This review, in light of current information, focuses on the beneficial effects of PPARγ agonist in homocysteine-associated hypertension and vascular remodeling in diabetes.Dysfunction of macro- and microvessels is a major cause of morbidity and mortality in patients with cardio-renovascular diseases such as atherosclerosis, hypertension, and diabetes. Renal failure and impairment of renal function due to vasoconstriction of the glomerular arteriole in diabetic nephropathy leads to renal volume retention and increase in plasma homocysteine level. Homocysteine, which is a nonprotein amino acid, at elevated levels is an independent cardio-renovascular risk factor. Homocysteine induces oxidative injury of vascular endothelial cells, involved in matrix remodeling through modulation of the matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) axis, and increased formation and accumulation of extracellular matrix protein, such as collagen. In heart this leads to increased endothelial-myocyte uncoupling resulting in diastolic dysfunction and hypertension. In the kidney, increased matrix accumulation in the glomerulus causes glomerulosclerosis resulting in hypofiltration, increased renal volume retention, and hypertension. PPAR The vascular endothelial cells play a major role in regulating vascular tone, and although endothelial cells expresses PPARα [α and its agonist on blood pressure is still uncertain and controversial [β/δ is the most widely expressed isoform that is expressed at low levels in almost all tissues. Studies in animal models have shown that although PPARδ does not have role in changing blood pressure, it does have antiatherogenic effect [γ is expressed at the highest levels in adipose tissue, where it regulates numerous genes and improves insulin sensitivity, increases fatty acid uptake, and decreases lipolysis. It was first described as an anti-inflammatory agent, however, the expression of PPARγ in vascular endothelial cells and vascular smooth muscle cells raises the possibility of its involvement in the regulation of vascular tone and blood pressure [The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear receptor family of ligand-activated transcription factors that regulate gene expression , 2. PPAR failure –7. Altho failure . PPARα ies PPARα , the rolc effect . PPARγ ipressure .γ, and activate the receptor, which in turn increases the insulin sensitivity and are clinically used to control hyperglycemia in type 2 diabetes. It is known that 65% of diabetic patients also suffer from hypertension and treatment with glitazone was also noted to lower blood pressure. Diabetic subjects also often experience renal volume retention. This is one of the mechanisms by which diabetic subjects accumulate homocysteine in the body. Interestingly, clinical research suggests that at elevated levels, homocysteine is an independent risk factor for greater mortality in type 2 diabetic patients as compared to nondiabetic subjects [γ activation on vasculature through homocysteine clearance, which leads to improvement of endothelial-dependent vascular relaxation, in addition to its known hypoglycemic activity, resulting in restoration of blood pressure in diabetic nephropathy.Glitazones are a class of drugs primarily used to treat type 2 diabetes and related diseases. Glitazones bind to PPAR, specifically PPARsubjects . In animsubjects . In thisIn diabetes, progressive renal failure leads to end-stage renal disease . Increasβ1 (TGF-β1) [Sustained elevation of blood pressure amplifies diabetic complications within the glomerulus by inducing impairment of autoregulation of the microcirculation, resulting in an increase in intraglomerular capillary pressure . The cha(TGF-β1) , enhance(TGF-β1)  and the (TGF-β1) . These m(TGF-β1) . In addi(TGF-β1) , 26.12/folate, (3) deficiency of CBS activity  and vitamin B6, and (4) renal insufficiency causing volume retention . HHcy is an independent vascular risk factor and plasma homocysteine increases during renal insufficiency , 28. Theetention . Herein,Elevated level of plasma homocysteine has always been associated with patients exhibiting chronic kidney diseases, especially end-stage renal disease (ESRD) and the prevalence of HHcy is strongly associated with decreased glomerular filtration rate (GFR) . Althougμmol/day, which is 1%), suggesting that most of the (99%) filtered homocysteine is reabsorbed by the kidney. The location of this uptake is reported to be on the basolateral tubule cell surface [β-synthase and cystathionase) and remethylation (methionine synthase) enzymes in human [α-ketobutyrate [The kidney is capable of filtering homocysteine, as it does for other amino acids. However, the amount of filtered homocysteine found in urine is minimal  plays an important role in maintenance of tissue architecture and normal physiological function. Remodeling of extracellular matrix (ECM) is a dynamic process and excessive ECM deposition is a pathophysiological phenomenon of diseased condition that could lead to hypertension –64. A nu threats . Among M threats . Type IV threats , 65–67.  threats . It was, threats , and thi threats , 68, 69. threats , which w threats  where pr threats . This warteriole . A propoγ agonist (CZ)-treated diabetic mice without any alteration of plasma homocysteine level [γ agonist was found to improve myocardial relaxation in vitro in both an endothelium dependent and independent way [γ agonist CZ, normalized the relaxation of cardiac rings, suggesting the attributed role of CZ in endothelial-myocyte recoupling in diabetes [γ activation promoted tissue clearance of homocysteine thereby improving endothelium dependent cardiac relaxation. On the other hand endothelium independent relaxation was improved in part by recoupling of endothelium and myocyte [Until recently, it was our main concern to control systolic blood pressure and to keep this pressure as close as possible to normal level to minimize hypertension-associated morbidity and mortality. Recent studies however, have shifted our attention to diastolic hypertension which can be as harmful as systolic hypertension. A constant elevated diastolic pressure increases the risk of heart damage, brain damage, and kidney problems as well. One of the causes of diastolic hypertension is diastolic dysfunction, which demonstrates hypertrophy of the cardiomyocytes, increased interstitial collagen deposition and/or infiltration of the myocardium leading to endothelial-myocyte uncoupling. It is estimated that, although the majority of cardiac muscle is myocyte, sixteen percent of the myocardial mass is capillaries and the inner lining of the capillaries are made up endothelium . The capne level . The decdent way . Endothedent way . Interesdiabetes . This st myocyte . A possiN-homocysteinylation through the formation of amide bonds with protein lysine residues [N-linked protein Hcy (N-Hcy-protein) has been reported to be elevated in hyperhomocysteinemia [Although the homocysteine is linked to blood pressure, a direct cause and effect relationship of hyperhomocysteinemia and hypertension has not been established. The mechanisms that could explain this relationship include homocysteine-induced arteriolar constriction, renal dysfunction, increased sodium absorption, increased arterial stiffness, and endothelial damage . Other presidues , which aresidues . N-linketeinemia –81, and teinemia . Proteinteinemia , which cγ produces a number of isoforms which control a variety of pathways including lipid metabolism, insulin sensitivity, and inflammation [γ ligation to reduce circulating homocysteine concentration [γ ligands are able to reduce circulating homocysteine concentrations fit well with a role of PPARγ in modulating homocysteine turnover [γ in diabetic subjects reduced tissue homocysteine level and normalized systolic blood pressure [γ activation reduces hypertension through reduction of homocysteine, at least in part. However, as direct link of hyperhomocysteinemia and hypertension is still not established, the issue of whether or not the reduction of homocysteine level through PPARγ activation reduces blood pressure remains debatable and controversial. Future studies are needed to establish a direct cause and effect relationship between hyperhomocysteinemia and hypertension, if any. Nonetheless, it is time to speculate that hyperhomocysteinemia contributes to elevate blood pressure in the pathogenesis of renal disease, for example, diabetic nephropathy, and PPARγ is an effective target molecule to regulate hypertension, at least in part, through the reduction of homocysteine, where renal insufficiency upregulates homocysteine.Genetic variations have been demonstrated to play an important role in determining plasma homocysteine levels. For example, sequence variation of methylenetetrahydrofolate reductase (MTHFR) gene has been shown to influence circulating homocysteine level , and seqammation . Therefontration , 87. Thuturnover , 87. We pressure . Thus, i2S) has been known for the decades as a noxious gaseous molecule with an intoxicating effect on the brain and central nervous system. Recent findings, however, reported that it is an effective molecule to regulate blood pressure [2S is generated in the mammalian tissue from L-cysteine, and homocysteine is the precursor of L-cysteine. Physiologically, homocysteine is metabolized by three transulfuration pathway enzymes, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST). At elevated levels, homocysteine has been shown to reduce activity of CSE, thereby reducing the production of H2S [2S defends organs from several pathophysiological conditions, such as oxidative stress, ischemia-reperfusion, and hypertension [2S decreases hydrogen peroxide (H2O2), peroxynitrite (ONOO–), and superoxide anion (O2●–) generation induced by homocysteine in a cell culture model [Hydrogen sulfide  increases insulin sensitivity and reduces plasma glucose level, therefore reduces inflammation; (2) promotes tissue clearance of homocysteine level and thus, reduces oxidative stress and inflammation; (3) normalizes CSE enzymatic activity, thereby raises the possibility of endogenous H2S generation, which has been documented as an anti-inflammatory and antihypertensive gaseous molecule at physiological levels [It is known that rise in blood pressure causes chronic inflammation of the endothelium which is, in turn, responsible for further endothelial damage and worsening blood pressure. On the other hand, several metabolic disorders such as dyslipidemia, hyperhomocysteinemia, diabetes, and obesity cause inflammation followed by a subsequent rise of blood pressure. Inflammatory disease such as atherosclerosis is a major complication of hypertension , and plal levels , 103. ThIt is well established through decades with many large prospective studies that hyperhomocysteinemia predicts increased risk of vascular events including stroke, venous thromboembolism, and death , 105. Maγ agonists may be beneficial in preventing vasculopathies in cardiac and renal tissues associated with increased homocysteine content in diabetic subjects. Moreover, PPARγ ligand seems to be promising in preventing hypertension associated with increased homocysteine level in diabetes. Although at present it is premature to conclude homocysteine causes hypertension, there is substantial indirect evidence which supports homocysteine-associated rise in blood pressure. Further studies are needed to elucidate the contributing role of homocysteine to regulate blood pressure, and precise mechanism of hypertension modulation associated with hyperhomocysteinemia by PPARγ induction warrants special attention.Diabetes is the most common single factor of cardiovascular and renal damage in patients with diabetes mellitus. Diabetes causes tissue accumulation of homocysteine both in cardiac and glomerular tissue. This increased tissue content of homocysteine exacerbates cardiovasculopathy and nephropathy in diabetes, in addition to the detrimental effect of diabetes. PPAR


Blood pressure levels may vary in children because of genetic, ethnic and socioeconomic factors. To date, there have been no large national studies in Saudi Arabia on blood pressure in children. Therefore, we sought to establish representative blood pressure reference centiles for Saudi Arabian children and adolescents.We selected a sample of children and adolescents aged from birth to 18 years by multi-stage probability sampling of the Saudi population. The selected sample represented Saudi children from the whole country. Data were collected through a house-to-house survey of all selected households in all 13 regions in the country. Data were analyzed to study the distribution pattern of systolic (SBP) and diastolic blood pressure (DBP) and to develop reference values. The 90th percentile of SBP and DBP values for each age were compared with values from a Turkish and an American study.A total of 16 226 Saudi children and adolescents from birth to 18 years were studied. Blood pressure rose steadily with age in both boys and girls. The average annual increase in SBP was 1.66 mm Hg for boys and 1.44 mm Hg for girls. The average annual increase in DBP was 0.83 mm Hg for boys and 0.77 mm Hg for girls. DBP rose sharply in boys at the age of 18 years. Values for the 90th percentile of both SBP and DBP varied in Saudi children from their Turkish and American counterparts for all age groups.Blood pressure values in this study differed from those from other studies in developing countries and in the United States, indicating that comparison across studies is difficult and from that every population should use their own normal standards to define measured blood pressure levels in children. The assessment of blood pressure (BP) and prevention of hypertension in children and adolescents has become a worldwide priority.A number of epidemiological studies have established normal blood pressure values in different populations,78Our study was part of the Health Profile of the Saudi Arabian Children and Adolescents project, which was a house-to-house survey of 14000 randomly selected households from all provinces in Saudi Arabia, including urban and rural areas. Households were randomly selected by a multi-stage probability sampling procedure from a stratified listing based on the updated 2000-2001 census. This computerized process was performed with the assistance of the General Directorate of Statistics, Ministry of Planning, who provided details of the selected households in cities and villages, including road and street maps. A sub-sample was selected randomly from the original main sample to measure blood pressure. Workshop training of field teams was conducted in each of the 13 regions of the country. The workshops included oral presentations and small group training on procedures for locating selected households, explanations of the questionnaire, family interviews, clinical examinations of the children and the taking of measurements and recording of data. The training included practical demonstrations to members of the field teams on how to use and maintain the blood pressure measurement devices.Specific guidelines in Arabic and English were provided to the members of the teams. Each team consisted of one physician and one to two female nurses. The clinical examination of the children and adolescents was performed by the physicians to determine eligibility for measurements. Only healthy children and adolescents as determined by interview, clinical examinations and anthropometric measurements were eligible for measurement of BP. The survey questionnaire was designed to provide basic information about the subject, including birth date, perinatal history, nutrition, childhood illnesses, socioeconomic status of the family and body measurements. The exact birth date was considered to be particularly important and acceptable only when it was completely recorded from an official document. The exact date of measurement was also noted, both dates essential for the determination of the exact age at the time of measurements.Electronic devices using oscillometric techniques were used in the study. The devices fulfilled the American Association for the Advancement of Medical Instrumentation (AAMI), and were graded A for both systolic and diastolic pressure under the British Hypertension Society (BHS) protocol, as recommended by the European Society of Hypertension.4Data collection was performed over a period of 2 years (2004-2005) by house-to-house visits. Precautions were taken to ensure reliability and accuracy of measurements. In addition to the use of equipment known for high accuracy, intra- and inter-observer reliability were tested by selection of 1% of the children to be re-measured by the same or another observer. Multiple frequency analysis was used to detect any missing data, inconsistencies and other types of errors. All question-able data were double-checked.The SAS system software was used. Descriptive statistics  were used to explore the data. Correlation and simple regression analysis were used to assess the linear relationship between two continuous variables. All values were related to the age and sex of the children. The criteria used to establish normal and abnormal were similar to those of the Second Task Force report on blood pressure control in children , , (high >95th percentile).45A total of 16 226 Saudi Arabian children (7928 girls and 8298 boys) from birth to 18 years of age were examined in this study. Smooth percentile values of systolic blood pressure (SBP) and diastolic blood pressure (DBP) for these children according to age and sex are shown in Tables The incorporation of blood pressure measurement into the routine pediatric examination as well as the publication of national norms for blood pressure in children not only enables detection of significant asymptomatic hypertension secondary to a previously undetected disorder, but also confirms that mild elevation in blood pressure during childhood is more common than previously recognized, particularly in adolescents.25The standard blood pressure percentile tables for children and adolescents provide arterial pressure values frequently seen in a large numbers of subjects presumed to be normal. Reference norms developed for one particular population may not be applicable to another because of racial, ethnical and cultural differences across the world.The definition of normal blood pressure values in children is based on mercury sphygmomanometry.46152012152014Clinic blood pressure measurements tend to be higher than home measurements,It is of interest to compare our results statistically with those of other studies in other developing countries or in the United States, but it should be noted that the comparison of blood pressure values across these studies is difficult, since different criteria were employed.47


Despite the many antihypertensive medications available, two-thirds of patients with hypertension do not achieve blood pressure control. This is thought to be due to a combination of poor patient education, poor medication adherence, and "clinical inertia." The present trial evaluates an intervention consisting of health coaching, home blood pressure monitoring, and home medication titration as a method to address these three causes of poor hypertension control.The randomized controlled trial will include 300 patients with poorly controlled hypertension. Participants will be recruited from a primary care clinic in a teaching hospital that primarily serves low-income populations.An intervention group of 150 participants will receive health coaching, home blood pressure monitoring, and home-titration of antihypertensive medications during 6 months. The control group (n = 150) will receive health coaching plus home blood pressure monitoring for the same duration. A passive control group will receive usual care. Blood pressure measurements will take place at baseline, and after 6 and 12 months. The primary outcome will be change in systolic blood pressure after 6 and 12 months. Secondary outcomes measured will be change in diastolic blood pressure, adverse events, and patient and provider satisfaction.The present study is designed to assess whether the 3-pronged approach of health coaching, home blood pressure monitoring, and home medication titration can successfully improve blood pressure, and if so, whether this effect persists beyond the period of the intervention.ClinicalTrials.gov identifier: NCT01013857 Hypertension remains a leading cause of preventable death despite the availability of evidence-based treatments. Even small reductions in high blood pressure have major impacts in clinical outcomes and health care spending: a 2 mm Hg decrease in systolic blood pressure (SBP) or diastolic blood pressure (DBP) significantly reduces risk of stroke, coronary heart disease, and mortality from vascular causes . In the Poor blood pressure control is frequently attributed to low rates of medication adherence. Indeed, several studies have shown that only fifty to seventy percent of patients take their blood pressure medications correctly . One expIn the traditional primary care setting, patients comprehend as little as half of what their physicians convey during the appointment . Yet impLack of treatment intensification by clinicians may be equally, if not more, important than medication adherence in attributing to poor control in hypertensive patients. Higher rates of treatment intensification are associated with improved blood pressure control . HoweverIn addition to providing patients with self-management support, health coaches, using physician-created algorithms, can relay physician advice on medication intensification to patients without a physician visit. In this way, health coaches can address both the patient and physician factors associated with poor blood pressure control.A series of publications have shown that ambulatory blood pressures better predict cardiovascular risk compared to clinic blood pressure readings . One stuBased on the findings cited in the previous paragraphs, the present study was designed to combine health coaching, home blood pressure monitoring, and home-titration of antihypertensive medications to overcome the tri-fold barriers of inadequate health education, poor medication adherence and clinical inertia. This study is the first to use health coaches with some or no formal clinical training in place of RNs, pharmacists, or physicians for this purpose.Our study investigates whether weekly telephone coaching on home blood pressure monitoring and medication adherence results in improved blood pressure control during a 6 month coaching period. Furthermore, we aim to determine whether home-titration of antihypertensive medications further increases this benefit, and whether these effects are sustained 6 months after the coaching period has ended.Hypertensive patients are randomly assigned to one of two groups:1) Control group: Patients receive weekly health coaching phone calls on home blood pressure monitoring, medication understanding, and medication adherence.2) Active group: Patients receive weekly health coaching phone calls on home blood pressure monitoring and medication understanding and adherence, as well as assistance with home-titration of their antihypertensive medications.A passive control group, receiving usual care, will be evaluated by retrospective chart review upon the completion of the study.Ethical approval to conduct this study has been granted by the Committee on Human Research at the University of California, San Francisco .All participants are low-income English, Spanish, Cantonese, or Vietnamese speaking patients who receive primary care at the Family Health Center in San Francisco General Hospital. The Family Health Center is a primary care clinic in a teaching hospital.Patients are eligible for the study if they have a documented blood pressure greater than or equal to 145/90 on two or more separate visits in the past year. SBP must be greater or equal to 145 or DBP greater or equal to 90 on both readings. The two readings can include an elevated reading taken on the day that the patient is enrolled. Eligible patients are not required to carry a diagnosis of hypertension or be prescribed antihypertensive medications at enrollment. Patients must speak Cantonese, English, Spanish, or Vietnamese.Patients are excluded from the study if they are less than 30 years of age, their most recent creatinine is greater than 1.5 mg/dl, they have class III or IV heart failure, their life expectancy is less than one year or they have reduced cognitive capacity as determined by the patient's PCP. Patients with reduced cognition are included in the study if they have a known caregiver, such as a family member, capable of assisting the patient with home blood pressure monitoring and medication titration, and speaking with the health coach each week.San Francisco's Department of Public Health electronic patient registry was searched for patients that: (1) are assigned to a PCP at San Francisco General Hospital's Family Health Center, (2) have a diagnosis of hypertension, (3) are greater than or equal to thirty years of age, (4) have no documented serum creatinine reading greater than 1.5 mg/dl, and (5) speak Cantonese, English, Spanish, or Vietnamese.PCPs are given the list of their screened patients and are asked to exclude patients whom they believed would be unable to monitor their blood pressure or follow medication titration instructions due to physical or cognitive disability, psychiatric illness, or other reasons.Additionally, patients with elevated blood pressures in the clinic are screened and recruited. Clinic staff or PCPs alert the study's health coaches if any patient has a blood pressure greater than 145/90 measured during intake. Health coaches review the chart to see if the patient met the eligibility criteria, including a blood pressure greater than 145/90 on a separate visit in the previous year. If not referred directly by the PCP, the health coach approaches the patient's PCP to see if the patient was eligible in terms of cognitive ability and life expectancy.Eligible patients are approached by a language-concordant health coach at the time of their primary care appointment and interviewed to ensure that they: (1) plan to continue coming to the Family Health Center for the next year, (2) have a telephone, (3) are willing to check their blood pressure at least twice a week, and (4) are willing to learn how to change their blood pressure medicines from home if enrolled in the active group. If patients answer yes to all of the above, they are given IRB-approved informed consent for enrollment in the study.Patients are given a home blood pressure monitor (Omron model HEM-711AC) and trained in its use. They are also given a calendar logbook in which to record their blood pressures and heart rates. In order to ensure comprehension, health coaches request that patients "teach back" the process of checking their blood pressure and recording the values in their logbook.At the completion of the training and consent process, health coaches and patients learn the patient's randomly generated enrollment assignment to either the active or control group. The health coach also confirms with the patient any currently prescribed antihypertensive medications and dosages.Sample size calculation for detecting change in systolic blood pressure as the primary outcome used a standard deviation of 15 mm Hg was used based on prior studies that have reported standard deviations ranging from 10 to 20 mm Hg. 15 mm Hg was also the standard deviation used to calculate sample size for a recent study . To be aChi-square tests , t-test , and non-parametric tests  will be used to compare the two groups with respect to demographic characteristics, blood pressure at the time of enrollment, number and type of medications, length of time since diagnosis of hypertension, number of clinic visits in the past 12 months, primary language, and co-morbidities. The primary outcome, change in systolic blood pressure at 6 months, will be compared between the two groups using a simple t-test against the usual null hypothesis of no difference. Analyses will be performed to assess the impact, if any, of adjusting for any differences in group characteristics using multivariate analysis of variance (MANOVA). If the unadjusted (t-test) and adjusted  results differ, the analysis of variance approach will take precedence.Secondary outcomes will include difference in diastolic blood pressure, the proportion of patients achieving BP < 140/90, and proportion of patients reporting medication side effects . These will be examined as per primary outcomes. Further analyses will be conducted to look for evidence of effect modification by pre-specified subgroups: starting systolic BP (≥ 160 vs. <160), by English as primary language (Y/N), and age (< median versus ≥ median). These analyses will be reported as exploratory.Health coaches are employees and volunteers at the UCSF Department of Family and Community Medicine. Of the 10 health coaches, eight have no formal clinical training. Health coaches attend at least two training sessions co-taught by a clinician and medical student who are part of the study team. Training topics include health coaching, basic hypertension pathophysiology, antihypertensive medication therapy, side effects (including red-flag symptoms), home blood pressure monitoring, standard home titration algorithms, emergency protocols, and patient confidentiality. Each health coach tracks a panel of five to thirty patients concurrently. The two principal investigators - both physicians - are available to answer questions about clinical cases and study protocols, as was occasionally necessary throughout the study.Health coaches telephone each of the patients in their panel on a weekly basis, and completed an encounter form for each phone call. If available, health coaches also meet patients face-to-face before or after a PCP appointment at the Family Health Center during the 6 month coaching period. Health coaches also arrange for patients to meet specifically with them in clinic if they were having trouble using their blood pressure monitor or if face-to-face medication education was needed.Data recorded during weekly telephone health coaching encounters includes: (1) usual, highest and lowest recorded BP for that week; (2) current BP (only collected if BP was not monitored regularly that week or if readings were highly variable); (3) usual, highest and lowest heart rate (HR); (4) current heart rate (only collected if heart rate not monitored regularly or if readings were highly variable).In addition, patients are asked how many days they measured their blood pressure that week, how many days they miss taking an antihypertensive medication, whether they are having any side effects from these medications, and whether they have had any major events such as falls or unplanned visits to the hospital emergency room. Patients in both groups are encouraged to make an action plan with their health coach for improving their blood pressure by the next week. Action plans involve health coaches and patients agreeing on a concrete course of action to move toward a general goal of improved blood pressure . PatientAntihypertensive medications were titrated using an algorithm adapted from Kaiser Permanente (see figure The primary outcome is systolic blood pressure measured at 0 months (enrollment), 6 months (end of coaching intervention period) and 12 months. Secondary outcome measures include diastolic blood pressure, side effects, adverse events, and patient and provider satisfaction.After 6 months of participation in the study, patients are asked to respond to a number of questions regarding their experience working with their health coach, including satisfaction with the health coach, with monitoring blood pressure at home, and - if applicable - with changing blood pressure medicines without visiting their doctor.Advancements in antihypertensive medications offer the possibility of dramatically reducing the incidence of heart attacks and strokes worldwide. Evidence-based guidelines for hypertension are widely distributed. However, persistently poor levels of blood pressure control can only be addressed by confronting the triple barriers of poor patient understanding, low medication adherence, and clinical inertia. The current study is based on the concept that these three barriers result in large part from PCPs lacking time to adequately manage common chronic illnesses . The invIn our study, we trained health coaches with some or no prior medical training to discuss blood pressure goals and antihypertensive medications with patients over the phone, thus eliminating the time constraint of the fifteen-minute physician visit. In one group, health coaches titrate medications according to an algorithm, thus preventing long revisit intervals from delaying appropriate medication intensification.We hypothesize that both arms of the intervention will increase the number of patients with controlled hypertension at six and twelve months relative to the passive control group. We further hypothesize that patients in the active group, who are coached on home-titration, will achieve blood pressure control that is equal or better than that of patients in the control group, with no home-titration of antihypertensive medications.The authors declare that they have no competing interests.HB, VN, DT, and TB conceived the study. DT planned the statistical analysis, and conducted sample size calculation. All authors were responsible for the drafting of this paper and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/9/456/prepub


The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF. Chronic heart failure (CHF) is a common condition with poor prognosis . CHF is The current perception is that CHF is a paradigm of energetic failure affecting cardiac and skeletal muscles, progressing to contractile failure, worsening physical disability, and eventually death. This radical shift in concept is supported by the change from treatment with sympathomimetic drugs to beta blockers. Given that in late 1980’s decreased left ventricular systolic function, cardiac enlargement and heart failure were considered absolute or relative contraindication to ET, it is now increasingly apparent that the lack of physical activity leads to skeletal muscle atrophy, exercise intolerance, venous thrombosis & pulmonary embolism . TherefoIt is unclear however, as to what extent the observed beneficial effects of ET in CHF patients are based on cardiac improvement. Whether exercise therapy improves cardiac and skeletal muscle cells energy metabolism of patients with CHF is unknown. Here, we review the role of exercise therapy in the management of patients with CHF. In this review, focus is on the different modes of ET, duration, exercise dynamics in the context of cardiac rehabilitation and heart failure. Finally, we also present current knowledge on the effects of ET on changes to energy metabolism for chronic heart failure patients.In normal circumstances, heart muscle maintains blood circulation in states of both rest and high peripheral demand a process that requires the transfer of vast amounts of energy between various compartments. The energy transfer process is usually permanent, adaptable, rapidly regulated, and highly efficientt. In contrast, the failing heart has been described as energy starved . In the Another recent development in the understanding of energy metabolism has been in the area of the transcriptional regulation and signaling pathways involved in the maintenance of energy homeostasis and mitochondrial biogenesis for the failing heart . The mit1).Evidence suggests a state of heightened immune activation in CHF. -22 Pro-i“Respiratory muscle deoxygenation” implies that ventilation/perfusion mismatching is caused by the diaphragm and intercostal muscle metabolic impairments. While these exist, ventilation/perfusion mismatching is caused largely by an impaired cardiac output response to exercise . Evidenc2) is reduced in CHF patients [2 in HF includes a lower exercise cardiac output response, reduced nutrient blood flow to the active skeletal muscles, along with skeletal muscle abnormalities such as a reduced percentage of type-I fibres, weakened oxidative capacity and a reduction in the capillary density [ET in CHF works by many factors and trials demonstrate that peak oxygen uptake (VOpatients . The rat density . Skeleta density -33. Thes density . These m density .2 max.) is now more commonly accepted as a direct measure of cardio-respiratory endurance during exercise of increasing intensity [2 max and survival in CHF [2 [However, due to concerns regarding accuracy and reliability of ET, the  is increased suggesting that ventilation/perfusion defects develop during exercise . Furtheret al, suggested that in patients with HF, an increase in capillary density would be a favourable adaptation. Moreover, the authors noticed a significant reduction in the microvascular density in patients’ with CHF without major differences in other histologic and biochemical aerobic markers [Histological and metabolic abnormalities of muscle cells, and skeletal muscle wasting have been described in CHF patients . Anaerob markers . The ske markers , 30. ET  markers ,54.CHF patients have a subnormal peripheral blood flow response to exercise. This is not only due to reduced cardiac output but also to an abnormal peripheral vasodilatory response. The abnormal peripheral vasodilatory response to ischaemic challenge could be due to a variety of stimuli including isotonic and isometric exercise, adrenergic blockade, and ischemia and arterial vasodilatation -55. An aExercise training also enhances oxidative capacity of the skeletal muscle and corrects endothelial dysfunction of the skeletal musculature in ischemic and dilated cardiomyopathy . This coThere is relatively very little information available in the literature on the effect of ET on circulating EPC in patient with CHF. Single centred studies with small number of patients have shown that intensive and moderate ET for long periods increased circulating levels of EPC in normal subjects . Increasin vitro. The authors further reported reduced neovascularization capacity despite similar contents of hematopoietic stem cells in vivo [et al reported that moderate-to-severe CHF is not associated with elevated EPC levels in the systemic circulation. They also could not demonstrate a measurable cardiac uptake of EPC in this cohort [Dimmeler’s group previously reported the inverse relationship between the patients with coronary artery disease (CAD) and circulating EPC levels and function . Further in vivo . Similars cohort .CHF patients experience progressive decline in the quality of life (QOL), limiting their routine daily activity due to the early onset of dyspnoea and fatigue. In addition depression and isolation are common in these patients. Even patients with stable heart failure suffer reduced QOL as symptoms relief is not complete .Only a few studies of heart failure patients participating in exercise training programme have included the QOL questionnaire in their study protocol. In addition the QOL measurement tools vary and the results are inconsistent. The majority of the trials used “Minnesota Living with Heart Failure questionnaire” that assesses disease-specific health-related QOL and its effects on daily life , 60. HowIt is still not clear, whether ET in HF has any long term effects on QOL as no strong correlation exists between measures of health related QOL and central hemodynamic abnormalities and exercise intolerance . NeverthCurrently there is no published large randomised controlled trial studying the long term clinical effectiveness of ET in CHF patients. Recently published literature comprises of mostly single centred experience containing small number of patients with short follow up. Belardinelli & co-workers analysed 99 patients with a mean follow up of 3.4 yrs. In their study, patients in the exercise training group had fewer deaths  (P=0.01); fewer hospitalizations for chronic heart failure (P=0.02); fewer cardiac events (P=0.006); increased peak oxygen consumption per unit time (P<0.001) and thallium uptake (P<0.001); and improved qualify of life at 2, 14, and 26 months .P < .0001). The authors suggested a dose response with improved survival benefit for patients with CHF participating in cardiac rehabilitation [Whellan & colleagues identified 70 patients in their database with HF who participated in Cardiac Rehabilitation (CR) program. Participation in CR> 6 sessions was associated with significantly improved survival . During this same period, 26 exercising and 41 non-exercising subjects died . The authors suggested that ET is safe and effective in patients with heart failure. The risk of adverse events may be reduced, but further studies are required to determine whether there are any survival benefits [Tenenbaum  1.6 yrs . Smart abenefits .As discussed earlier, cardiac failure itself is a syndrome of circulatory failure, secondary to ventricular dysfunction. This primarily ventricular dysfunction is followed by a variety of neurohumoral, peripheral circulatory, skeletal muscle, and respiratory adaptations which determine the syndrome's clinical presentation and prognosis more than the primary ventricular dysfunction itself. Traditionally, avoidance of exercise was thus advocated in all forms and stages of heart failure . However2 in ml/kg/min) during exercise. With ET, the observed improvements are sometimes small, but may have a major impact on quality of life in CHF patients. The difference after training is reflected in the patient's ability to cope with the physical demands of day to day activity, thus preventing the need for continuous bed rest and the loss of independence which often results in the need for chronic care.Poor left ventricular function is not necessarily synonymous with CHF, which is characterized by reduced tissue oxygen supply. The best method of evaluating the disease state of a patient with a compromised heart is cardiopulmonary exercise testing, that is, the measurement of oxygen consumption  and its possible detrimental effects are very distinct from dynamic resistive exercise prescription in cardiovascular patients. Several investigators have shown that the acute haemodynamic responses during resistance exercise in CHF patients were similar or lower than for aerobic exercise of comparable intensity.Contraindications for CHF patients participating in such ET programme are the same as for patients with coronary artery disease . While oFurther research is thus necessary to confirm the role of ET as a treatment for patients with CHF, and to determine the most appropriate intensity, mode, and duration of training. Training can comprise overall endurance training monitored by heart rate, interval training based on percentage of maximum exercise level, or strength training. It has been suggested -68 that In conclusion, exercise training in CHF patients has some merits and as discussed in this review, the changes induced by exercise at molecular level are well documented. However, how these changes translate into symptom improvement and QOL transformation is still not clear; in part due to lack of standardisation of the different ET protocols used. But before such patients can participate in a training programme, it is important to clarify the pathophysiology of their heart failure and thus identify their limiting factors. Finally the patient's individual profile requires definition: the training programme must be tailored to the patient's specific limitations and desired level of activity. Nevertheless, with the existing pool of evidence ET may safely be advocated to patients by health professionals keeping in view of their HF pathophysiology; whilst awaiting results from more robust large randomised studies.


A number of intervention studies have shown that therapy with angiotensin receptor blockers, such as irbesartan, can improve metabolic parameters and reduce the incidence of diabetes mellitus. It is unknown whether this observation also holds true in routine clinical settings.We evaluated the effect of irbesartan (150 mg or 300 mg/d) together with or without hydrochlorothiazide (12.5 mg/d) in 3259 German patients. A total of 750 primary care physicians evaluated up to 5 subsequent patients with metabolic syndrome (58.9% diabetic), in whom irbesartan therapy was newly initiated (87%) or continued (13%).Six months of irbesartan therapy decreased systolic blood pressure by 14% (157.4 ± 14.7 vs. 135.0 ± 10.7 mmHg) and diastolic blood pressure by 13% (92.9 ± 9.2 vs. 80.8 ± 6.8 mmHg). This was associated with a decrease in body weight (-2.3%), fasting glucose (-9.5%), HbA1c (-4.6%), LDL-cholesterol (-11%), triglycerides (-16%) and gamma-GT (-12%) and an increase in HDL-cholesterol (+5%). These changes were somewhat more pronounced in male than in female patients and in obese than in lean patients. Changes in glucose concentration and HbA1c were much more prominent in diabetic patients.Irbesartan therapy improves metabolic parameters in routine clinical settings. Thus, our study confirms previously published results from large intervention trials and extends the findings to routine clinical practice. The metabolic syndrome which describes the concomitant presence of visceral obesity, insulin resistance or glucose intolerance, atherogenic dyslipidemia and hypertension is highly prevalent (approximately 25%) in Germany. The risk of developing diabetes mellitus type 2 for subjects with the metabolic syndrome is increased five-to nine-fold ,2. In adLarge clinical trials evaluated the effect of angiotensin receptor blockers (ARB) on cardiovascular end points, generally showing very positive results. Therefore ARB and ACE-Inhibitors are now considered first line therapy in hypertensive patients with the metabolic syndrome ,5. An anThus, a large body of data indicates that interfering with the angiotensin system has positive effects on metabolic parameters. However, it is unknown whether these positive effects can also be observed in daily routine clinical practice, although recently published data from a post authorization trial indicate that this may be the case . We therA total of 3259 patients participated in this prospective, 6-month, open-label, observational, post-authorization survey. The patients were recruited from 649 general practitioners throughout Germany, who included up to 5 subsequent patients who fulfilled the inclusion criteria specified below and who at the time of the index visit were either already on irbesartan therapy or in whom irbesartan therapy was started at that time point. All subjects had elevated blood pressure (>130/85 mmHg or antihypertensive therapy). In addition, at least two of the following criteria were present: abdominal obesity  or >88 cm ), elevated triglycerides (>150 mg/dl), decreased HDL-cholesterol , elevated fasting glucose (>110 mg/dl). The characteristics of the subjects are shown in Table Each subject was evaluated three times: At baseline (index visit), after three months and after six months. Patients were evaluated using a standardized form with which data on duration of hypertension, duration of metabolic syndrome, nicotine and alcohol consumption, blood pressure, pulse, weight, height, waist circumference, medications, lab-values  were collected.Mean and standard deviation as well as median and range were used to describe the population. t-tests were used to evaluate intergender differences, differences between diabetic and non-diabetic patients, and differences between different doses. Non-parametric tests were used for statistical evaluation were appropriate. SAS, version 9.1 was used for statistical analysis. The analysis was performed by GKM – Gesellschaft fuer Therapieforschung, Munich, Germany.In this cohort of German hypertensive patients 49.1% did not take any antihypertensive medications at the index visit, while 50.9% were taking at least one antihypertensive drug. At baseline 423 patients (13.2%) were taking irbesartan, while in all others irbesartan therapy was initiated at the index visit. Furthermore, the patients were also taking a significant number of other medications (Table In this study 594 patients (18.8%) were treated with irbesartan 150 mg/d, 665 patients (21%) with irbesartan 300 mg/d, 754 patients (23.8%) with 150 mg irbesartan and 12.5 mg hydrochlorothiazide and the rest (36.4%) with irbesartan 300 mg/d and 12.5 mg hydrochlorothiazide. During the observation period the number of patients treated with irbesartan 150 mg/d decreased slightly (from 42.6% to 37.0%) while those groups taking 300 mg/d increased (from 57.4% to 63%).Within the observation period (6 months) systolic blood pressure decreased from 157.4 ± 14.7 mmHg to 135.0 ± 10.9 mmHg (-22.3%). Diastolic blood pressure decreased from 92.9 ± 9.2 mmHg to 80.8 ± 6.8 mmHg (-12.1%). Thus, the rate of patients with systolic blood pressure <130 mmHg increased from 1.6% to 20.4%. While the rate of patients with systolic blood pressure >180 mmHg decreased from 9.4 to 0.4%. Similarly, diastolic blood pressure was <85 mmHg in 15.7% at the index visit and 67% after 6 months of therapy. The rate of patients who had blood pressure <140/90 mmHg increased from 4.9 to 59.2%.During the observation period the body weight decreased from 91.4 ± 15 kg to 89.3 ± 14.6 kg (-2.2%). This decrease was somewhat more pronounced in men (-2.5%) than in women (-1.4%). Similarly waist circumference decreased from 106.4 to 104.3 cm .The effect on metabolic parameters is shown in Table 2) than in leaner patients. HbA1c and fasting glucose reduction was significant in diabetic and non-diabetic patients, but was much more pronounced in those with diabetes. All other parameters decreased in diabetic and non-diabetic patients, however, improvement was overall more pronounced in patients with diabetes  than in older (≥62 years), in more obese . Notably, we also observed a small but significant decrease in body weight, which also indicates that some of the beneficial effects observed during the study are related to the study-in effect. On the other hand, as outlined above, irbesartan stimulates PPAR-gamma dependent pathways and thus results in an altered flux of free fatty acids, which may affect nutritional behavior and caloric intake. Furthermore, metabolic improvement was related to blood pressure reduction. It therefore cannot be decided whether the improvement in metabolic parameters is specific for irbesartan (or ARB therapy) or the result of blood pressure reduction. However, a number of large intervention trials have shown that the effect of ARB therapy on metabolic parameters reaches beyond blood pressure reduction.The present study indicates that hypertensive patients with metabolic syndrome with and without diabetes benefit from irbesartan therapy not only with respect to blood pressure reduction but also with respect to a significant improvement of metabolic parameters such as glucose, lipids and liver values.KGP has received speaker's fees from Bristol-Myers Squibb.KG participated in the design of the study and the analysis of the data and drafted the manuscript. FM participated in the design of the study and helped to draft the manuscript. MK conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


We sought to determine and compare the effects of vasopressin, fluid resuscitation and saline placebo on haemodynamic variables and short-term survival in an abdominal vascular injury model with uncontrolled haemorrhagic shock in pigs.n = 7), fluid resuscitation , or a single injection of saline placebo (n = 5). Vasopressin-treated animals were then given a continuous infusion of 0.08 U/kg per min vasopressin, whereas the remaining two groups received saline placebo at an equal rate of infusion. After 30 min of experimental therapy bleeding was controlled by surgical intervention, and further fluid resuscitation was performed. Thereafter, the animals were observed for an additional hour.During general anaesthesia, a midline laparotomy was performed on 19 domestic pigs, followed by an incision (width about 5 cm and depth 0.5 cm) across the mesenterial shaft. When mean arterial blood pressure was below 20 mmHg, and heart rate had declined progressively, experimental therapy was initiated. At that point, animals were randomly assigned to receive vasopressin .After 68 ± 19 min (mean ± standard deviation) of uncontrolled bleeding, experimental therapy was initiated; at that time total blood loss and mean arterial blood pressure were similar between groups (not significant). Mean arterial blood pressure increased in both vasopressin-treated and fluid-resuscitated animals from about 15 mmHg to about 55 mmHg within 5 min, but afterward it decreased more rapidly in the fluid resuscitation group; mean arterial blood pressure in the placebo group never increased. Seven out of seven vasopressin-treated animals survived, whereas six out of seven fluid-resuscitated and five out of five placebo pigs died before surgical intervention was initiated (Vasopressin, but not fluid resuscitation or saline placebo, ensured short-term survival in this vascular injury model with uncontrolled haemorrhagic shock in sedated pigs. For haemodynamic stabilization of critically injured patients with uncontrolled haemorrhagic shock, current advanced trauma life support guidelines recommend infusion of crystalloid or colloid solutions. Interestingly, there appears to be no evidence either for or against early or large amounts of intravenous fluid administration in uncontrolled haemorrhage ,2. AlthoOne way to promote vasoconstriction may be to inject vasopressin, which has potent vasoconstrictive effects, even in severe acidosis and developed vasoplegia. In porcine models of uncontrolled haemorrhagic shock after liver trauma, vasopressin was superior to fluid resuscitation, adrenaline (epinephrine), and saline placebo in terms of blood loss, haemodynamic variables, and survival -5. In agThe purpose of the present study was to compare the effects of vasopressin with those of fluid resuscitation and saline placebo on haemodynamic variables and short-term survival in an abdominal vascular injury model of uncontrolled haemorrhagic shock. Our null hypothesis was that there would be no differences in study end-points.The project was approved by the Austrian Federal Animal Investigational Committee, and the animals were managed in accordance with the American Physiological Society institutional guidelines and the Position of the American Heart Association on Research Animal Use, as adopted on 11 November 1984. Animal care and use were performed by qualified individuals and under the supervision of veterinarians, and all facilities and transportation complied with current legal requirements and guidelines. Anaesthesia was used in all surgical interventions, any unnecessary suffering was avoided and research was terminated if unnecessary pain or stress resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care.2O positive end-expiratory pressure, and tidal volume adjusted to maintain normocapnia. Anaesthesia was maintained with propofol (6 to 8 mg/kg per hour) and a single injection of piritramide (30 mg) [®, B. Braun, Melsungen, Germany) were administered during the preparation phase. A standard lead II electrocardiograph was used to monitor cardiac rhythm; depth of anaesthesia was judged according to blood pressure, heart rate and electroencephalography .This study was conducted in 19 healthy swine, aged 12 to 16 weeks and weighing 30 to 40 kg. The animals were fasted overnight, but they had free access to water. The pigs were pre-medicated with azaperone (4 mg/kg intramuscularly) and atropine (0.1 mg/kg intramuscularly) 1 hour before surgery, and anaesthesia was induced with propofol (1 to 2 mg/kg intravenously). After intubation during spontaneous respiration, the pigs were ventilated using a volume controlled ventilator  with 35% oxygen at 20 breaths/minute, 5 cmH (30 mg) . Muscle If cardiovascular variables or electroencephalography indicated reduced depth of anaesthesia, then additional propofol and piritramide were given. Body temperature was maintained between 38.0°C (100.4°F) and 39.0°C (102.2°F). A 7-Fr catheter was advanced into the descending aorta via a femoral cut-down for withdrawal of arterial blood samples and measurement of arterial blood pressure. A 7.5-Fr pulmonary artery catheter was placed via cut-down in the neck for measurement of right atrial and pulmonary artery pressures. Blood pressure was measured using a saline-filled catheter attached to a pressure transducer , which was calibrated to atmospheric pressure at the level of the right atrium. Pressure tracings were recorded using a data acquisition system . Blood gases were measured using a blood gas analyzer ; end-tidal carbon dioxide was measured using an infrared absorption analyzer .Figure ®; Parke-Davis/Pfizer, Karlsruhe, Germany) diluted to 20 ml with saline (n = 7); fluid resuscitation ; or a single injection of 20 ml saline placebo (n = 5). Fluid resuscitation was initially set at about 2 ml/kg per min over the first 10 min. If this approach failed to restore arterial blood pressure, then fluid resuscitation was enhanced to about 8 ml/kg per min. We used a combination of Ringer's lactate and gelatine solution for fluid resuscitation, because it is the usual strategy in Europe. Vasopressin-treated animals were then given a continuous infusion of 0.08 U/kg per min vasopressin, whereas the remaining two groups received saline placebo at an equal rate of infusion.At that point, the 19 animals were randomly assigned to receive one of the following: 0.4 U/kg vasopressin  or into a covered bucket . Hence, our vasopressin-treated and placebo-treated animals received no additional fluid during experimental therapy. The infusion rate was enhanced to 8 ml/kg per min after 10 min of experimental therapy if mean arterial pressure did not increase to above 40 mmHg. When mean arterial blood pressure reached aortic hydrostatic pressure (about 10 mmHg) and end-tidal carbon dioxide was 10 mmHg or less, the animals were declared dead and administered an overdose of fentanyl, propofol and potassium chloride.After 30 min of experimental therapy, bleeding was controlled by surgical intervention in all surviving pigs. Additionally, fluid therapy (25 ml/kg lactated Ringer's and 25 ml/kg 3% gelatine solution) was started, and haemodynamic variables and blood gases were measured over an additional observation period of 60 min. Afterward, the pigs were killed as described above.P value < 0.05 were considered significant. Because of rapidly changing number of surviving animals in the experimental therapy phase, we did not perform further statistical analysis.Values are expressed as mean ± standard deviation. The comparability of baseline data was verified using one-way analysis of variance. Survival rates were compared using Kaplan-Meier methods with log rank (Mantel Cox) comparison of cumulative survival by treatment group, and were corrected using the Bonferroni method for multiple comparisons. Differences with a two-tailed Before induction of haemorrhage, there were no differences in haemodynamic variables, blood gases, weight, or temperature between groups. Experimental therapy was initiated after 76 ± 24 min in the vasopressin group, 63 ± 19 min in the fluid resuscitation group and 64 ± 9 min in the saline placebo group (not significant). At that time, mean arterial blood pressure .After initiating experimental therapy, the heart rate remained at about 210 beats/min in the vasopressin group, but it decreased from about 180 to about 120 beats/min in the fluid resuscitation and saline placebo groups Figure . Mean arIn this porcine model of vascular injury of uncontrolled haemorrhagic shock, vasopressin maintained cardiocirculatory function at a level that was sufficient to permit at least short-term survival. In contrast, within 20 min of experimental therapy, six out of seven fluid-resuscitated and five out of five placebo-treated animals died.Bleeding was initiated in this model of uncontrolled haemorrhagic shock by an incision to the mesenteric shaft. Thus, we simulated a blood vessel injury, which is often associated with blunt trauma and a subsequent high mortality rate . DosagesVasopressin has been investigated in various catecholamine-refractory shock states, such as cardiac arrest -15 and vThe data reported thus far about the type of fluid resuscitation -25, the 1 receptors and therefore reduced blood flow in skin, muscle, fat tissue and gut. Accordingly, vasopressin shifts blood away from the bleeding side toward the heart and brain [In our model, fluid resuscitation initially improved mean arterial blood pressure rapidly, followed by cardiovascular collapse and death in six out of seven pigs, owing to increased blood loss. This observation is in full agreement with findings in a porcine model of severe liver trauma resulting in uncontrolled haemorrhagic shock . The undnd brain , thus deOur observations in the fluid resuscitation group may suggest both advantages and disadvantages of our resuscitation protocols. Although an increasing end-tidal carbon dioxide level (+100%) in fluid-resuscitated animals indicated a significant increase in cardiac output, this increase in perfusion simply increased blood loss at the injury site, resulting in fatal blood loss. Haemodynamic development in our only surviving fluid-resuscitated animal lagged behind that in the nonsurviving fluid-resuscitated animals, which might have ensured survival. Accordingly, although fluid resuscitation is beneficial during controlled haemorrhagic shock, fluid resuscitation given during uncontrolled haemorrhagic shock may simply increase mean arterial blood pressure to a level at which the cardiovascular system becomes similar to an overflowing bath tub, reflecting ineffective therapy.There are several limitations of our study that should be noted. Because this experiment had to be performed during general anaesthesia because of ethical considerations, the effects of anaesthetic agents such as propofol and piritramid might have had a confounding effect. We cannot state whether hypoperfusion of the gut results in organ damage, therefore limiting long-term survival. Also, we have no information about regional blood flow during experimental therapy, histological samples, or neurological outcome. Although a pulmonary artery catheter was placed inn the animals, we did not obtain cardiac output measurements because it was not possible to perform both multiple blood gas and cardiac output measurements simultaneously in this very dynamic model. We were unable to perform coagulation monitoring, and no fresh frozen plasma, thrombocytes, or clotting factors were administered because of limitations in laboratory and haematology resources. Furthermore, we did not employ blood transfusion, because this is not available in our emergency service. Also, we did not study the effect of a combination of vasopressin and fluid resuscitation in this study. Different vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin) may result in a different haemodynamic responses to exogenously administered arginine vasopressin. Also, the present model reflects severe but local trauma; whether our experience can be extrapolated to patients with additional trauma, such as multiple fractures, requires investigation. Moreover, our pigs were intubated and undergoing continuous positive pressure ventilation throughout the experiment. Cardiopulmonary resuscitation was omitted in this model to allow us to compare fluid resuscitation with vasopressin treatment.Vasopressin but not fluid resuscitation or saline placebo ensured short-term survival in this vascular injury model of uncontrolled haemorrhagic shock in sedated pigs.• Vasopressin treatment, but not fluid resuscitation or saline placebo, ensured short-term survival in this vascular injury model of uncontrolled haemorrhagic shock in pigs.In 2002 VW received a grant from Aguettant Laboratories , a company that has applied for registration of vasopressin with the European authorities. There is no personal conflict of interest.Data from a previous study  are beinKHS designed the study protocol, conducted the laboratory work and wrote the manuscript. HGW helped to design the study protocol and was involved in laboratory work. ACK was involved in laboratory work and writing of the manuscript. WGV helped to design the study protocol and was involved writing of the manuscript. AK conducted all surgical work and was involved in the study design. KHL designed the study protocol and helped to interpret the data. VW designed the study protocol, supervised the laboratory work and was involved in writing the manuscript. All authors read the final draft of the manuscript and agreed with its content and data interpretation.


The ankle blood pressure is commonly used as a ratio to the brachial blood pressure, called ankle-brachial index (ABI). Very few studies have considered the independent value of the ankle blood pressure without indexing it to the brachial blood pressure. We examined the value of ankle blood pressure, together with the exercise blood pressure, as a predictor of cardiovascular (CVD) and total mortality.A prospective follow-up study of 3,858 consecutive ambulatory patients  referred to a symptom-limited exercise test between August 1989 and December 1995. The cohort was followed up for all-cause and CVD mortality until December 31, 2004, by record linkage with the National Causes-of-Death Register. The independent value of ankle blood pressure as a predictor of cardiovascular and total mortality was assessed using Cox proportional hazards modelling.The average follow-up time was 14 years, during which 346 persons died, 108 of them due to CVD. Persons with normal (<140 mmHg) resting brachial blood pressure, ankle blood pressure < 175 mmHg and exercise blood pressure at moderate exercise level ≤215 mmHg at baseline investigation, had the best prognosis and were taken as the reference category. Among persons with elevated ankle blood pressure (≥175 mmHg) but normal or borderline resting brachial pressure and normal exercise blood pressure (≤215 mmHg) at moderate exercise level the multivariate-adjusted hazard ratios  for CVD and total mortality were 2.70 (1.52 – 4.80) and 2.13 (1.58 – 2.85), respectively. Similar and equally significant HRs were observed in persons with both elevated ankle blood pressure and elevated exercise blood pressure, as well as in those persons with elevated exercise blood pressure but ankle blood pressure < 175 mmHg.These results suggest that the ankle blood pressure has an independent value as a marker of arterial stiffness or subclinical atherosclerosis and a risk of future mortality in middle-aged, asymptomatic persons. There are several established procedures for estimating subclinical atherosclerotic changes in human arteries. Increased carotid intima-media thickness is associated with future cerebrovascular and cardiovascular events ,2. PulseThe ankle blood pressure is usually measured in conjunction with the arm blood pressure and the ankle-brachial pressure index (ABI) is calculated. Decreased index is strongly associated with cardiovascular diseases -16. AlsoPatients with exaggerated exercise blood pressure reaction have increased cardiovascular disease morbidity compared with those with normal exercise blood pressure reaction -22. It iWe hypothesized that in the beginning of the arterial stiffening and atherosclerosis the ankle blood pressure may be determined by local factors only, i.e., blood pressure and the elastic properties of arteries. The elevated ankle blood pressure might be one of the earliest signs of adverse changes in the cardiovascular system. Stenotic changes with abnormal ABI are fairly seldom seen in middle-aged persons ,14. AnklLong-term prospective studies on the value of ankle blood pressure in middle-age persons are currently sparse. Therefore, the aim of the present study was to assess the independent value of ankle blood pressure, together with the brachial exercise blood pressure, as a predictor of cardiovascular and total mortality during the average follow-up of 14 years.Subjects for this investigation were derived from a group of 4,038 consecutive ambulatory patients, who underwent symptom-limited bicycle exercise test at the Helsinki Deaconess Institute between August 1989 and December 1995. The patients were referred by occupational health physicians to a symptom-limited exercise test to rule out coronary heart disease and evaluate physical fitness. More precisely, 1,734 were sent for the evaluation of physical fitness, 1,799 for diagnostic testing due to chest pain or shortness of breath, 488 because of suspected arrhythmias and 17 for mixed reasons, mainly for suspicion of exercise-induced asthma. Patients with a history of myocardial infarction, percutaneous coronary angioplasty, coronary artery bypass grafting, congestive heart failure or stroke, were excluded from the analysis. The final study group consisted of 3,858 patients. The study was approved by the Ethical Committee of the National Public Health Institute.Brachial blood pressure was measured by trained technicians using the auscultatory method with a standard sphygmomanometer from the left arm of the subject in a supine position after a 5 minute rest. The ankle blood pressure was simultaneously measured from the right leg using a Doppler probe with a mercury sphygmomanometer. If the pulse of the posterior tibial artery was absent, the ankle blood pressure measurements were taken on the dorsalis pedis artery.Exercise testing was conducted on an electronically braked bicycle. The starting load was 50 Watts for men and 40 Watts for women, and the load was increased every 3 minutes by 50 Watts for men and 40 Watts for women. Blood pressure was measured with a sphygmomanometer at 2 minutes at all loads and immediately prior to test termination. Readings were recorded to the nearest 5 mmHg. The 2-minute blood pressure recording at the moderate exercise level (150 W for men and 120 W for women) was used in the analyses. If that level was not reached, blood pressure from the lower level was used. The test was continued until a subject refused to continue, or until the attending physician felt it unsafe to continue. The criteria for myocardial ischaemia during the exercise test were ischaemic changes in ECG defined as ST depression >1.0 mm at 60 ms after the J-point with typical ischaemic complaints.Other risk factors assessed at baseline were age, gender, body mass index (BMI), smoking status, medical history, parental history of early cardiovascular disease, physical working capacity, self-reported history of cardiovascular diseases, total cholesterol and glucose.Subjects were divided into five groups based on resting ankle and exercise blood pressure at the moderate exercise level : 1) Reference group, where the resting ankle blood pressure was < 175 mmHg and the exercise blood pressure ≤ 215 mmHg; 2) patients with elevated ankle blood pressure (≥175 mmHg) but normal exercise blood pressure (≤215 mmHg); 3) patients with elevated ankle (≥175 mmHg) and elevated exercise blood pressure (>215 mmHg); 4) elevated exercise blood pressure (>215 mmHg), but ankle blood pressure <175 mmHg; and 5) patients who could not be classified. Group 4 consists of patients with a discrepancy between the ankle blood pressure and brachial exercise systolic blood pressure, which indicated significant stenotic changes along the conduit vessels. The unclassifiable group could not reach the moderate exercise level because of a specified reason (for example ischaemic heart disease) or an unspecific reason .The mortality follow-up data were available up to 15 years (range 12 – 15 years) after the exercise test, until December 31st, 2004. Deaths were ascertained by record linkage of the study data to the National Causes-of-Death Register, on the basis of the personal identification code unique to every resident of Finland. Thanks to the country-wide register, the coverage of the follow-up was 100%.In the Causes-of-Death Register deaths were coded according to the Ninth  and Tenth (since the beginning of 1996) versions of the International Classification of Diseases (ICD). The primary endpoint was cardiovascular death, and all-cause mortality was used as a secondary endpoint. ICD-9 codes 410 to 414, 431, 436, 798, 4330A, 4331A, 3339A, 4341A, 4349A, 4376A or ICD-10 codes I20–I25, I46, I61, I63–I64, R96, R98 as the underlying cause of death were taken as cardiovascular deaths. Altogether, 346 persons died during the follow-up, 108 of the deaths were cardiovascular. As a whole, the study consisted of 52,234 person-years of follow-up.Data are expressed as mean ± SD for continuous variables, or counts and proportions for categorical variables. The following cardiovascular risk factors were dichotomized: early parental cardiovascular death (yes or no), self-reported elevated cholesterol , self-reported elevated blood glucose  and current smoking (yes or no). Age, BMI, smoking  and blood pressure (mmHg) were handled as continuous variables.Continuous variables were compared between the blood pressure groups with analysis of variance and proportions with chi-square tests. Univariate associations between different blood pressure indicators were evaluated with Pearson's product-moment correlation coefficients.Associations between the blood pressure groups and mortality were analyzed using Kaplan-Meier survival curves and log-rank tests. Cox proportional hazard models were used for estimating the multivariate-adjusted independent associations of the blood pressure groups with total and cardiovascular mortality. Results were expressed as hazard ratios (HR) and 95% confidence intervals (CI) compared to the reference group. The basic models were adjusted for age and sex. The larger models were further adjusted for BMI, physical working capacity , self-reported blood glucose and cholesterol, current smoking and early parental history of cardiovascular disease. The statistical analyses were carried out with R (Version 2.3.1).The mean age at baseline was 50.5 ± 10.0 years (range 15 – 84), and the mean BMI was 26.1 ± 3.8 kg/m2. The mean brachial blood pressure was 133.1 ± 18.7/85.3 ± 10.9 mmHg) and pulse 73.8 ± 12.9/min. The correlation coefficient between the brachial blood pressure at rest and the exercise blood pressure at the moderate exercise level  was 0.548  in men and 0.649  in women. The correlation coefficient between the ankle blood pressure and systolic blood pressure at the moderate exercise level was 0.543 (P < 0.0001) in men and 0.597 (P < 0.0001) in women.Table In patients (n = 791) with elevated ankle blood pressure (≥175 mmHg) and normal exercise blood pressure the resting brachial blood pressure was normal or slightly elevated: 144 ± 17/90 ± 10 mmHg. Of this group 36% were on cardiovascular medication. In patients without any medication (n = 510) the blood pressure was normal or slightly elevated: 142.2 ± 15/90.0 ± 10.1 mmHg. In this whole group, 116 (14.7%) patients died during the follow-up period, 37 (4.7%) due to cardiovascular causes.Among patients (n = 509) with elevated ankle blood pressure and elevated exercise blood pressure the male sex dominated. The brachial blood pressure at rest was elevated: 152.8 ± 17/94.0 ± 10 mmHg. Compared with the previous group, BMI and ankle blood pressure were also higher and the smoking history was longer. In patients without any medication (n = 348) the mean blood pressure at rest was elevated: 150.6 ± 16/93.1 ± 10 mmHg. Myocardial ischaemia during exercise was diagnosed in 44 (8.6%) patients. The all-cause mortality in this group was 58 patients (11.4%) and the mortality due to cardiovascular disease was 20 patients (3.9%).In patients with the discrepancy between the ankle blood pressure and systolic blood pressure  there was no correlation between the ankle blood pressure and exercise blood pressure at moderate level  among men and r = 0.059, n = 21, p = 0.80 among women). Compared with the reference group the ankle blood pressure was a bit higher. The male sex dominated (201/222) in this group, and smoking was more common than in groups 1 and 2. Fifteen per cent were on cardiovascular medication. Myocardial ischaemia was diagnosed in 14 patients (6.3%), two of them died during the follow-up. The all-cause mortality was 22 patients (9.9%) and the mortality due to cardiovascular causes was 8 (3.6%).The fifth group (n = 133) was older. They could not tolerate moderate exercise level because of ischaemic heart disease (n = 71) or leg atherosclerotic disease . Abnormal lung function was observed in 10 patients (oxygen <90%). Almost half of this group (45.2%) died during the follow-up period, 23 (17.3%) due to cardiovascular causes. There were 43 patients with low fitness without any specific reason. Twenty (47%) of them died during the follow-up period, 6 (14%) due to cardiovascular causes. They tended to be current (n = 19) or ex-smokers (n = 7). The male sex dominated (36/43). Nine were on antihypertensive medication.Figure Compared with group 1, the age and sex-adjusted hazard ratios of CVD and all-cause mortality were significantly elevated in all other groups Table . FurtherFor comparison, we calculated the HRs for the different levels of ankle blood pressure alone Table . PatientIn the present study, we demonstrated that the ankle blood pressure gives us important information about the status of the arterial tree in middle-aged asymptomatic individuals. The main finding was that even those persons among whom the elevated ankle blood pressure was the only abnormal finding had 2.7-fold higher multivariate-adjusted risk of CDV death and 2.1-fold higher risk of death from any cause than persons with normal brachial, ankle and exercise blood pressures. This suggests that the measurement of ankle blood pressure could be a relatively simple, inexpensive and non-invasive tool for assessing early, subclinical atherosclerotic changes in young and middle-aged individuals. This finding is consistent with earlier studies suggesting a J-shaped association between ABI and CVD risk ,17,18.At least three independent lower-extremity large-vessel characteristics determine the ankle blood pressure: local pressure, elasticity of the vessels and the pulse wave. Arterial stiffness with increased pulse wave velocity and augmented pulse pressure cause a strong cyclic stretching on vascular smooth muscle cells -26. HypeAlthough the importance of exercise hypertension remains controversial, the majority of recent studies show that an exaggerated systolic blood pressure response to exercise is an independent predictor of future hypertension and CVD mortality -20,26-29The categorization of our study cohort into five subgroups enabled a logical understanding of the chronological sequence of adverse changes in the ankle blood pressure. In patients with normal ankle, arm and exercise blood pressure, both CVD and total mortality during the follow-up were low even among persons with an abnormal exercise test. The elevated ankle blood pressure either with or without elevated exercise blood pressure was significantly associated with CVD mortality and all-cause mortality. It is associated with abnormally high ABI, which has also been found in other studies ,18.Patients with elevated exercise blood pressure but ankle blood pressure ≥175 mmHg are a more discrete group. With our cut-points (ankle blood pressure ≥175 mmHg and exercise blood pressure at moderate exercise level > 215 mmHg) they formed a group in which CVD and all-cause mortality were at the same level as in patients with elevated ankle blood pressure. The discrepancy between the ankle and exercise blood pressures can be explained by hemodynamically significant stenotic changes along the conduit vessels. The poor correlation between the exercise brachial blood pressure and the ankle blood pressure is in accordance with the existence of stenotic changes. Also, abnormally low ABI was observed in group 4 compared with the reference group.Normally there is a strong correlation between the arm, ankle and exercise blood pressures as long as the stenotic changes along the conduit vessels are minor. Similar correlation between the systolic blood pressure and maximal or submaximal exercise blood pressure has been found in other studies . ElevateLow cardiovascular fitness is associated with premature mortality. The literature is filled with long-term follow-up studies, conducted in relatively healthy populations -36, or fOur study has certain limitations. The patients were referred by occupational health physicians and thus they do not represent a random sample of the general population. The reference group is a predominantly well-educated group. The ankle blood pressure was measured from one leg only. The blood glucose and total cholesterol were self-reported and only half of the patients knew their glucose value. However, our purpose was not to explain the aetiology of elevated ankle blood pressure but to examine its prognostic value. These limitations of our study should not affect the validity of the findings. Furthermore, most patients with a diagnosed MI during the follow-up had received pharmacological therapy or undergone invasive therapeutic procedures and their lifestyle had changed. Such a bias has probably led to an underestimation, rather than an overestimation, of the prognostic significance of elevated ankle blood pressure.In the present study we showed that the ankle blood pressure – without indexing to arm blood pressure – has an independent value as a marker of subclinical atherosclerosis in asymptomatic middle-aged patients. The elevated ankle blood pressure is one of the earliest sign of the adverse changes in the arteries. It identifies high-risk individuals and may provide the necessary motivation to promote lifestyle changes. On the other hand, exaggerated exercise blood pressure reaction with normal ankle blood pressure reveals those patients with stenotic changes along the conduit vessels. They are likely to need more detailed investigations and intensive therapy. Thus, measurement of the ankle blood pressure could be an inexpensive and non-invasive tool which helps to assess the CVD risk and to guide the intensity of other examinations and therapies.The author(s) declare that they have no competing interests.HH: Conceived the idea of the study, investigated the patients, carried out part of the statistical analyses and wrote the first draft of the manuscript.RP: Took care of the data management and part of the statistical analyses. Contributed to the interpretation of the results and commented on the manuscript with important intellectual content.VS: Supervised the study. Contributed to the follow-up of the patients and interpretation of the statistical analyses. Commented on the manuscript with important intellectual content.All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here: