+ version 15.0 statistical package will be used .In order to ensure data quality, the nursing professionals in charge of data collection will receive specific training. Regular external monitoring will then be performed in the six health centers to verify adequate application of methods, both in performing the different examinations and collecting the information. At La Alamedilla health center, a measurement of arterial stiffness (PWV and AIx) with SphygmoCor System (gold standard) for the purpose of confirming correct determination of these parameters.The main limitation in the first phase of the study is that it is a cross-sectional design and therefore only allows detection of association and not causal relationship. This problem is expected to be solved in the second phase with randomized clinical trial that is planned. Selection of the sample was randomized and so it would ideally represent the population without cardiovascular disease seen in primary care, but the losses suffered by the cohort during follow-up were close to 20% and this may have influenced the representativeness of the population attending primary care centers.In order to guarantee data confidentiality, all the electronic and paper copies of the protocol, signed informed consent documents and results of the tests made in each of the patients will be kept locked in a safe place, and only the study investigators will have access to the data on the subjects who agree to participate in the study.The study has been approved  by the research ethics committee from health area of Salamanca and complies with Spanish data protection law 15/1999 and its recently developed specifications  1720/2007). Knowledge and agreement to cooperate has been established with the implicated services, signed by the legal representative of the centre.It is expected to confirm the hypothesis that healthy lifestyles -physical activity and healthy diet- produce an improvement in circadian pattern of blood pressure, PWV, and AIx as indicators of central arterial stiffness and impaired vascular function, in carotid intima-media thickness as an indicator of impaired vascular structure, and in endothelial damage assessed by endoglin and OPG.Determining that sustained physical activity and the change from sedentary to active as well as a healthy diet improve circadian pattern, arterial elasticity and carotid intima-media thickness may improve lifestyle intervention programs. These interventions could improve cardiovascular risk profile in some parameters not routinely assessed with the traditional risk scales. This baseline assessment will provide essential information for the subsequently planned interventional clinical trial to test the improvement in these parameters with a specific intervention.The use of a new tool such as the Radial Pulse Wave Acquisition Device (BPro) and Pulse Wave Application Software (A-Pulse), and verification of their feasibility and convenience of use may help to generalize the evaluation of certain cardiovascular parameters that increase vascular risk and are not routinely assessed. If our hypotheses are confirmed, molecules such as OPG or endoglin could be used as early markers of endothelial dysfunction.From the results of this study, an interventional approach could be obtained to delay arterial aging that combines physical exercise and diet. This approach based on healthy lifestyles could be a powerful tool to stop vascular aging.ABPM: Ambulatory blood pressure monitoring; PWV: Pulse Wave Velocity; AIx: Augmentation Index; ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial; CAFÉ: Conduit Artery Function Evaluation; OPG: Osteoprotegerina; DASH: Dietary Approaches to Stop Hypertension; PEPAF: Experimental Program for Physical Activity Promotion; BMI: Body mass index; SBP: Systolic blood pressure; DPB: Diastolic blood pressure; ESH: European Society of Hypertension; AAMI: Association for Advancement of medical Instrumentation; PWA: Pulse Wave Analysis; IMT: Intima-media thickness; ABI: Ankle-brachial index; PAR: Physical Activity Recall; MET: Metabolic equivalent; VO2max: Maximum oxygen consumption.The authors declare that they have no competing interests.Conception of the idea for the study: LGO, MAGM and JIRR. Development of the protocol, organization and funding: LGO, JIRR, C MC, ACS, AGA, NGV, EISN, CPA and MAGM. Writing of the manuscript: LGO and MAGM. All the authors have read the draft critically, to make contributions, and have approved the final text. The project will be developed by Evident group.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/233/prepub


The aim of the present study was to compare serum levels of soluble forms of interleukin-2 receptor, CD4 and CD8, released by lymphocytes during activation of the immune system, in patients with allergic bronchial asthma, with those in healthy subjects. Significantly higher levels of soluble IL-2R and soluble CD4 were found in patients with asthma compared with the control group. In contrast, lower levels of soluble CD8 values were found in patients with asthma compared to the control group. Significant correlations were found for both sIL-2R and sCD4 and these two molecules, with lung function measured as bronchial responsiveness to inhaled methacholine. These results strengthen previous suggestions that in allergic bronchial asthma, activation of T cells plays a significant role in the disease pathogenesis.


Theoretically, angiotensin II receptor blockers (ARBs) have certain advantages over angiotensin-converting enzyme inhibitors, but the contribution of these advantages to the clinical effect of ARBs is not known.To compare the efficacy and tolerability of telmisartan with enalapril in patients of essential hypertension.Patients of mild to moderate hypertension were randomized to receive either 40 mg of telmisartan or enalapril 10 mg once a day orally for 12 weeks. At each visit, the systolic blood pressure (BP), diastolic BP and heart rate of each patient were recorded. Investigations such as hemogram hemoglobin, total leucocytes count , serum creatinine, serum glutamic oxaloacetic transaminase, serum glutamic pyruric transaminase  random blood sugar and urine examination were performed at baseline and after 12 weeks of the treatment period.P > 0.05). However, the mean reduction in diastolic BP achieved with telmisartan at 12 weeks was significantly higher (P < 0.001) than that achieved with enalapril after the corresponding period. The overall frequency of adverse-effects was similar. However, in the enalapril group, the incidence of dry cough was higher as compared to that in the telmisartan group .The mean reduction in systolic BP in the telmisartan/enalapril group was 26.38 ± 10.98/26.74 ± 8.24 mmHg while the mean reduction in diastolic BP in the telmisartan/enalapril group was 14 ± 2.98/9.71 ± 4.23 mmHg, respectively, at 12 weeks. When the reduction in systolic BP in the two groups was compared, there was no significant difference between the groups (Telmisartan produces a greater reduction in diastolic BP than enalapril and is free from the adverse-effect of dry cough that is commonly encountered with enalapril. Hypertension is a “life time” condition and, if left untreated, leads to lethal complications. The rennin–angiotensin system plays an important role in the regulation of normal blood pressure (BP) and also in the pathogenesis and maintenance of essential hypertension.Currently, two classes of drugs that attenuate the action of angiotensin II and act as antihypertensive agents by different mechanisms are available, which include angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). ACE inhibitors act by reducing the biosynthesis of angiotensin II by blocking the action of ACE on angiotensin I but do not inhibit the alternative non-ACE angiotensin II generating pathways whereas ARBs block the AT1 receptor-mediated actions of angiotensin II without inhibiting the synthesis of angiotensin II. Taking into consideration the alternative pathways of angiotensin II generation, ARBs reduce the activation of AT1 receptor more effectively than do ACE inhibitors.[The current place of ARBs in the treatment of essential hypertension is as an alternative to ACE inhibitors in patients who do not tolerate them due to adverse-effects.But, there is constant debate over the comparative efficacy of ACE inhibitors and ARBs due to the additional advantages of ARBs over ACE inhibitors.Hence, this study was undertaken to evaluate whether the above-mentioned theoretical benefits actually translate into clinically observable benefits in patients of mild to moderate essential hypertension.The ACE inhibitor, enalapril, and ARB, telmisartan, were used in the present study.The study was conducted in the Out-Patient Department of Medicine, Government Medical College, Miraj, after the approval of the Institutional Ethics Committee. This was a prospective, open, randomized, comparative, controlled clinical trial.A total of 80 patients were enrolled in the study as per the selection criteria. Patients with mild to moderate essential hypertension of either sex within the age group of 18–65 years were included in the study. They were either newly diagnosed patients or were those who had discontinued antihypertensive medication voluntarily for more than 4 weeks.The following categories of patients were excluded from the study: patients on other antihypertensive therapy, patients of secondary hypertension, patients with impaired liver function defined as SGOT or SGPT >2 times the normal limit, patients with impaired kidney function confirmed by serum creatinine >2 mg/dl, pregnant and lactating females, patients with history suggestive of obstructive biliary disease, cholestasis or severe hepatic impairment and female patients of the child-bearing age group not using medically approved contraceptives.The patients were enrolled after informed and written consent as per the inclusion and exclusion criteria. Current medical history and diagnosis were noted during the first visit. Patients were randomly assigned to receive either telmisartan or enalapril, with 40 patients in each group.Group A patients received 40 mg of telmisartan once a day orally for 12 weeks while group B patients received 10 mg of enalapril once a day orally for 12 weeks.After enrollment into the study, follow-up was performed after 2 weeks, 4 weeks, 8 weeks and 12 weeks. At each visit, complete clinical examination was carried out, including a recording of systolic and diastolic blood pressure (BP) of each patient using a mercury sphygmomanometer by the auscultation method. The BP was recorded in a sitting position after 10 min of rest. The pressure at which the sounds were first heard was taken as the systolic pressure and the pressure at which the sounds disappeared was taken as the diastolic pressure.The heart rate was also measured at each visit. Investigations such as hemogram , serum creatinine, SGOT, SGPT, random blood sugar and urine examination were performed during the first visit and after 12 weeks of the study period.The primary efficacy end point was the change from baseline sitting diastolic BP. Other end points included change from baseline in systolic BP. Patients who did not complete the full 12 weeks of therapy as per the study regulations were not included for statistical analysis. Safety was assessed in terms of both subjective and objective systemic adverse-effects. Subjective symptoms such as headache, dizziness, fatigue, back pain, dyspepsia, myalgia, pruritus, nausea and dry cough were assessed by questioning the patient at each visit. Objective signs like rash and hypotension were obtained and biochemical examination was carried out.P-value <0.05 was taken as significant and P-value <0.001 was taken as highly significant, while P >0.05 was considered as insignificant.Qualitative data on adverse-effects were analyzed by using the Z-test for difference between proportions. Quantitative data were analyzed by using the Z-test for difference between means. A Baseline clinical characteristics of patients receiving telmisartan and enalapril were compared. The two groups were similar and comparable as regards systolic BP, diastolic BP and heart rate before treatment.P < 0.001) at 2 weeks, 4 weeks, 8 weeks and 12 weeks of therapy when compared with the baseline readings.In the telmisartan-treated group, the mean systolic BP prior to treatment was 154.72 ± 12.52 mmHg. After treatment, the systolic BP reduced to 143.16 ± 10.33 mmHg, 138.94 ± 9.47 mmHg, 133.61 ± 8.29 mmHg and 128.33 ± 7.50 mmHg at 2 weeks, 4 weeks, 8 weeks and 12, weeks respectively. The reduction in systolic BP was found to be statistically significant (P < 0.001) at 2 weeks, 4 weeks, 8 weeks and 12 weeks of therapy when compared with the baseline readings.The mean diastolic BP before telmisartan treatment was 98.22 ± 3.78 mmHg. After treatment, the diastolic BP reduced to 90.05 ± 1.47 mmHg, 88.94 ± 2.36 mmHg, 86.44 ± 3.61 mmHg and 84.22 ± 3.78 mmHg at 2 weeks, 4 weeks, 8 weeks and 12 weeks, respectively. The reduction in diastolic BP was found to be statistically significant (P < 0.001) at 2 weeks, 4 weeks, 8 weeks and 12 weeks of therapy when compared with the baseline readings.In the enalapril-treated group, the mean systolic BP prior to treatment was 156.05 ± 10.56 mmHg. After treatment, the systolic BP reduced to 141.6 ± 17.94 mmHg, 139.82 ± 9.37 mmHg, 133.77 ± 8.53 mmHg and 129.31 ± 7.32 mmHg at 2 weeks, 4 weeks, 8 weeks and 12 weeks, respectively. The reduction in the mean systolic BP was found to be statistically significant (P < 0.001) at 2 weeks, 4 weeks, 8 weeks and 12 weeks of therapy when compared with the baseline readings.The mean diastolic BP before enalapril treatment was 98.34 ± 4.45 mmHg. After treatment, the diastolic BP reduced to 90.62 ± 1.66 mmHg, 89.77 ± 1.26 mmHg, 89.37 ± 2.04 mmHg and 88.63 ± 1.35 mmHg at 2 weeks, 4 weeks, 8 weeks and 12 weeks, respectively. The reduction in the diastolic BP with enalapril was found to be statistically significant (P > 0.05).The mean reduction in systolic BP in the telmisartan/enalapril group was 11.56 ± 6.39/14.45 ± 19.88 mmHg, 15.77 ± 8.65/16.22 ± 6.63 mmHg, 21.11 ± 8.53/22.28 ± 7.39 mmHg and 26.38 ± 10.98/26.74 ± 8.24 mmHg, respectively, at 2 weeks, 4 weeks, 8 weeks and 12 weeks. When the reduction in systolic BP in the two groups was compared, there was no significant difference between the groups (P > 0.05).The mean reductions in diastolic BP in the telmisartan/enalapril group were 8.16 ± 3.32/7.71 ± 3.91 mmHg and 9.27 ± 3.73/8.57 ± 3.93 mmHg, respectively, at 2 weeks and 4 weeks. When the values were compared in both the treatment groups, the difference was not statistically significant (P < 0.001) than that achieved with enalapril at the corresponding period.The mean reductions in diastolic BP in the telmisartan/enalapril groups at 8 weeks and 12 weeks were 11.78 ± 3.34/8.97 ± 3.8 mmHg and 14 ± 2.98/9.71 ± 4.23 mmHg, respectively. The mean reduction in diastolic BP achieved with telmisartan at 8 weeks and 12 weeks was significantly higher (P > 0.05). In the enalapril-treated group, the incidence of dry cough was 11.43% while it was 0% in the telmisartan-treated group. When both the groups were compared, the incidence of dry cough was significantly higher in the enalapril group as compared with the telmisartan group (P < 0.05).The safety analysis was performed on all patients who completed the study. A total of 8.33% of the patients reported some sort of adverse-effects like fatigue (2.77%), headache (2.77%) and dizziness (2.77%) in the telmisartan group whereas this figure was 22.85% in the enalapril group, with noted adverse-effects like fatigue (2.85%), headache (2.85%), dizziness (2.85%), nausea (2.85%) and dry cough (11.43%). However, this difference in the frequency of adverse-effects between the groups was not statistically significant  and an insurmountable antagonism at angiotensin II receptors. Once-daily telmisartan has been reported to attenuate angiotensin II-induced increases in the diastolic and systolic BP and it is said to have a rapid antihypertensive effect within 3 h of administration of a single oral dose, and BP control is reported to be sustained throughout the 24-h dosage interval, including the last 6 h of the dosage interval.[2 blockers temporarily as and when required, whereas this figure was 20% for the enalapril group. These patients were included because treatment of hypertension is life-long and patients often need these drugs temporarily.The two groups were comparable to each other in terms of age, weight and baseline characteristics such as sex ratio, smoking and alcohol habits. 22.5% of the patients in the telmisartan group had received other medications like non-steroidal anti-inflammatory drugs  antibiotics and HIn the present study, 32.5% of the patients of the telmisartan group and 37.5% of the patients of the enalapril group were previously on antihypertensive therapy. They had discontinued therapy voluntarily due to economic constraints or other reasons for 4 weeks or more before enrollment into the study. The period of 4 weeks was sufficient to washout the effect of any previous antihypertensive drug.nd, 4th, 8th and 12th week. When efficacy of telmisartan was compared with enalapril, we found that telmisartan was as effective as enalapril in reducing systolic BP [Thus, in the present study, we have observed that both telmisartan and enalapril are effective agents in reducing both systolic and diastolic BP throughout the study period when measured at the 2tolic BP , but teltolic BP .P < 0.05).This finding of our study is similar to that of another study in whichP = 0.02). In another comparative multicentric trial[P = 0.013; diastolic BP, P = 0.002).In a randomized, double-blind, double-dummy, parallel group study, telmisarric trial between This greater reduction in the mean diastolic BP associated with telmisartan might be due to the selective blockade of the angiotensin II AT1 receptor so that the actions of angiotensin II produced by the alternative pathway are also blocked. This does not happen with enalapril, which inhibits ACE but not the other non-ACE angiotensin II generating pathways.Secondly, telmisartan selectively blocks only the AT1 receptor and not the AT2 receptors and thus the actions of angiotensin II that are mediated through AT2 receptors are not blocked. AT2 receptor stimulation by angiotensin II causes vasodilatation via bradykinin, nitric oxide and c-GMP, causing natriuresis. Therefore, angiotensin II, by activating the AT2 receptor, produces vasodilatation and natriuresis, which may also contribute to the antihypertensive action of ARBs like telmisartan.Most ARBs decrease the systolic and diastolic BP significantly as compared to baseline values but most studies utilizing telmisartan have shown a favorable decrease in the diastolic BP over and above the ACE inhibitor. This might not be a class effect of ARBs as some studies utilizing other ARBs like losartan and valsartan have not shown such effects. The charBoth telmisartan and enalapril did not produce any adverse impact on various parameters like hemoglobin, TLC, serum creatinine, SGOT, SGPT and random blood sugar. This again indicates a good safety profile of telmisartan.Thus, it can be concluded that telmisartan is as effective as enalapril in reducing systolic BP but produces a greater reduction in diastolic BP than enalapril and is free from the adverse-effect of dry cough, which is commonly encountered with enalapril.Thus, because of its efficacy throughout 24 h and because of a better tolerability, telmisartan could be preferred as a first-line drug among the ARBs for the treatment of mild to moderate essential hypertension.One of the striking differences between previous studies comparing ACE inhibitors and ARBs and the present study is the significantly greater reduction in diastolic BP with telmisartan as compared with enalapril. However, there is strong evidence that systolic BP is a better predictor of cardiovascular events among elderly as compared with diastolic BP. The role


Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives  in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined . Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.Clinicaltrials.gov NCT00605072 In addition to its role in developing cardiovascular disease and stroke, hypertension is also a risk factor for cognitive impairment -5 Althou2, a measure of brain endothelial function[The process by which hypertension can affect cognitive and executive function is not clear. It is likely to be, in part, related to the cerebral blood flow (CBF) regulatory system. This is supported by the evidence that lower CBF measured by Transcranial Doppler (TCD) is associated with progressive decline in cognitive function For exam function Taken toFrom a neuro-humoral standpoint, multiple systems may be involved in the relation between hypertension and cognitive function. However, a paucity of evidence point to the renin angiotensin system (RAS). Anatomically, angiotensin II (Ang II) and its receptors are located in neurons inside the blood brain barrier and in the cerebrovascular endothelial cells and circumventricular organs Function2[Ang II impairs endothelial function, which has been linked to poor cognitive function and early Alzheimer's disease -33 The r2 Ang II p2-32,40 ThMultiple observational and experimental studies, although not universally consistent, have shown that use of antihypertensives may provide cognitive protection in the elderly population However,Drugs that inhibit RAS include angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). ACEI block ACE and decrease Ang II production, whereas ARB block the angiotensin receptor type 1 but not type 2,44 ACEI In addition to their effect on cognitive function, animal and human studies have suggested that both ACEI and ARB are associated with improved cerebral hemodynamics,57 In spOf the two classes, recent studies have shown that ARB may be superior to ACEI or diuretics in providing neuro-protection and improving vascular function,64,68 BoOur objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives ) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory decline.The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals with hypertension and early cognitive impairment are being recruited from the greater Boston area. Evaluated at the cardiovascular research laboratory at the Institute for Aging Research, and then randomized to candesartan, lisinopril, or HCTZ ("active control") for 12 months. Currently recruitment efforts include various community activities, faith-based community events, health fairs, advertisements, and mail out announcements. Figure (1) 60 years or older; (2) hypertension: defined as a systolic blood pressure (SBP) of 140 mm Hg or greater or diastolic blood pressure (DBP) 90 mm Hg or greater or receiving antihypertensive medications; (3) early cognitive impairment without dementia defined as executive impairment (measured by the executive clock draw test (CLOX))  or early(1) Intolerance to 2 of the study medications; (2) SBP >200/DBP >110 mm Hg if not on treatment or SBP > 180/DBP > 100 mm Hg if on antihypertensive therapy; (3) Mini-Mental-Status-exam (MMSE)<20 or a clinical diagnosis of dementia or Alzheimer's disease; (4) elevated serum creatinine or serum potassium at baseline; (5) receiving >2 antihypertensives; (6) Comorbid illnesses ; and (7) inability to perform the study procedures.Individuals who are currently receiving 1 or 2 antihypertensives are eligible to participate if the participant and the primary care provider are willing to taper their antihypertensives. The medication is tapered while carefully monitoring blood pressure using a standard protocol in our laboratory .The intervention is treatment with lisinopril, candesartan, or HCTZ. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. The starting dose is 10 mg increased to 20 mg then 40 mg of lisinopril; 8 mg increased to 16 mg then 32 mg of candesartan; and 12.5 mg increased to 25 mg of HCTZ. Titration occurs every 2 weeks until blood pressure is <140/90 mm Hg. If blood pressure is still not controlled, long acting nifedipine is added at 30 mg increased to 60 mg and 90 mg in 2 week increments. If still not controlled, a beta-blocker is added at 12.5 mg increased to 25 mg and 50 mg of long-acting metoprolol.The randomization is performed using computer generated random numbers leading to a random allocation sequence. This random allocation is performed at the central pharmacy at Hebrew SeniorLife. Both study personnel and participants are blinded to the group assignment.The following are the study phases:(i) Screen: This includes: (1) informed consent, (2) 2 seated blood pressure measurements separated by 5 minutes, (3) executive function and memory assessments, and (4) inclusion/exclusion criteria assessment. Eligible participants are scheduled for the Baseline visit. If they are receiving antihypertensives, they are also given the automated blood pressure measurement machine. Instructions on using the machine, tapering the antihypertensives, frequency of measurements, a diary, and appropriate phone numbers are provided.(ii) Baseline evaluation and randomization: during this visit, participants undergo blood pressure measurements, cognitive assessments, physical measures, and TCD procedures. Randomization to one of the 3 antihypertensive medications occurs after the baseline visit.(iii) Follow up: Participants are then seen every 2 weeks until blood pressure control (<140/90 mm Hg) is achieved. During these visits, blood pressure measurements, medication adjustments and assessments of potential adverse events are completed. Participants are then followed for 12 months after achieving target blood pressure (<140/90 mm Hg) and evaluated at 1, 3, 6, and 12 months. At each evaluation, blood pressure, adverse events, pill count (to assess compliance), use of other medications is assessed, and blood samples are drawn as outlined in Table (i) Health Interview and exam: Demographics, social history and habits, family history, medication inventory, physica(ii) Neuropsychological assessment: The battery of tests we chose for both screening and for the outcome measures was selected with the following considerations: brevity, validation in a similar elderly population, and sensitivity to detect impairment change over the study period.The screening tests include: the executive clock draw test part 1 (CLOX1) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) immediate memory domain. We selected the CLOX1 as a screening tool to detect those with executive function abnormalities. The subject draws a clock in response to the examiner's request. CLOX1 is sensitive to detect executive function It has hselected this test because it is sensitive to detect frontal lobe pathology in patients with increased cerebrovascular and cardiovascular risk such as those with hypertension[selected this test since it can detect abnormalities with encoding.The study outcome cognitive tests include Trail Making test (A and B), Hopkins Verbal Learning Test - Revised (HVLT-R), and the Digit Span Test. The Trail Making test requires the connection of sequentially numbered circles (A), and the connection of circles marked by numbers and letters in an alternating sequence (B). This test is considered a benchmark of executive function. We ertension,10 The Hertension We selecertension It consiertension We selec2 [2 is used to assess CO2 vasoreactivity [(iii) Cerebral Blood Flow and its regulation: CBF autoregulation and cerebral vasoreactivity are assessed by TCD using standard procedures described previously Blood fl2  followedactivity .(iv) Biochemical measurement is done to monitor for adverse events: hyperkalemia and renal failure. RAS activity is assessed using plasma renin activity and aldosterone levels Plasma a: We are screening for potential adverse events through self-report by the participant or the next of kin. These include: dizziness, vertigo, light-headedness, weakness, swollen lip or tongue or both, hospitalizations, cough, falls, angioedema, renal insufficiency, and hyperkalemia with ACEI and ARB. Hypokalemia may occur with HCTZ (potassium will be supplemented). The incidence of cough with ACEI varies but 5% is the most commonly reported rate [(v) Adverse events (AE)ted rate . Angioedted rate . Screeniintention-to-treat principle. We will use Mixed Models since we have correlated repeat observations and this procedure is not significantly affected by missing data[primary independent variable is group assignment . A sample size of 100 will allow us to successfully complete at least 90  participants. A 30 per group  allows us to detect at least between group differences in the change (from baseline to 12 months) of 0.46 standard deviation units . Figure All analyses will follow the sing data,95 We wiAging of the population will lead to increase prevalence of hypertension and cognitive difficulties. To date, there are no available data to provide guidelines for treatment of hypertension in those with cognitive impairment. The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that have not reached the threshold of dementia. Observational studies have been conflicting and some suggest that treatment of hypertension may have a negative effect on cognitive function -98. TherThe role of the RAS in aging is important because of the available therapeutic intervention for this system. Recently, RAS is a critical system in vascular biology and recently in neuroscience. Identifying an impact of ACEI or ARB on cognitive or cerebrovascular function will provide additional mechanistic and therapeutic evidence of the role of RAS in aging.The authors declare that they have no competing interests.IH, LL and WM were involved in developing the basic idea for the study. VN was further involved in developing the idea and the transcranial Doppler and antihypertensive taper protocols. IH and MH are responsible for the data collection. All authors contributed to the final manuscript by reading and correcting draft versions.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/9/48/prepub


Walking and cardiovascular mortality are inversely associated in type 2 diabetes, but few studies have objectively measured associations of walking with individual cardiovascular risk factors. Such information would be useful for “dosing” daily steps in clinical practice. This study aimed to quantify decrements in blood pressure and glycated hemoglobin (A1C) per 1,000 daily step increments.2 respectively. A 1,000 daily step increment among women was associated with a −2.6 (95% CI: −4.1 to −1.1) mm Hg change in systolic and a −1.4 (95% CI: −2.2 to −0.6) mm Hg change in diastolic blood pressure. Among men, corresponding changes were −0.7 (95% CI: −2.1 to 0.7) and −0.6 (95% CI: −1.4 to 0.3) mm Hg, respectively. Sex differences were confirmed in combined models. Step counts and A1C did not demonstrate clinically important associations.Two hundred and one subjects with type 2 diabetes underwent assessments of step counts (pedometer-measured), blood pressure, A1C and anthropometric parameters. Due to missing data, the final analysis was conducted on 83 women and 102 men, with a mean age of 60 years. Associations of daily steps with blood pressure and A1C were evaluated using sex-specific multivariate linear regression models . Potential sex differences were confirmed in a combined model (women and men) with interaction terms. Mean values for daily steps, blood pressure, A1C and BMI were 5,357 steps/day; 137/80 mm Hg; 7.7% and 30.4 kg/mA 1,000 steps/day increment is associated with important blood pressure decrements among women with type 2 diabetes but the data were inconclusive among men. Targeted “dose increments” of 1,000 steps/day in women may lead to measurable blood pressure reductions. This information may be of potential use in the titration or “dosing” of daily steps. No associations were found between step count increments and A1C. Physical activity is associated with lower rates of all-cause mortality in the general population In healthy adults aged 26–80 years, lower levels of pedometer or accelerometer-based categories of physical activity have been shown to be associated with a higher odds or prevalence of adverse cardio-metabolic risk factors Well-designed observational studies evaluating the associations of objectively measured walking with individual cardiovascular risk factors are an important preliminary stage in determining whether walking is of measurable benefit in an already-treated population with type 2 diabetes. By providing estimates of step-related improvements in individual cardiovascular risk factors, this information can be used to facilitate the development of “walking prescriptions”. The availability of step counters or pedometers for real-time measurement of walking makes this strategy both practical and economically feasible. A widely used classification scheme for daily step counts initially proposed by Tudor-Locke and Bassett Specifically, the present study aims to quantify the changes in systolic blood pressure, diastolic blood pressure, and A1C associated with each 1,000 daily step increment among women and men with type 2 diabetes. At a moderate walking pace, 1,000 steps per day may be achieved in approximately ten minutes; thus a 1,000 steps/day increment arguably represents a feasible “dose increase in daily steps,” keeping an eye to eventual clinical application Data for the present study were derived from a cohort study designed to assess for seasonal differences in step counts and A1C. Data collection procedures for our cohort have been detailed previously but are summarized here 2Two hundred and one adults followed for type 2 diabetes were recruited through McGill University affiliated outpatient clinics between June 2006 and June 2008 . To ensure the accuracy of the pedometer measurements, participants were required to have a normal gait and a BMI ≤40 kg/mDemographic information  and a detailed medical history (including duration of diabetes and current medication use) were obtained via questionnaire and interview at each study centre visit. Data were collected on cardiovascular risk factors, physical activity including daily steps, anthropometric parameters and dietary information, as outlined below. All assessments were performed at our study centre at the McGill University Health Centre . For the purpose of our analyses, ‘smokers’ included persons who quit smoking less than a year prior to entry into the study.Blood pressure measurements were taken in the left arm using an appropriate-sized cuff (Omron HEM 747 IC blood pressure monitor) after a 15 minute rest period. A1C was measured from blood samples collected at each visit using high-pressure liquid chromatography.Daily step counts were measured using Yamax SW-200 pedometers. The accuracy and reliability of this device has been previously demonstrated Weight and height were assessed to the nearest tenth of a kilogram  and tenth of a centimeter (SECA 214 stadiometer) respectively, with the subject wearing light clothing and with shoes removed. Waist circumference was measured midway between the iliac crest and the lower rib margin. Hip circumference was measured at the point of greatest posterior extension of the buttocks. The waist-to-hip ratio was calculated by dividing the waist circumference by the hip circumference. BMI was calculated by dividing the weight in kilograms by the square of the height in meters. The Quebec Food Frequency Questionnaire (FFQ), previously validated in a sample of adults in the Montreal region, was used to gather dietary information Procedures were approved by the Institutional Review Boards (IRB) of McGill University and participating institutions . All study participants provided written informed consent prior to the clinical assessments.Participants were classified by daily step quartiles based on their first visit data . CharactMultivariate linear regression was applied to these data to evaluate the associations of daily steps with systolic and diastolic blood pressure and A1C in separate models with adjustment for potential confounders. Each model was constructed separately for women and men. Models combining data from women and men were also examined, with an interaction term between sex and daily steps, to verify sex differences suggested by sex-specific models. Residual plots of the most representative models were examined to verify that the assumptions of linear regression were met. We examined potential confounders by comparing the beta-coefficients of the determinant variable of interest across models containing various combinations of potential confounding variables. Covariates having the strongest impact on this beta-coefficient were identified as statistically important confounders and retained in the final model. These analyses were conducted using the R statistical package, version 2.8.0 .Although our primary analysis was based on study participants' first visit data, each participant had up to four data points over the course of the year. We used a two-level hierarchical modeling on these data to examine within-individual associations of blood pressure (systolic and diastolic) and A1C with daily steps. The first level of this model included linear regression models of each outcome within each subject over time. At the second level of these models, the slopes from the first models were regressed against potential predictors. Previous analyses of our data demonstrated that habitual walking patterns differ by season It was determined that a sample size of 160 would allow us to examine up to 8 variables in a given model with reasonable accuracy 2) and applying the classification scheme developed by Tudor-Locke and Bassett, 44% were ‘sedentary’, 32% were ‘low-active’, 20% were ‘somewhat active’, 4% were ‘active’ and no study participant was ‘highly active’ Two hundred and one individuals  completed a first assessment. Thirteen participants were excluded because of missing A1C, blood pressure readings or pedometer data. The analyses presented were conducted on 188 participants  for whom the data were complete. First visit assessments were conducted throughout the year . Women comprised 46% of the cohort. The mean age of the population was 60.3 years, their average duration of diabetes was 9.6 years, and 68% of the cohort was Caucasian. Approximately 23% had stable cardiovascular disease with a four-fold higher prevalence among the men compared with the women (30% versus 8%). Participants were obese ) change in systolic blood pressure . The datOur analyses suggest that habitual walking decreases blood pressure among persons with type 2 diabetes. A 1,000 daily step increment was associated with as much as a 2.5 mm Hg lower systolic and a 1.4 mm Hg lower diastolic blood pressure among women treated for type 2 diabetes. In a longitudinal “within-individual” analysis, a 1,000 daily step increment was associated with a 1.4 mm Hg lower systolic blood pressure among women . Daily steps were not as strongly associated with blood pressure in the men. Finally, our analyses did not demonstrate a clinically important association between daily steps and A1C in either women or men treated for type 2 diabetes. Clearly, further study is required to confirm these preliminary findings and to verify thresholds of benefit. Nonetheless, our findings indicate that daily step dose increments of 1,000 steps/day could lead to clinically important blood pressure decrements in women with type 2 diabetes.Pedometer-based intervention trials in type 2 diabetes have achieved increases in daily step counts The stronger association of physical activity with blood pressure among the women in this study is consistent with other data showing greater physical activity-associated reductions in blood pressure among women compared with men Our analyses also demonstrated a stronger association between blood pressure and daily steps in the fall and winter compared with the spring and summer in women with type 2 diabetes, in the within-individual analyses. On average, the blood pressure was higher and exercise levels lower in the fall-winter seasons than the spring-summer months. This observed seasonal difference may therefore be reflecting a greater sensitivity of higher blood pressures to daily steps, or a threshold effect, such that an increase in daily step counts may have greater benefits at the lower levels of activity in the fall and winter months.Our findings support the need for a large pedometer-based intervention trial that examines the impact of 1,000 daily step increments on blood pressure in type 2 diabetes. Furthermore, since our study population is restricted to patients with diabetes being treated at tertiary care facilities, future studies in a less selected population may have greater generalisability. While our findings indicate a stronger association of step counts and blood pressure in women with type 2 diabetes, a larger study may have confirmed an association in men, albeit likely with a “dose” greater than 1,000 steps/day. We acknowledge that step counts may include not only walking but all step-related physical activity such as dancing or stair-climbing, although walking is the most frequent type of physical activity reported by diabetes patients.Our study is limited by its cross-sectional nature, and as such the associations described cannot be assumed to be causal. Furthermore, we acknowledge the potential for walking pace and the intensity of walking to impact the cardiovascular risk factors evaluated. Randomized control studies employing strategies to account for the pace of walking are needed to confirm these associations and to define dose-response thresholds of benefit in populations for which its use is intended. Community-based studies should also be performed to validate the efficacy of pedometer-based “walking prescriptions”.Despite these limitations, we believe that our findings are a critical first step in establishing dose-response curves for step counts with blood pressure in patients treated for diabetes and could facilitate the development of individual exercise prescriptions that provide patients with more tangible goals for physical activity. Given the economic feasibility and acceptability of walking in sedentary populations, a prescription of daily steps may prove to be an effective and accepted therapeutic intervention for improving control of cardiovascular risk factors such as blood pressure.


Monitoring of cardiac output and blood pressure are standard procedures in critical care medicine. Traditionally, invasive techniques like pulmonary artery catheter (PAC) and arterial catheters are widely used. Invasiveness bears many risks of deleterious complications. Therefore, a noninvasive reliable cardiac output (CO) and blood pressure monitoring system could improve the safety of cardiac monitoring. The aim of the present study was to compare a noninvasive versus a standard invasive cardiovascular monitoring system.Nexfin HD is a continuous noninvasive blood pressure and cardiac output monitor system and is based on the development of the pulsatile unloading of the finger arterial walls using an inflatable finger cuff. During continuous BP measurement CO is calculated. We included 10 patients with standard invasive cardiac monitoring system  comparing invasively obtained data to the data collected noninvasively using the Nexfin HD.2 = 0.67 with a bias of -2 mmHg and two standard deviations of ± 16 mmHg. Correlation between CO derived from PAC and the Nexfin HD was r2 = 0.83 with a bias of 0.23 l/min and two standard deviations of ± 2.1 l/min; the percentage error was 29%.Correlation between mean arterial pressure measured with the standard arterial monitoring system and the Nexfin HD was rAlthough the noninvasive CO measurement appears promising, the noninvasive blood pressure assessment is clearly less reliable than the invasively measured blood pressure. Therefore, according to the present data application of the Nexfin HD monitoring system in the ICU cannot be recommended generally. Whether such a tool might be reliable in certain critically ill patients remains to be determined. Cardiovascular monitoring is a standard procedure in critical care medicine. Traditionally invasive techniques like pulmonary artery catheter (PAC) and peripheral artery catheters are widely used -3. A furFollowing approval by the local Ethics Committee which waived the need for written informed consent for this retrospective data analysis, patient data from a total of 10 patients treated on our intensive care unit in 2007 were analyzed.The method of the Nexfin HD  is based on the development of the pulsatile unloading of the finger arterial walls using an inflatable finger cuff with a built-in photoelectric plethysmograph. While continuously measuring BP the monitor calculates CO. The method is described in detail by de Wilde and colleagues . The monData of ten critically ill patients in need of cardiovascular monitoring with PAC  and invasive blood pressure measurement  in which the Nexfin HD was additionally used during the stay in the ICU were collected. Hourly Nexfin HD measurements obtained during an 8 hour period were compared to arterial blood pressure values and CO, respectively. A total of 80 data points for blood pressure and CO were included.Apart from PAC monitoring which was used in a standardized fashion -3, the NThe results between the 2 methods were analyzed statistically using correlation and linear regression analysis, including calculation of bias and precision   as well A total of ten critically ill patients monitored with PAC, standard invasive arterial blood pressure monitoring and Nexfin HD were included in this study. Arrhythmias were not present during the recording periods. Four patients were lung transplant recipients, 4 patients were liver transplant recipients and 2 suffered from severe ARDS.Mean age of the patients was 54 ± 12 years, average weight was 74 ± 17 kg, average height was 168 ± 15 cm, average mean arterial pressure (MAP) was 77 ± 13 mmHg, mean heart rate was 98 ± 18 bpm; four of the 10 patients were males.All patients required norepinephrine as a vasoconstrictor agent for hemodynamic stability. Mean norepinephrine dose during data assessment was 12 ± 12 μg/min (range 2-29 μg/min). Mean SAPS II score was 36 ± 17 and the ICU mortality was 3/10 (30%).2 = 0.67. Average MAP derived invasively was 80 ± 12 mmHg with a bias of -2 mmHg and 2 standard deviations of ± 16 mmHg.Correlation, regression analysis and the Bland-Altman analysis are shown in Figure 2 = 0.83. Mean CO determined by PAC was 7.2 ± 2.3 l/min with a bias of 0.23 l/min, two standard deviations of ± 2.1 l/min and the percentage error was 29%.Correlation, regression analysis and the Bland-Altman analysis are shown in Figure The present study revealed that the noninvasive Nexfin HD system cannot substitute standard invasive blood pressure measurement while CO monitoring appears more reliable in the presently investigated group of ten critically ill patients.2 = 0.67). This is in contrast to the results reported by Schattenkerk et al, who described a good correlation between the Nexfin HD and blood pressure measurements determined by the Riva-Rocchi/Korotkoff technique (RRK) [The mean difference in MAP between the 2 methods was 2 ± 8 mmHg (2 SD were ± 16 mmHg and rue (RRK) . MethodoA possible explanation for the observed difference between the 2 systems might be diminished arterial perfusion in the fingers of our subjects. However, based on the fact that for the same norepinephrine concentration noninvasive blood pressure was higher compared to the invasive blood pressure in approximately 50% of the investigated patients it appears that the finger plethysmography was not to associated with impaired perfusion.Clinical and therapeutic decision making is weakened by the calculated standard deviation of ± 8 mmHg for the MAP determined by the Nexfin HD device. I.e., for a MAP 65 mmHg, the defined blood pressure target in septic patients , we mustTherefore, our comparison of blood pressure measurement indicates that the noninvasive technique cannot properly replace an invasive system.CO determined non-invasively using the Nexfin HD device was within the recommended limits of agreement, suggesting a fair to good accuracy. However, CO measurement- although very interesting in critically ill patients - does not have the same importance within the therapy of critically ill patients as the MAP. Contrary to MAP CO is not a target value within the early goal directed therapy (EGDT) for septic patients . Thus, aGiven the small sample size the results must be interpreted very carefully. Interestingly, the original work of Bland and Altman which describes the statistical method used in this paper  was baseImportantly, there were no clinical signs of disturbed microcirculation of the fingers in these patients (discolored and cold fingers) during application of the finger cuff, indicating a safe use of the Nexfin HD system. The noninvasiveness of this technique allows to avoid potential complications related to the invasive nature of the other techniques.Furthermore, this new finger plethysmography system is very easy to use and quickly to install within minutes and therefore could offer a quick and initial hemodynamic overview, possibly providing important information on trend of MAP and CO. This would allow to bridge the time until a longer lasting invasive monitoring can be installed in the case of a deteriorating patient.Although CO measurement seems promising, noninvasive blood pressure assessed by the Nexfin HD device is clearly less reliable than invasive blood pressure measurement. Therefore, according to our data application of the Nexfin HD monitoring system cannot generally be recommended for the ICU. Whether such a tool is reliable in certain groups of critically ill patients has yet to be determined.The authors declare that they have no competing interests.JFS and MB designed the study, performed statistical analysis and drafted parts of the manuscript. RS and SRC collected data and drafted parts of the manuscript. RL and BZ collected the data. TAN assisted in statistical analysis and performed graphs. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Controlling blood pressure with drugs is a key aspect of cardiovascular disease prevention, but until recently has been the sole preserve of health professionals. Self-management of hypertension is an under researched area in which potential benefits for both patients and professionals are great.The telemonitoring and self-management in hypertension trial (TASMINH2) will be a primary care based randomised controlled trial with embedded economic and qualitative analyses in order to evaluate the costs and effects of increasing patient involvement in blood pressure management, specifically with respect to home monitoring and self titration of antihypertensive medication compared to usual care. Provision of remote monitoring results to participating practices will ensure that practice staff are able to engage with self management and provide assistance where required. 478 patients will be recruited from general practices in the West Midlands, which is sufficient to detect clinically significant differences in systolic blood pressure between self-management and usual care of 5 mmHg with 90% power. Patients will be excluded if they demonstrate an inability to self monitor, their blood pressure is below 140/90 or above 200/100, they are on three or more antihypertensive medications, have a terminal disease or their blood pressure is not managed by their general practitioner.The primary end point is change in mean systolic blood pressure (mmHg) between baseline and each follow up point (6 months and 12 months). Secondary outcomes will include change in mean diastolic blood pressure, costs, adverse events, health behaviours, illness perceptions, beliefs about medication, medication compliance and anxiety. Modelling will evaluate the impact of costs and effects on a system wide basis. The qualitative analysis will draw upon the views of users, informal carers and professionals regarding the acceptability of self-management and prerequisites for future widespread implementation should the trial show this approach to be efficacious.The TASMINH2 trial will provide important new evidence regarding the costs and effects of self monitoring with telemonitoring in a representative primary care hypertensive population.ISRCTN17585681 National and international surveys have found that despite some recent improvements, the blood pressure of many people with hypertension remains poorly controlled. ,2 This iThere are many potential reasons for sub-optimal blood pressure control. Hypertension is largely asymptomatic with little biological feedback to patients in terms of blood pressure control. Treatment is generally life long and may be associated with dose related side effects. It is therefore perhaps not surprising that adherence to antihypertensive medication is often poor with around half of hypertensive patients discontinuing new prescriptions for antihypertensive drugs in the first six months.It is not simply a question of motivating patients. Research in UK general practice has shown a lack of professional action in the presence of high recorded blood pressures along with a reluctance to prescribe for isolated systolic hypertension. Fear of There is good evidence for both pharmacological and non-pharmacological interventions. The adveFour previous randomised studies have evaluated the efficacy of telemonitoring in conjunction with self-monitoring of hypertension and other interventions but none have been adequately powered, followed up for more than six months, or set in the UK. -14 Does self-management with telemonitoring and titration of antihypertensive medication by people with poorly controlled hypertension result in better control of blood pressure?2) Is self-management with telemonitoring and titration of antihypertensive medication by people with poorly controlled hypertension cost effective?3) Is self-management with telemonitoring and titration of antihypertensive medication achievable in routine practice and is it acceptable to patients?4) What are the views and experiences of patients, informal carers and healthcare professionals of self-management with telemonitoring and titration of antihypertensive medication?The primary outcome of the trial will be the change in mean systolic blood pressure (mmHg) between baseline and each follow up point (6 months and 12 months), measured in the surgery by the research team. Additional secondary outcomes will include change in mean diastolic blood pressure, adverse events , health behaviours, illness perceptions, beliefs about medication, medication compliance, patient satisfaction, costs and reasons for non-participation as well as the qualitative analysis and health economic modelling beyond the trial outcomes.TASMINH2 is a primary care based, unblinded, randomised controlled trial with embedded economic and qualitative analyses in order to evaluate the costs and effects of increasing patient involvement in blood pressure management.Full ethical approval for this trial has been obtained from Sandwell and West Birmingham local ethics committee , whilst site specific ethical approval and R & D approval was obtained from the relevant local ethics committees and Primary Care Trusts. A trial steering group will monitor study progress.Usual care will consist of the participant seeing their General Practitioner (GP) (Family Physician) and/or nurse periodically for blood pressure measurement and/or adjustment of medication at the discretion of the GP.Self-management will consist of self-monitoring of blood pressure with electronic transmission of readings, and self titration of medication dependant on the self-monitoring readings.Participants will be trained to monitor their blood pressure using an automated electronic sphygmomanometer. Home readings will be transmitted to the research team via the telemonitoring system. Patients will self-monitor blood pressure daily for the first week of each month of the study. They will be provided with a guideline that contains simple colour coded instructions. Very high or very low readings will require checking by the participant's practice. Four or more above target readings in two consecutive months will require a change in medication. Below target readings will simply require further monitoring the following month.Target blood pressures will be based on the NICE hypertension guideline with adjustment of 10/5 mmHg as recommended by the British Hypertension Society to reflect home as compared to office readings. ,22 PeoplParticipants will be trained in the use of the telemonitoring equipment at baseline and home visits  will be available if required to set up equipment. The equipment consists of a standard validated automated electronic sphygmomanometer (Omron 705-IT) with a modem for telemonitoring (Melexis I-modem). Blood pressure data (including time and date) will be transferred to the research team from the memory of the electronic sphygmomanometer via an internet connection. Practices will receive summary data from the research team once each month, by report to allow incorporation into clinical records systems. In addition, blood pressure recordings will also be available to patients via a secure internet site which will summarise individual patient's monitoring results.Each participant will be given an individually tailored two step self management algorithm through which to adjust medication according to measured blood pressure. The choice of medication changes will be decided in conjunction with their own GP. Each step will represent a single medication change  that will be made following raised readings in two consecutive months. Medication choice will remain that of the GP who will be provided with a copy of the NICE hypertension management algorithm to aid choice of medication. If patients have used both steps of their self-management algorithm they will return to the GP and a new two step plan will be devised. As the study will last for 12 months, patients will not require any more than two such management plans. Any additional monitoring  will be the responsibility, and at the discretion, of the GP.Included with the letter of invitation to take part in the trial, will be a form for people to voluntarily return should they wish to decline the invitation. As well as asking for their reasons for wishing to decline, this form will also seek permission to send a further questionnaire and/or gain their permission for the research team to have access to their medical records. The further questionnaire will be similar to that which will be used in the research clinics/follow-up sessions with people enrolled in the study. Following-up those who decline to take part will provide useful information regarding the generalisability of the trial results, as well as providing a greater insight into the reasons why people may not wish to self-manage their hypertension.The study population will comprise of people with poorly controlled treated hypertension managed in primary care. Eligibility criteria will be age between 35–85, treated hypertension, and blood pressure greater than 140/90. Exclusion criteria will be inability to self-monitor , postural hypotension (systolic blood pressure drop >20 mmHg), more than two antihypertensive medications, terminal disease, and blood pressure not managed by their GP. . A memberParticipants who withdraw from the trial will not be replaced, but asked if they are prepared to continue to attend follow-up clinics. Analysis will be by intention to treat.Randomisation of patients with uncontrolled hypertension will be to either usual care or self-management of their hypertension and will take place centrally via telephone or internet using the process of minimisation taking into account practice, sex, diabetic/chronic kidney disease status, baseline blood pressure and age.At baseline all patients will attend a clinic at which the study will be explained, informed consent gained and questionnaires regarding demographics, past medical history, self-efficacy and attitudinal compliance will be completed Table . MeasureAll patients will be asked to attend two follow-up clinics; one at 6 months and one at 12 months. Each clinic will be timetabled for approximately half an hour, in which time patients will have their blood pressure measured by the research team using a validated automated electronic sphygmomanometer, and will be asked to complete a questionnaire similar to that completed at baseline. Additionally, the research team will check that patients in the intervention arm are using the blood pressure monitors correctly. This is shown in Figure A sample size of 191 people per group is required for 90% power assuming a standard deviation of 15 mmHg and a difference in reduction of blood pressure of at least 5 mmHg between intervention and control groups. A reduction of 5 mmHg systolic blood pressure is plausible in comparison with other studies of self-monitoring of blood pressure and should result in around 19% reduction in stroke risk. Clinic measurements are used as the primary end point as these are comparable to most treatment studies. Based on the drop out rate from the initial TASMINH self monitoring trial, and taking into account the additional requirements of this trial, a 20% drop out rate during follow-up is assumed, meaning that a sample size of 239 per group will need to be randomised, i.e., 478 people. We estimate that between 10–15 practices will be required i.e., 35–50 patients per practice.Analysis will be on an intention to treat basis for complete cases. A sensitivity analysis will examine the potential effect of missing data. This will include replacement of missing data by the most recent previous data or by the mean of the series. The principal analysis will be performed using both raw and adjusted data and will be performed at the end of the trial after all data has been collected. The primary analysis will be using general linear modelling (GLM) to compare intervention and control systolic blood pressure at follow-up adjusting for baseline blood pressure, practice (as a random effect), diabetic or CKD status and sex. Planned sub group analyses will be of diabetic vs non-diabetic patients, older vs younger (65 as threshold), males vs females, better controlled at baseline vs worse controlled at baseline (> vs < 155 mmHg systolic).The cost analysis will include all key resources associated with the self-management intervention and related health and social care services, and will adopt a broad perspective to include NHS, social care and patient costs. The implication of this being that we will measure the basic set-up and delivery costs of the self-management package, in addition to costs falling on other health and social care agencies and the research participants themselves. Health sector cost data  will be collected prospectively by routine practice computer systems and downloaded by the research team at the final follow up visit. Intervention costs, including equipment and training, will be collected by the research team. Patient costs and broader social care resource use will be collected using a modified version of a patient cost questionnaire used successfully by the researchers in other settings. Unit cost data will be ascertained for consultation and referral costs for PCT and system modelling. Drug costs will be extracted from a contemporaneous BNF.The economic analysis will involve use of cost-consequences analysis,  whereby A cost benefit analysis will be performed using willingness-to-pay data collected through a postal survey towards the end of the trial. These approaches will allow us to capture in a quantitative manner the broader non-health benefits of self-management.Purposive sampling will be used to choose patients (both intervention and control), informal carers and healthcare professionals (up to 20 of each) to allow a wide range of views and experiences of self-monitoring. This will be followed by seeking a further theoretical sample within each group with selection guided by emerging data analysis in order to extend and challenge earlier data and interpretation, and test the integrity and credibility of the developing analysis. This theData from patients and informal carers will be collected by confidential, face-to-face interview in patients' own homes, and from healthcare professionals in their GP practice using an interview topic prompt. PatientsAll interviews will be audio-taped and transcribed and entered into the NVivo software package for qualitative data analysis.Constant comparative analysis will be used to interpret the data. To maximThe results of this trial will be directly applicable to primary care in the UK. As only half of the approximately 12% of the adult population who are receiving treatment for hypertension are controlled to recognised targets, should self management of hypertension with telemonitoring be found to be a successful strategy, then it would be applicable to many hundreds of thousands of individuals in the UK and beyond.We anticipate that the potential risks of this study are low and similar to those attributable to usual care. Particular issues are where a patient finds an excessively high or low reading and the possibility of increased anxiety due to the study. The patient guideline will advise contact with the supervising physician or nurse in the case of excessively high or low readings. Training of participants will cover repeated measurements in the case of unusually high or low readings and a helpline will be available should subjects require advice over and above that available in the guideline. We will carefully collect data on adverse events.The authors declare that they have no competing interests.RM, JM, RHob, RHol, SG, SB, PL and BW were responsible for identifying the research question and contributing to the drafting of the study protocol. EB and MJ have contributed to the development of the protocol and study design as members of the research team. RM and EB were responsible for the drafting of this paper although all authors provided comments on the drafts and have read and approved the final version.The pre-publication history for this paper can be accessed here:


Pulmonary arterial pressure (PAP) varies considerably in heart failure (HF) despite similar degrees of left ventricular (LV) dysfunction. Bradykinin alters vascular tone and common variations in the kinin B2 receptor (BDKRB2) gene exists. We hypothesized that genetic variation in this receptor would influence PAP in HF.131 HF patients (>1yr history systolic HF), without COPD, not currently smoking, BMI < 40, without atrial fibrillation completed the study which included a blood draw for genotyping and neurohormones , an echocardiogram for cardiac function and systolic PAP (PAPsys).2. Forty-six patients (35%) were homozygous for the +9 allele, 58 (44%) were heterozygous (+9/−9) and 27 (21%) were homozygous for the −9 allele of the BDKRB2. PAPsys averaged 42 ± 13, 38 ± 12, and 35 ± 11 mmHg for +9/+9, +9/−9 and −9/−9, respectively (p = 0.03). There was a trend towards gene effect for plasma ACE with the highest values in +9/+9 and lowest in −9/−9 patients . There were no differences in plasma bradykinin or A-II, LVEF, or NYHA across genotypes.Mean LVEF was 29% ± 12%, NYHA class 2 ± 1, age 56 ± 12 yr, BMI 28 ± 5 kg/mThese data suggest the +9/+9 polymorphism of the BDKRB2 receptor influences pulmonary vascular tone in stable HF. Patients with heart failure (HF) often develop pulmonary venous hypertension (PH) with an associated reactive component causing elevations in pulmonary vascular resistance (PVR). Pulmonary hypertension, secondary to HF, is a common result of systolic or diastolic dysfunction which results in a hemodynamic shift to the pulmonary circulation, elevated pulmonary venous pressure, and subsequent elevation of pulmonary artery pressure (PAP) and right ventricular pressure.As part of the renin-angiotensin-aldosterone system, bradykinin (BK) plays an important role in the cardiovascular system by influencing blood pressure and cell proliferation.12Despite the growing understanding that bradykinin demonstrates strong vasodilatory properties in the systemic circulation, little is known regarding the influence of bradykinin, bradykinin receptor regulation, or bradykinin receptor genotype variants on the regulation of pulmonary vascular tonality.2, and non-smokers with a smoking history <15 pack-years. Patients were treated with standard optimized medications for HF at the time of the study. All participants gave written informed consent after being provided a description of study requirements. The study protocol was approved by the Mayo Clinic Institutional Review Board; all procedures of this investigation conformed to the principles outlined in the Declaration of Helsinki and followed Institutional and Health Insurance Portability and Accountability Act guidelines.Patients were recruited prospectively from the Mayo Clinic heart failure service and the Cardiovascular Health Clinic over the period of 2000 to 2004. Inclusion criteria included all of the following: patients with a history of ischemic or dilated cardiomyopathy, stable HF symptoms (>3 months), duration of HF symptoms >1 year, left ventricular ejection fraction (EF) ≤50%, body mass index (BMI) <40 kg/mResting supine Doppler and 2D echocardiographic measurements were performed at rest in the supine position according to the recommendations of the American Society of Echocardiography.20Left atrial (LA) dimension, left ventricular (LV) mass, LV internal dimension during systole and diastole , LV posterior wall thickness and left atrial end-diastolic dimension were assessed by 2D apical 2- and 4-chamber views. Estimates of mass were calculated using the formula of Troy and colleagues.23Blood was drawn into Vacutainer tubes with and without EDTA and chilled until centrifuged at 4 °C at 2500 rpm for 10 minutes. Serum and plasma aliquots (1 mL) were transferred into 12 × 75 mm polystyrene tubes and frozen at −80 °C until assayed. Plasma angiotensin converting enzyme (ACE) activity was determined by spectrophotometric methods using reagents from Sigma . Dopamine, epinephrine, norepinephrine, angiotensin II (A-II), and atrial natriuretic peptide (ANP) were assessed according to standard methods developed in the Mayo Clinic immunochemical core laboratory. Plasma bradykinin was measured by radioimmunoassay . Brain natriuretic peptide was measured by specific immunoradiometric assay using two monoclonal antibodies against human BNP, one recognizing a carboxy-terminal sequence and the other the ring structure of human BNP.® DNA Isolation kit. Polymerase chain reaction (PCR) was enhanced for high G/C content with Q solution  and conducted using the following primer sequence; (forward) 5′-GCC CTT GAA AGA TGA GCT G-3′ and (reverse) 5′-AAC TCC CCA CGA CCA CAG-3′.Buffy coat was obtained from whole blood collected in EDTA treated tubes and extracted using the Gentra Systems PuregeneStatistical analysis and graphic presentation were accomplished using SAS  to compare differences across genotypes. Univariate linear regression models and Mantel Haenszel chi-squared tests for linear trends were constructed to investigate the associations of patient demographics, plasma neurohormones, and echocardiographic variables with bradykinin genotype considered as a 3-level ordinate variable. Multiple variable linear regression models were also constructed; adjusting covariates included age, gender, body weight, height, and exercise history. Hardy-Weinberg equilibrium was tested by chi square analysis. Statistical significance was set at an alpha level of 0.05 for all analyses. Data are presented as mean ± standard deviation (SD) unless otherwise indicated.Participant clinical characteristics and medication use at the time of the study, according to genotype, are reported in The results of the functional and structural echocardiographic evaluation are shown in To assess the independence of the genotypes on PAPsys, a multiple linear regression model was constructed, adjusting for age, gender, height, weight, and exercise history. After adjustment, there was a significant association between the level of PAPsys and the homozygous +9 genotype (p = 0.02) . After aThis study evaluated the influence of the bradykinin B2 receptor genotype (BDKRB2) on pulmonary vascular pressure in patients with stable HF. Our results suggest patients homozygous for the +9 polymorphism demonstrate elevated PAPsys despite no significant differences in functional or structural cardiac parameters or heart failure severity. Further, the relationship between PAPsys and genotype polymorphism (p = 0.03) was strengthened after adjusting for potential confounding variables including age, height, weight, gender, and exercise history (p = 0.016). Although ACE levels were low due to chronic pharmacologic suppression, there remained evidence for a relationship between the BDKRB2 genotypes and plasma angiotensin converting enzyme levels. Further, the relationship between ACE levels and genotype was enhanced after adjusting for ACE inhibitor usage.Patients with primary systolic HF have a reduced cardiac reserve which is associated with neurohumoral activation of the renin-angiotensin-aldosterone system and peripheral vasoconstriction. Through blocking the enzyme responsible for conversion of angiotensin I to angiotensin II, ACE inhibitor therapy limits the generation of angiotensin II and thereby reduces the associated vasoconstriction and sodium and water retention. Therapy with ACE inhibition has known benefits in patients with heart failure including improvements in functional capacity, morbidity, and mortality.13Bradykinin is a potent endothelium-dependent vasodilator that has a brief duration of action with a plasma half-life of approximately 15–30 seconds due to its rapid degradation by ACE.Bradykinin demonstrates strong vasodilatory properties in the systemic circulation. Interestingly, little is known regarding the influence of bradykinin, bradykinin receptor regulation, or bradykinin receptor genotype variants on the regulation of pulmonary vascular tonality. In the systemic circulation, bradykinin plays an integral role in vascular regulation. Hornig and colleagues suggest that bradykinin contributes to flow mediated dilation of the brachial artery. These authors have shown that the independent infusion of the BDKRB2 antagonist icatibant results in a 33% reduction of flow-mediated dilation despite no significant effect on baseline arterial diameter or blood flow velocity. After infusion of the ACE inhibitor quinaprilat, flow-mediated dilation increased significantly by 46%. The coinfusion of icatibant and quinaprilat produced a reduction in flow-mediated dilation similar to icatibant alone suggesting bradykinin is fundamental in regulating vascular tone via the BDKRB2.13Antagonism of the BDKRB2 also attenuates the short-term blood pressure lowering effects of ACE inhibition. Squire and colleagues have shown, in healthy men on a normo-sodium diet, that icatibant elicits a significant increase in mean arterial pressure. This would suggest a role for bradykinin in basal control of blood pressure. Further, when icatibant was co-administered with the ACE inhibitor perindoprilat the normal reduction in mean arterial pressure was attenuated despite no effect on neurohormonal responses to perindoprilat.14In the pulmonary circulation, Taraseviciene-Stewart and colleagues examined the influence of a long-acting BDKRB2 agonist on pulmonary artery pressure in rats with severe pulmonary hypertension. These authors demonstrated that the administration of the stable BDKRB2 agonist B9972 reduced pulmonary artery pressure, right ventricular hypertrophy, and decreased number of apoptosis derived plexiform lesions in the obliterated vessels.11Despite the understanding of bradykinins role in peripheral vascular tonality, little work has been done with regards to the specific polymorphisms of the BDKRB2 and vascular tonality either in the systemic or pulmonary circulations. In a prospective study, Dhamrait and colleagues demonstrated a significant contribution of the BDKRB2 +9/+9 polymorphism to the coronary artery disease risk associated with systemic hypertension.43A potential limitation to this study is the use of echo-derived measures of pulmonary artery pressure. Although this methodology has been well validated by a number of investigators, it does not allow for the evaluation of pulmonary vascular resistance thus limiting the robustness of our analysis.The results of the present study further the findings of others in a number of ways. First, despite maximization of pharmacologically mediated therapeutic regimens which include ACE inhibitor therapy, patients with heart failure continue to develop pulmonary arterial hypertension via a reactive component, most likely mediated through pulmonary arterial endothelial dysfunction. Second, independent of traditional measures cardiac structure and function or circulating plasma levels of neurohumoral markers indicative of activation of the renin-angiotensin-aldosterone system; patients who are homozygous +9 for the BDKRB2 polymorphism demonstrate significantly elevated levels of pulmonary artery systolic pressure. These results highlight the strength of the genetic contribution to the reactive component of secondary pulmonary hypertension in HF and provide more defined pathways to the development of pulmonary hypertension which may ultimately lead to more personalized treatment strategies in this population.