The prevalence and diagnostic value of heart failure symptoms in elderly primary care patients with hypertension is unknown.To assess the prevalence, sensitivity, specificity, positive and negative predictive value of symptoms in association with an abnormal echocardiogram.Cross-sectional screening study in five general practices in the south-east of the Netherlands.Between June 2010 and January 2013, 591 primary care hypertension patients aged between 60 and 85 years were included, without known heart failure and not treated by a cardiologist. All patients underwent an echocardiogram and a structured interview including assessment of heart failure symptoms: shortness of breath, fatigue, oedema, cold extremities, and restless sleep.Restless sleep was reported by 25 %, cold extremities by 23 %, fatigue by 19 %, shortness of breath by 17 %, and oedema by 13 %. Oedema was the only symptom significantly associated with an abnormal echocardiogram , apart from higher age , previous myocardial infarction , and a systolic blood pressure of >160 mmHg . Screening with echocardiography might be considered in patients with oedema. Hypertension is highly prevalent, with the Framingham study showing a lifetime risk for developing hypertension of 90 % in people with a normal blood pressure at age 55 . A high Several important patient-reported symptoms of heart failure are oedema, dyspnoea, and fatigue –16. BecaEchocardiography is seen as the gold standard for the diagnosis or confirmation of cardiac dysfunction associated with heart failure  and can Until now it is unclear in elderly primary care patients with hypertension which heart failure symptoms may be associated with an abnormal echocardiogram. The objectives of the current study were to examine (1) the prevalence of symptoms which are in general related to cardiac dysfunction reflected by an abnormal echocardiogram, (2) the sensitivity, specificity, positive, and negative predictive value of symptoms of an abnormal echocardiogram, and (3) the relation between the symptoms and an abnormal echocardiogram, after adjustment for several confounders.Between June 2010 and January 2013, primary care patients aged between 60 and 85 years, with an International Classification of Primary Care for hypertension (K86 or K87) as captured from their medical record, were recruited from five general practices affiliated with the primary care organisation PoZoB  for this cross-sectional study. Exclusion criteria were: previous diagnosis of heart failure, current treatment by a cardiologist, history of severe psychiatric illness other than mood/anxiety disorders and/or cognitive impairments (e.g. dementia), terminal cancer, and insufficient knowledge of the Dutch language. This study was approved by the medical ethics committee of the Elisabeth Hospital in Tilburg, the Netherlands.Eligible patients received written information about the study by mail and were asked to sign an informed consent form. Patients were contacted by phone, and in case of informed consent an appointment for an interview at their local GP office was scheduled. This interview consisted of a structured interview of 1 h by a trained nurse. At the end of the intake, an appointment for the echocardiogram was scheduled which also took place at the local GP office.Information on demographic and clinical variables was obtained from purpose-designed questions in the interview and included gender, age, marital status, and educational level. Furthermore, blood pressure was measured twice and the average blood pressure was used to dichotomise systolic blood pressure (>160 mmHg was cut-off). Height and weight were measured in order to calculate the body mass index (BMI). Information on clinical variables retrieved from the patients’ medical records included myocardial infarction (MI) and peripheral arterial disease.Information on heart failure symptoms was obtained during the interview. Structured and standardised questions were used to assess heart failure symptoms. Symptoms were dichotomised (yes/no) and defined as: shortness of breath during moderate exertion , regularly occurring fatigue, oedema of the legs, ankles and/or feet, having cold extremities, and restless sleep, during the past 4 weeks.The echocardiogram was performed and evaluated by an experienced echocardiographer of the local primary care laboratory located in Eindhoven, the Netherlands. All the echocardiograms were reviewed by a cardiologist specialised in echocardiography, who indicated if the echocardiogram was abnormal according to a protocol suitable for primary care, based on current guidelines , 24. TheStatistical analyses were performed using the IBM Statistical Package for the Social Sciences version 18.0. Differences in baseline characteristics were compared between normal and abnormal echocardiograms and assessed with Chi-square tests or Student’s/Welch’s T-tests when appropriate. For each symptom and clinical variable, the sensitivity, specificity, positive predictive value, and negative predictive value with 95 % confidence intervals were calculated.Adjusted odds ratios were calculated using multiple logistic regression, with an abnormal echocardiogram  as dependent variable. A possible relation between symptoms and an abnormal echocardiogram were adjusted for age, gender, education, having a partner, previous MI, peripheral arterial disease, and elevated systolic blood pressure of >160 mmHg.n = 5), leaving a total of 591 (65 %) patients for analysis.From 6 different GP practices, 913 eligible patients with hypertension were approached and 619 (68 %) patients agreed to participate. Of these participants, 2 were excluded post-hoc because they met the exclusion criterion of being treated by a cardiologist, 5 were excluded post-hoc because the echocardiogram was not of sufficient quality and 16 patients did not have an echocardiogram, of which 3 were admitted to the hospital, 1 died, and 12 did not show up. Patients with congenital disease and/or hypertrophic cardiomyopathy were excluded from analyses (n = 262). Patients with an abnormal echocardiogram were significantly older, less often had a partner, were more likely to have had a previous MI, and had a higher systolic blood pressure as compared with the patients with a normal echocardiogram. Abnormalities on the echocardiogram were present in 30 % of the study sample (Table Tables le Table .Table 2Bn = 149). The most sensitive was shortness of breath with a sensitivity of 32 %. The most specific symptom was oedema of the ankles, feet, or legs, with a high specificity of 90 %. Oedema also had the highest positive predictive value (45 %) and negative predictive value (73 %) for an abnormal echocardiogram  limiting generalisability to other populations with more ethnic diversity. Another limitation is that we do not have detailed demographic information of the non-responders. However, the response rate in the current study was almost 70 %. Moreover, the current design was not used to assess prevalence figures but rather to evaluate whether signs and symptoms could be associated with echocardiogram outcome.Previous research showed that the most common symptoms associated with heart failure are oedema, dyspnoea, and fatigue , 15. HowAlthough breathlessness is the most commonly reported symptom in established heart failure in primary care , our finIn the majority of cases the GP is involved in the initial diagnosis of heart failure . Therefo


Diabetes affects approximately 250 million people in the world.Cardiovascular autonomic neuropathy is a common complication of diabetesthat leads to severe postural hypotension, exercise intolerance, andincreased incidence of silent myocardial infarction.To determine the variability of heart rate (HR) and systolic blood pressure(SBP) in recently diagnosed diabetic patients.The study included 30 patients with a diagnosis of type 2 diabetes of lessthan 2 years and 30 healthy controls. We used a Finapres® device to measureduring five minutes beat-to-beat HR and blood pressure in three experimentalconditions: supine position, standing position, and rhythmic breathing at0.1 Hz. The results were analyzed in the time and frequency domains.In the HR analysis, statistically significant differences were found in thetime domain, specifically on short-term values such as standard deviation ofNN intervals (SDNN), root mean square of successive differences (RMSSD), andnumber of pairs of successive NNs that differ by more than 50 ms (pNN50). Inthe BP analysis, there were no significant differences, but there was asympathetic dominance in all three conditions. The baroreflex sensitivity(BRS) decreased in patients with early diabetes compared with healthysubjects during the standing maneuver.There is a decrease in HR variability in patients with early type 2 diabetes.No changes were observed in the BP analysis in the supine position, butthere were changes in BRS with the standing maneuver, probably due tosympathetic hyperactivity. CAN is detected inabout 7% of both types 1 and 2 DM at the time of the diagnosis. The annual increasein prevalence of CAN has been reported to be around 6% in type 2 DM7.Cardiovascular autonomic neuropathy (CAN) is a common type of autonomic dysfunctionin patients with DM and is associated with abnormalities in the control of the heartrate (HR), with loss of its variability, decreased baroreceptor sensitivity (BRS),and late changes in vascular dynamics8. Thisprevalence may increase to 65% with increasing age and DM duration6. CAN has been linked to tachycardia at rest, orthostatichypotension, exercise intolerance, increased incidence of asymptomatic ischemia,myocardial infarction, and decreased rate of survival after myocardialinfarction3.The prevalence of confirmed CAN  in clinical studies in unselected populations, includingpatients with type 1 or 2 DM, varies from 16.6 to 20%9. The HRvariability (HRV) based on IBI variations in short-term or long‑term recordings maybe represented, according to the type of mathematical processing, by the HRVanalysis in the time domain and frequency domain 10.In healthy individuals, HR has a high inter-beat interval (IBI) variability ratewhich fluctuates with breathing, increasing during inspiration and decreasing duringexpiration9.In short-term recordings, different spectral components may be identified dependingon their frequencies in Hz. High-frequency (HF) components are considered an area ofvagal influence, whereas low-frequency (LF) components are under sympathetic andsome vagal influence, although baroreceptor influences have also beenpostulated9.Standardized protocols of autonomic load  for examination of the HRV spectral analysis in short-term recordingsimpose a stress element to assess the level and reactivity of both sympathetic andparasympathetic systemsThe objective of this study was to determine beat-to-beat HR and blood pressure (BP)variabilities in patients with type 2 DM with less than two years of diagnosis andcompare the results with variabilities in these parameters in healthy subjects.A descriptive, transversal, prolective, comparative, and non-randomized study wasdeveloped with individuals of both genders, including 30 diabetic subjects with lessthan two years from the diagnosis and 30 healthy subjects between 30 and 60years.The subjects with DM were identified from a monitoring protocol of a cohort ofpatients with insulin resistance. During follow-up of these patients, a 75-gram oralglucose tolerance test was performed periodically, and when the results confirmedthe diagnosis of DM, the patient was invited to participate in the study. Urinalysisruled out proteinuria and kidney damage, whereas nerve conduction velocities wereperformed to rule out somatic peripheral neuropathy. These studies were performed toassess damage to these organs by long-standing hyperglycemia. Finally, the patientswere required to have a normal funduscopic exam performed by a certified neurologistto rule out diabetic retinopathy at the time of the study. These variables weredetermined as control parameters to ensure that the duration of the DM was not toolong.11.Atherosclerotic peripheral vascular disease was absent in all patients, based on acarotid intima-media thickness below 0.685 mm (0.659-0.691 mm). This is the rangeestablished by the CARMELA study (2011) for the maximum age of the patients includedin our study (60 years)The project was approved by the Ethics and Research Committee of the institution andwas in compliance with the Declaration of Helsinki. Before testing, each participantsigned an informed consent form.Prior to the study, the cases had capillary blood glucose levels between 60 mg/dL and200 mg/dL. We requested the subjects in both groups to be free from any stimulantsubstances 24 hours prior to the study and to have at least 8 hours of sleep thenight before. We excluded patients with underlying diseases with an autonomiccomponent or of any other nature which could interfere with the test results.Measurement of the two variables of interest – BP and IBI – was carried out withFinometer® , during three maneuvers (registered for fiveminutes each one):Supine position.Standing after one minute of stabilization.Rhythmic breathing of 6 cycles per minute paced electronically.The data obtained from the time series of IBI in milliseconds (ms) and systolic BP(SBP) in mmHg (for each heart beat) in these three conditions were analyzed withtime diagram, histogram, autoregressive analysis, and fast Fourier transform.The time series were manually cleaned from artifacts or premature beats. Astatistical analysis was performed in the time and frequency domains using the SPSSsoftware. Mean, standard deviation (SD), standard error and coefficient of variationfor the time domain were obtained. Using Beatscope (Finometer’s own program toextract the time series of IBI in ms and BP in mmHg), the time series weretransferred to Excel for statistical evaluation. For the spectral analysis, we usedSPSS, MatLab, Kubios, and Nevrokard. The level of statistical significance was setat p ≤ 0.05.There were no significant differences between the two groups in the variables age,gender, SBP, and fasting glucose .Body maNone of the patients presented abnormal sensory or motor peripheral nerve conductionvelocities, F responses or H reflexes. Sympathetic skin responses were present withnormal amplitudes and latencies.In the first maneuver, the patient was placed in the supine position for five minutesafter one minute of stabilization. In healthy subjects, HR and BP had relatively lowvariability, without sudden changes in frequencies . This waIn the second maneuver, the subjects were asked to stand up after a 5-minute supinerest. Immediately after standing up, the BP decreased and the HR increased as aconsequence of baroreceptor action. These variables returned to their baselinelevels within approximately 30 seconds, reaching their highest point at 15 seconds.This has been documented as the 15/30 index or Ewing score, a normal physiologicalphenomenon.Rhythmic breathing started with the aid of a visual metronome with 5-secondinspirations and 5-second exhalations during a recording time of 5 minutes. Thiscondition resulted in graphs with more regularity and wider variations in BP and HR,showing an integrity of the baroreflex in both cases. However, there was again alower variability in diabetic compared with healthy subjects.When we conducted the numerical analysis, we obtained punctual values that allowedthe comparison of the variables established for our objectives.The HR values in the supine position are summarized in Although no differences in the mean HR in beats per minute were found between the twogroups, there were significant differences in the SD of these means, the SD of theNN intervals (SDNN), the root mean square of successive differences (RMSSD), and theNN50 percentage (pNN50). In all cases, the values were higher in healthy subjectscompared with diabetics , reflecting a higher variability in the control group. Whenthe total power (TP) and its components LF and HF were analyzed, values weresignificantly higher in healthy subjects, with a predominance of LFs. Afternormalizing these data, we found no difference between the groups.The stimulus from the position modification generated changes in the HR, withdifferences observed only in SD, SDNN, RMSSD, and p-NN50 with higher values forcontrol subjects. In TP, we observed that the proportions cited in the previousTable were maintained. However, on a global level, slightly higher values wereobserved, with a prevalence of LF both in absolute values as in normalized units(nu).2, as well as in nu, when compared with thevalues obtained in the standing and supine positions. The spectral analysisregarding predominance of LF or HF suggests either a sympathetic or parasympatheticpredominance.In the spectral analysis, a significantly higher TP was found in healthy comparedwith diabetic subjects. It should be noted that the LFs were higher both in punctualvalues in msIn the supine position, we found no differences in the SBP parameters .When the standing maneuver was performed , SBP reaResults of the analysis of SBP with rhythmic breathing are summarized in The BRS expresses the sensitivity in the response of the IBI to increasing ordecreasing SBP. A significant difference was observed in BRS in the standingposition, which was lower in the diabetic group compared with that obtained in thecontrol group.12. As CAN progresses,parasympathetic denervation is followed by compensatory sympathetic overdrive,resulting in abnormal cardiac autonomic reflex tests followed by symptomatic CAN. Ata stage in which sympathetic denervation of the blood vessels is occurring,autonomic dysfunction correlates clinically with postural hypotension12. The time scale for theprogression is unclear, but it is estimated that many patients with subclinical CANwill develop features of cardiac involvement within 5 years of developing abnormalparameters in the frequency and time domains13.During an initial subclinical stage, CAN is detected through abnormalities in thedomains of frequency and time of the HRV spectral analysis and in BRS tests. Theseabnormalities can even be present at the time of the diagnosis of DM14 showed in ameta-analysis an increased mortality among diabetic patients with autonomicneuropathy compared with those without this neuropathy. The risk rate for silentmyocardial ischemia in the group with autonomic neuropathy was 1.96 . When they analyzed the mortality rate in 2900 subjects, the relativerisk of death in patients with DM and autonomic neuropathy was 2.14 14. These datahave great importance and suggest that autonomic testing should be an integral partof the approach in all diabetics.Ziegler et al.15. It has been suggested that the earliest indicatorof diabetic autonomic neuropathy is CAN16.Although these studies have included diabetic patients, most have been conducted inpatients with at least 5 years of disease or with chronic diseases, such asperipheral neuropathy, nephropathy, and retinopathy17. There are only a few studiesconducted to analyze specifically the short-term (beat-to-beatvariability) HRV values in the time domain, or including spectral analysis to assessthe sympathetic or parasympathetic influence in the frequency domain.Although HRV has been commonly assessed as part of the evaluation of cardiacautonomic neuropathy, the variability in BP has been much less studiedExploratory studies at different stages of the disease are important for theunderstanding of its natural course. In this study, age, gender, basal BP, andfasting glucose were statistically similar in both groups, although there was aslight difference in BMI, which was higher in the diabetic group. This is explainedby a higher prevalence of overweight in type 2 diabetic patients .18. No statisticalsignificance was also found between nu values.With the patient in a supine position, there is no stimulus to determine adominance of the sympathetic over the parasympathetic system. There is nogravity influence and activation of baroreceptors is only determined by changesin BP mediated by respiratory movements. In this first maneuver, a statisticallysignificant difference was found in the SD of the HR of diabetics compared withcontrol subjects. This indicates that the variability in patients with DM islower than that registered in healthy subjects. This is confirmed in theshort-term IBI (in ms) analysis with calculation of the SD of this record(SDNN), root mean square of successive differences (RMSDD), number of times thatthis consecutive interval from one heart beat to another exceeds 50 milliseconds(NN50), and percentage of these events with regard to the complete series ofregistered heart beats (pNN50). There is also a greater TP in this maneuver,dominated by LF over HF. By normalizing these units, the bias produced by verylow frequencies (VLF) is eliminated. No practical value has been defined forVLF19.In the standing position, a physical challenge is imposed by gravity whichproduces a momentary sudden fall in BP that never exceeds 40 mmHg and acompensatory tachycardia lasting approximately 15 seconds. This maneuveractivates sympathetic pathways, so when there is damage to either autonomicbranch, an imbalance is detected in the described measurements. It has beenestablished in diabetic patients that parasympathetic fibers to the heart arethe first to suffer some damage, so it is possible to find early tachycardia indiabetic patients compared with healthy subjectsWe found no differences in mean frequencies between diabetics and healthysubjects. However, in all other short-term variables such as SDNN, RMSSD, andpNN50, we found lower values in the diabetic compared with the control group,indicating a lower HRV. In this maneuver, and for both cases, there was apredominance of a sympathetic over a parasympathetic effect, which may beexplained by the fact that in early CAN stages there is still no importantsympathetic damage to cause sympathovagal imbalance. This probably indicatesthat short-term analysis factors  might be very usefulfor initial screening of CAN in these patients, even if the regulatory orsympathovagal balance is intact. This suggests that the loss of variability inpatients with DM may be the earliest manifestation of CAN.nu.During rhythmic breathing (at 0.1Hz), there was a predominance of LF(0.1–0.15Hz), implying a sympathetic challenge. The differences in theparameters were the same as those observed with the previous maneuver. However,here we noticed an important dominance of LF over HF, which indicates that thestimulus of rhythmic breathing conferred this sympathetic property. There was nodifference between groups in Hence, we found a lower HRV in patients with early DM when compared with healthysubjects, mainly due to parasympathetic damage to the heart, although earlysympathetic damage also occurs, but to a lesser extent -4.20.BP is mainly determined by cardiac output times peripheral resistance. Thesympathetic innervation of the heart controls the HR, ventricular contractility,and stroke volume. Although the cardiovagal innervation does not influencecontractility and stroke volume, it has a powerful influence on the HR either byinducing bradycardia or transient tachycardia with the withdrawal of itsactivity. Blood vessels have a vasomotion at approximately 0.1Hz (each 10seconds) mediated solely by the sympathetic innervation. The HF variability ofthe BP is probably transmitted only by the heart, whereas the LF variability isrelated to the LF variability of the heart and the LF variability due tovasomotion induced by the sympathetic nervous system. Therefore, in the spectralanalysis of the BP, there is a sympathetic or LF predominance. This influence isseen in patients with atrial fibrillation in whom HRV (either HF or LF) isabsent, but a variability in LF is maintained by the BPBaseline pressure in our experimental and control groups was within the normalrange and did not differ significantly between each other.In the supine position, we obtained values with the Finapres® for mean SBP, SD,maximum and minimum pressures, TP, and LF and HF that were not significantlydifferent. It is important to highlight that there were no differences betweengroups in the baseline analyses, which makes them comparable in regards to thechallenges imposed by the sympathetic stimulation (standing position andrhythmic breathing). It should be mentioned that the BP was slightly higher inthe diabetic group than in the control group, due to a dominance of thesympathetic control (LF).During the standing maneuver, SBP was higher in diabetic patients, both in mean,as well as in maximum and minimum numbers. However, the dominance stillrespected the sympathetic factor of LFs, and this response was even greater inthe control group. This might indicate that the vascular response is preservedin the control group, which has better mechanisms of BP regulation, whereas indiabetic patients, sympathetic hyperactivity to the vasculature is notcompletely balanced by the baroreceptor reflex.In the rhythmic breathing maneuver, we observed a sustained oscillation ofinspiration and expiration in which a sympathetic stimulus dominated over aparasympathetic one, not excluding the control of the latter by mechanisms ofBRS. In this maneuver, the only statistical significance was found in the meanSBP in diabetics compared with controls, derived predominantly from the factthat the DM group had higher maximum pressures than the control group. In thefrequency domain, TPs and its components LF and HF did not differ significantlybetween groups. This occurs when there is maintained sympathetic andparasympathetic integrity and is considered a normal response.In the supine position, the only difference was the lower LF values in diabeticscompared with controls, whereas LF/HF rates were similar. This lower response isdue to the absence of a gravitational stimulus.This pattern remained in the standing position, showing no difference betweenpressure and variability by SD. A significant difference was obtained in TPestablished by a dominance of LFs in which the control group showed highervalues because of better responses. However, this normal response to sympatheticdominance stimulation persists and does not affect the values measured inmmHg.In rhythmic breathing, the stimulus of the sympathetic effect dominated over theparasympathetic one, but in a similar proportion as in the two previousmaneuvers; once again, this did not modify the mean BP, nor its SD. The aboveshows that the sympathovagal control is intact in both groups, with broaderresponses in the frequency domain in the control compared with the diabeticgroup.As previously described, the analysis of the BRS derives from a quotient betweenthe IBI (expressed in ms) and the SBP (in mmHg). This reflects a cardiacresponse to changes in registered pressure and involves both sympathetic controlfor positive chronotropic effects in face of a BP decrease, as well asparasympathetic control for negative chronotropic effects in face of a BPincrease and requirement for IBI prolongation. It is, therefore, important topoint out the response to these two major maneuvers, supine position andstanding position.Our results demonstrate that there was no difference in baseline measurements inthe supine position, but there was a difference in the standing maneuver, inwhich control individuals showed a greater sensitivity when compared withdiabetic patients. This is because the SBPs were higher in diabetics, and sincethis variable is calculated as a quotient, it tends to a smaller number. Thesefindings could suggest a slightly lower parasympathetic response in diabeticscompared with controls.There is a decreased HRV in the supine and standing positions and during rhythmicbreathing in diabetics subjects with less than 2 years of diagnosis compared withcontrol subjects, determined by the SD and by the analysis of short-termvariabilities , probably associated with a parasympatheticfailure.nu, HR spectral values were similar in both groups. In standardvalues (no nu), the results were significant. It is possible thatthis loss of variability occurs with a relatively normal sympathetic balance, whichsuggests that short-term variables may be useful for the assessment of thevariability in conditions of good autonomic balance. Therefore, it is suggested thatthese variables may be the first to become abnormal in the DM spectrum.With There was no significant difference in SBP in diabetic patients with recent diagnosisin the analysis of the time and frequency domains. However, SBP in the standingposition tended to be higher in diabetics compared with controls, despite notreaching pathological values.During orthostatism, BRS was slightly decreased in diabetic subjects with recentdiagnosis compared with controls. This contrasts with the results in the supineposition, in which there was no difference, probably due to the absence ofgravitational stress.The analysis shows that the HRV is decreased in patients with recent-onset DM.This finding is relevant because only a few studies on HRV have been performedin patients with recent-onset DM, showing that cardiac autonomic neuropathyappears early in the disease. The control of BP is more complex because itinvolves vagal and sympathetic activity to the heart and sympathetic activity toresistant vessels. The sympathetic damage to blood vessels is probably preservedin the early stages of the disease and may be affected only in late stages.Therefore, more studies or different techniques are necessary to demonstratechanges in BP with analysis of either the time or frequency domains inrecent-onset DM. There seems to be sympathetic hyperactivity to the resistantblood vessels in early DM, as shown by the increase in BP in the standingposition, although more studies are required to elucidate this point.


Chronic heart failure (CHF) has been remained a leading cause of cardiovascular morbidity and mortaluty. The risk stratification of CHF individuals based on clinical criteria and biomarkers' models may improve medical care and probably increase efficacy of treatment strategy. However, various predictive models approved for CHF patients appear to be distinguished in their prognostications. The study aim was to evaluate whether biomarker risk prediction score is powerful tool for risk assessment of three-year fatal and non-fatal cardiovascular events in CHF patients.It was studied prospectively the incidence of fatal and non-fatal cardiovascular events in a cohort of 388 patients with ischemic-induced CHF within 3 years. Circulating biomarkers were collected at baseline of the study.+/annexin V+ endothelail-derived microparticles (EMPs) and CD31+/annexin V+ EMPs to CD14+CD309+ monuclear progenitor cells (MPCs) ratio. Index of cardiovascular risk was calculated by mathematical summation of all ranks of independent predictors, which occurred in the patients included in the study. Kaplan-Meier analysis showed that patients with CHF and the magnitude of the risk of less than 4 units have an advantage in survival when compared with patients for whom obtained higher values of cardiovascular risk score ranks.Independent predictors of clinical outcomes in patients with CHF were NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31+/annexin V+ EMPs to CD14+CD309+ MPCs ratio, allowing reliably predict the probability survival of patients with CHF.Biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31+/annexin V+ EMPs and CD31 Chronic heart failure (CHF) remains a leading cause of cardiovascular mortality and morbidity that is characterized steadily arised worldwide . As expeThe study population consisted of 388 consecutive patients with ischemic-induced CHF who underwent angiography or PCI between April 2010 to June 2014, as well as were referred as post-myocardial infarction subjects within this period in our five centers participated in this investigation. CHF was defined accordingly clinical practice guideline recommendations as asymptomatic (NYHA I class) and symptomatic (NYHA II-IV classes) left ventricular (LV) dysfunction (LV ejection fraction less 50 %) . Singes Sample size is calculated by using single population proportion formula by considering the following assumptions; 50 % prevalence assumption, 95 % confidence level of significance alpha 0.05 = 1.96, and 5 % margin of error, which results in the sample size of 388.2; brain injury within 3 months before the enrollment; pulmonary edema; tachyarrhythmia; valvular heart disease; thyrotoxicosis; ischemic stroke; intracranial hemorrhage; acute infections; surgery; trauma; all the ischemic events within 3 previous months; inflammations within a previous month; pregnancy; implanted pacemaker, any disorder that may discontinue patient’s participation in the study according to investigators were excluded from the study.All these patients were selected after reviewing 1427 discharge reports obtained from persons who were treated in Zaporozhye Regional Hospital, City Hospital #6, City Hospital #10, Zaporozhye Regional Center of Cardiovascular Diseases with primary diagnosis coronary artery disease (CAD). One hundred fifthly five subjects were excluded due incompliance of the study protocol because of no documented CAD was presented, which was determined when preexisting myocardial infarction and/or stenosis of coronary arteries were found. Among 1272 discharge reports were enrolled data regarding 388 patients with CHF. Patients with severe kidney and liver diseases; malignancy; creatinine plasma level above 440 μmol/L; estimated GFR index < 35 ml/min/мThe study protocol was approved by the Zaporozhye State medical University Ethnics committee review board. The study complied with the Declaration of Helsinki and voluntary informed written consent was obtained from all patients included in this study. The study was registered on ISRCTN BioMed Central (reference number is 30752).We analyzed cumulative survival related to ischemic-induced CHF, and additionally all-cause mortality was examined. Prognosis was assessed by the composite endpoint included all-cause death, CHF-related death or CHF hospitalization, censored at 3 years.Multispiral contract-enhanced computed tomography angiography has been performed for patients prior to the study entry on and Optima CT660  and Somatom Volume Zoom scanner  . After pTransthoracic B-mode echocardiography and Tissue Doppler Imaging were performed according to a conventional procedure on ACUSON scanner  using phased probe with modulated frequency of 2.5–5 МHz. Left ventricular end-diastolic and end-systolic volumes, and ejection fraction (LVEF) were measured by modified Simpson’s method . Inter- Calculation of glomerular filtration rate (GFR) was calculated by CKD-EPI formula .All biomarkers were determined at baseline. To measurement of biological marker concentrations, blood samples were drawn in the morning (at 7–8 a.m.) into cooled silicone test tubes. Samples were processed according to the recommendations of the manufacturer of the analytical technique used. They were centrifuged upon permanent cooling at 6,000 rpm for 3 min. Then, plasma was refrigerated immediately to be stored at a temperature −70 °С until measurement.Circulating NT-pro-BNP level was measured by immunoelectrochemoluminescent assay using sets produced by R&D Systems (USA). Serum concentrations of tumor necrosis factor alpha , solubilized Fas (sFas), sFas ligand, galectin-3, and adiponectine were determined in duplicate with commercially available enzyme-linked immunosorbent assay kits .Circulating bone-related proteins  were determined in duplicate by ELISA method using kits produced by IBL .The high-sensitivity C-reactive protein (hs-CRP) levels were measured by using nephelometric technique on AU640 analyzer manufactured by Diagnostic Systems Group (Japan).Concentrations of total cholesterol (TC) and cholesterol of high-density lipoproteins (HDLP) were measured by enzymatic method.A total of 100 μl of serum samples was assayed in parallel to known standard concentrations for each biological marker. The mean intra-assay coefficients of variation were <10 % of all cases.Mononuclear cells populations were phenotyped by flowcytofluorimetry by means of monoclonal antibodies labeled with FITC fluorochromes (fluorescein isothiocyanate) or double-labeled with FITC/PE (phycoerythrin)  to CD45, CD34, CD14, Tie-2, and СD309 (VEGFR2) antigens as per HD-FACS (High-Definition Fluorescence Activated Cell Sorter) methodology, with red blood cells removed obligatory with lysing buffer according to gating strategy of International Society of Hematotherapy and Graft Engineering sequential (ISHAGE protocol of gating strategy) . For eac−CD34+ cells. Proangiogenic phenotype for endothelial MPCs was determined as CD14+СD309 (VEGFR2)+Tie-2+ antigens. All data were obtained when laser beam is scattered in longitudinal and transversal directions in the flowcytometer. The scattergram results were analyzed by using Boolean principles for double or triple positive events.Circulating mononuclear progenitor cells (MPCs) have been identified as CD45μL annexin-V binding buffer was added. For each sample, 500 thousand events have been analyzed. EMPs gate was defined by size, using 0.8 and 1.1 mm beads . CD31+/annexin V+ and CD144+/CD31+/annexin V+ microparticles were defined as apoptotic EMPs. All EMPs positively labeled for CD62E+ were determined as EMPs produced due to activation of endothelial cells [Endothelial-derived apoptotic and activated microparticles were phenotyped by flow cytometry by phycoerythrin (PE)-conjugated monoclonal antibody against CD31 , CD144 , CD62E (E-selectin), and annexin V  followed by incubation with fluorescein isothiocyanate (FITC)-conjugated annexin V  per HD-FACS (High-Definition Fluorescence Activated Cell Sorter) methodology. The samples were then analyzed on a FC500 flow cytometer (Beckman Coulter). For determination of annexin V+ EMPs 400 al cells , 22.http://depts.washington.edu/shfm/windows.php and http://www.heartfailurerisk.org/ respectively.Risk calculation for CHF patients was performed using contemporary risk score models Seattle Heart Failure Model and Heart Failure Risk Calculator with on-line calculators available on: http://www.bcnbiohfcalculator.org/web/calculations [Additionally, risk of all-cause mortality was estimated with Barcelona Bio-HF a score model using calculator that is available free on: ulations .http://www.readmissionscore.org/heart_failure.php [Expected readmission rate for CHF subjects was calculated with on-line calculator based on results of National Heart Care Project: lure.php , 25.t-test or Mann–Whitney U-test were used. To compare categorical variables between groups, Chi2 test (χ2) and Fisher F exact test were used. The circulating EMPs, MPCs, and NT-pro-BNP level in the blood failed to have a normal distribution, while distribution of the hs-CRP, bone-related proteins, adiponectine, total cholesterol and cholesterol fractions had a normal character (estimated by means of Kolmogorov-Smirnov test) and was not subjected to any mathematical transformation. The factors, which could be associated potentially with clinical outcomes, were determined by Cox regression analysis. Receive Operation Characteristic (ROC) curves were constructed for assessment of optimal balanced cut-off points that were suitable for independent predictors of clinical outcomes. Areas under curves were compared using method provided by DeLong et al. (1988) [P < 0.05 was considered significant.Statistical analysis was performed with SPSS system for Windows, Version 22  and GraphPad Prism for Windows, Version 5 . The data were presented as mean (М) and standard deviation (±SD) or 95 % confidence interval (CI); median (Ме) and 25–75 % interquartile range (IQR), as well as numerous (n) and frequencies (%) for categorical variables. To compare the main parameters of patients’ groups , two-tailed Student . (1988) . ReclassThe characteristics of the patients participated in the study are depicted in Table +CD309+ and CD14+CD309+Tie2+, as well as increased both CD144+/CD31+/annexin V+ and CD31+/annexin V+ EMPs were found. Patients who experienced the composite endpoint have demonstrated a significant increased circulating level of creatinine, total cholesterol, HDL cholesterol, serum uric acid, NT-pro-BNP, hs-CRP, Gal-3, osteoprotegerin, osteopontin, osteonectin, sRANKL, adiponectin, and EMPs labeled CD31+/annexin V+, as well as sufficient decreased CD14+CD309+ MPCs and CD14+CD309+Tie2+ MPCs when compared with subjects who did not have cardiovascular outcomes.Overall, entire cohort of the subjects was characterized increased NT-pro-BNP, Gal-3, hs-CRP, bone-related proteins , sRANKL, and adiponectin. Therefore, depletion of circulating levels of MPCs labeled as CD14The majority patients with CHF were treated with ACE inhibitors or ARBs, beta-adrenoblockers, I/f blocker ivabradine, mineralocorticoid receptor antagonists, and antiplatelet drugs. Adding loop diuretics was done when fluid retention was determined. Dihydropyridine calcium channel blockers were added to previous treatment scheme when target level of BP was not achieved. Metformin and/or sitagliptin were used in type two diabetes patients as a component of contemporary treatment. Proportions of the patients of both cohorts who were treated with ACE inhibitors or ARBs, dihydropyridine calcium channel blockers, ivabradine, mineralocorticoid receptor antagonists, and metformin were similar. In opposite, aspirin and loop diuretics were prescribed frequently in patients who experienced the composite endpoint, while other antiplatelet drugs (unlike aspirin), beta-adrenoblockers, and statins were given rarely when compared with patients who did not have cardiovascular outcomes.Median follow-up was of 2.76 years (IQR = 1.8–3.4). During follow-up, 285 cardiovascular events  were determined. Thirty five patients were died due to advance of CHF, and eight cases of death were related with suddenly death, fatal myocardial infarction, and systemic thromboembolism. No other causes of death were defined. Additionally, 206 subjects were hospitalized repetitively due to worsening CHF and also 36 subjects were readmitted in the hospital due to other cardiovascular reasons.Actual and expected all-cause mortality rates and readmission rates in CHF patients enrolled in the study summarize in Table +CD309+Tie2+, and EMPs to CD14 + CD309+ MPCs ratio , whether C-statistic of the model with binary predictors containing sRANKL/osteoprotegerin ratio, MPCs labeled CD14+CD309+Tie2+, and CD31+/annexin V+ EMPs to CD14+CD309+ MPCs MPCs ratio did distinguish from ABC model .ROC curves analysis have shown that there were significant difference between AUCs for independent variables and AUC for standard model LVEF <40 %) . The distribution of the Biomarker risk prediction score in the CHF patients is Fig. χ2 = 11.9; Р = 0.001). Therefore, Odds ratio calculated for cumulative cardiovascular events steadily increases related with up of Biomarker risk prediction score rank per 1 point  of survival curves constructed for both patient cohorts stratified depending low (≤4 points) and high (≥5 points) risk.Figure Comparison of predictive values of different scores regarding all cause mortality and readmissions among CHF patients was reported in Table +/annexin V+ EMPs and MPCs with angiopoetic potency. The positive side of the multimarker approach is low dependence from demographic, metabolic comorbidities, and renal clearance that is crucial for various biomarker-based predictive models created for CHF patients [The results of the present study shown that the rank of the Biomarker risk prediction score was associated with cumulative clinical outcomes in CHF patients and that score system constructed biological markers may be capable to accurately identify patients at high-risk irrespective metabolic comorbidities. We included in the analysis several biological markers reflected different aspects and faces of the pathogenesis of CHF. Thus, in addition routinely measured biomechanical stress markers such as NT-pro-BNP, phenotypic marker at high risk of galectin-3 and the proinflammatory marker hs-CRP we have used multi-functional markers such as osteoprotegerin and its soluble receptor sRANKL, osteopontin, osteonectin, adiponectin, apoptotic CD31patients . Earlierpatients , 27. Howpatients . In addipatients , 6, 29. patients , 30. On patients . Moreovepatients , 34. TakA determination of the effectiveness and cost effectiveness of using biomarker risk scores might be sufficient for the clinicians because there is intense interest in the potential of novel circulating biomarkers to provide additional prognostic information beyond standard clinical measures. In this context, biomarker risk scores could help to optimize the care of CHF, especially in ambulatory patients. It has been suggested that the effects of biomarker risk scores in terms of prediction of CHF outcomes and costs are likely to be smaller than those associated with clinical-based care. However, research into the effectiveness and cost effectiveness of different strategies using biomarkers has been lacking. This is a serious limitation for assess of the clinical efficacy of biomarker risk scores that requires more investigations in this setting.Overall, proposed by us original Biomarker Risk Predictive Score looks optimistically and has as minimum similar predictive potent when compared with recently created scores, such as Seattle Heart Failure Model, Heart Failure Risk Calculator, National Heart Care Project, and Barcelona Bio-HF. However, Seattle Heart Failure Model, Heart Failure Risk Calculator, National Heart Care Projects may under estimate the risk of all cause mortality and recurrent hospitalizations among CHF patients irrespective of duration of the observation period, although Barcelona Bio-HF score has more much higher predictive value and accuracy for one year follow-up. Therefore, the assessment of two- and three-year all cause mortality rate with Barcelona Bio-HF score (with and without NT-pro-BNP assay) demonstrates significantly lower predictive value than original Biomarker Risk Predictive Score. More investigations are needed to be recognizing optimal combination of biomarkers incorporated in the novel predictive score.This study has some limitations. It is necessary to note that a large pool of nanoparticles might be produced after blood sampling due to destruction of platelets and blood cells. Therefore, preparation of isolates of microparticles in samples is the most sophisticated step for further examination. Venous citrated blood drawn from the fistula-free arm was performed obligatorily. We believe that these risks are systemic, and to minimize them, we refused to freeze the blood samples before measurement of microparticles. Although HD-FACS methodology is widely used, theoretically overlap between two or more fluorochromes might reflect some obstacles for further interpretation of obtained results. Another limitation of the present study is that a specific role of EMPs and PMCs is also possible and has not been characterized in depth in CHF patients. However, the authors suppose that these restrictions might have no significant impact on the study data interpretation. Additionally, retrospective, relative small sample size may limit the significance of the present study. However, this was not a randomized and controlled study. Therefore, we used univariate and multivariate Cox regression analysis adjusted heart failure medication. The authors believe that a greater cohort of patients with more incidences detected is desirable to improve the credibility of the study.In conclusion, we suggested that biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31+/annexin V+ EMPs and EMPs/CD14 + CD309+ MPCs ratio, allowing reliably predict the probability survival of patients with CHF, regardless of age, gender, state of the contractile function of the left ventricle and the number of comorbidities.


Background/Objectives. The objective of this study was to compare casual BP taken in a bariatric clinic to standardized guideline-concordant BP. Subjects/Methods. A cross sectional analysis was performed using baseline data from a weight management trial. Patients were recruited from a Canadian bariatric care program. Standardized BP was performed using a Watch BP oscillometric device. Casual in-clinic BP single readings, taken using a Welch Allyn oscillometric device, were chart-abstracted. Paired t-tests, Bland-Altman plots, and Pearson's correlations were used for analysis. Results. Data from 134 patients were analyzed. Mean age was 41.5 ± 8.9 y, mean BMI was 46.8 ± 6.5 kg/m2, and 40 (30%) had prior hypertension. Mean casual in-clinic BP was 128.8 ± 14.1/81.6 ± 9.9 mmHg and mean standardized BP was 133.2 ± 15.0/82.0 ± 10.3 mmHg (difference of −4.3 ± 12.0 for systolic (p < 0.0001) and −0.4 ± 10.0 mmHg for diastolic BP (p = 0.6)). Pearson's coefficients were 0.66 (p < 0.0001) for SBP and 0.50 (p < 0.0001) for DBP. 28.4% of casual versus 26.9% of standardized measurements were ≥140/90 mmHg (p < 0.0001). Conclusion. In this bariatric clinic, casual BP was unexpectedly lower than standardized BP. This could potentially lead to the underdiagnosis of hypertension. SeverHypertension is a very common comorbidity in the severely obese, affecting 65% of these individuals , 8. One In addition to these pitfalls, blood pressure measurement in clinical settings is frequently also inaccurate because care providers do not follow standardized measurement recommendations –14. CommGiven the high risk of spuriously elevated in-clinic measurements in the severely obese, we examined casual blood pressure measurements performed in large Canadian bariatric program, comparing these measurements to readings performed as part of a prospective clinical trial and taken while closely adhering to contemporary measurement recommendations . Our hypData from the first 184 patients enrolled in the evaluating self-management and educational support in severely obese patients awaiting multidisciplinary bariatric care (EVOLUTION) randomized controlled trial were analysed. These patients were prospectively enrolled in the study between June 2013 and June 2014. This nine-month trial, consisting of three study arms, has been previously described in detail . EVOLUTIPatients analyzed herein were recruited from the Edmonton Weight Wise program, which is a population-representative bariatric care program that has a central, region-wide, single-point-of-access referral system and serves a catchment population of 1.5 million. Weight Wise was established in 2005 and delivers integrated, patient-focused, evidence-based, interdisciplinary bariatric care  to severely obese patients.Data from the second EVOLUTION study visit were used. This visit took place three months after baseline enrolment and was scheduled to closely correspond to the initial Weight Wise clinic visit. We excluded patients whose EVOLUTION study visit was more than two weeks before or after their baseline clinic visit.Data collection was performed by a trained research assistant and included sociodemographics, self-reported medical history, anthropometrics, and blood pressure. Body weight was measured to the nearest 0.1 kg using a calibrated electronic bariatric scale  and height was measured to the nearest 0.1 cm using a wall-mounted stadiometer.Blood pressure measurements in EVOLUTION were performed according to recommended guidelines using an oscillometric blood pressure device  . Three rIn-clinic casual blood pressure readings were abstracted for EVOLUTION patients between September and October 2014 from the Weight Wise clinic. Clinic measurements were taken with a Welch Allyn Vital Signs Monitor 300 Series or Welch Allyn Connex Vital Signs Monitor  oscillometric blood pressure device. All cuff sizes, including the large adult size 12 (32–43 cm) and the thigh cuff size 13 (40.7–55 cm) were available. Standard practice in the clinic is to take a single reading in either arm with the patient in a seated position . A five-minute resting period is usually not observed, proper positioning is not routinely emphasized, and providers may or may not leave the room during the measurement. Service records indicated that the clinic devices were all statically calibrated between 2012 and 2014. Neither arm circumference nor information on the arm used for measurement (left versus right) was available. This represents what we believe to be “usual” clinical practice, with the exception that larger cuffs were routinely available.A subgroup analysis in the patients who had their in-clinic visit on the same day as the EVOLUTION study visit was performed. This analysis was also stratified by sequence of initial measurement (in-clinic measurement first followed by study visit measurement later that same day or vice versa).t-tests were used to compute p values. p values < 0.05 were considered statistically significant. Bland-Altman plots were generated to compare the casual in-clinic measurements to the standardized trial measurements across the range of blood pressure values [Descriptive analyses were first performed, including calculation of baseline characteristic means, medians, and proportions. Mean casual clinic blood pressure was compared to the mean standardized blood pressure taken in the EVOLUTION trial, with the latter considered the reference standard. Paired e values . PearsonOf the initial 184 patients, 7 (3.8%) were excluded because they did not have a blood pressure measurement recorded in their clinic chart. Additional 37 (20%) patients were excluded because their arm size was too large to be measured with the Watch BP Office. Of the remaining 140 patients, six patients were excluded because the clinic and EVOLUTION trial visit separated by more than two weeks. The remaining 134 patients were included in the analysis. Of these, 124 (93%) had their initial assessment at the Weight Wise clinic on the same day as the EVOLUTION trial visit. Sixty-seven of 124 patients (54%) had their in-clinic visit (and blood pressure measurement) prior to their study visit and the order was reversed in the remaining patients.2, 101 (75%) were females, and 40 (30%) had a prior history of hypertension.Baseline characteristics are summarized in p < 0.0001) and −0.4 ± 10.0 mm Hg for diastolic BP (p = 0.6)). BP differences  were similar in males (−5.3 ± 10.8/−0.7 ± 9.3 mmHg) and females (−4.0 ± 12.4/−0.3 ± 10.3 mmHg) and there was little correlation between the BP differences and BMI (−0.07 for systolic (p = 0.4) and (−0.12 for diastolic BP (p = 0.2))). The interarm difference in standardized blood pressure was minimal (0.5 ± 10.1/1.1 ± 7.3).Mean blood pressure is summarized in p < 0.0001) and diastolic readings were moderately correlated .Bland-Altman plots for systolic and diastolic BP showed considerable variability Figures  and 2. Ap < 0.001) and diastolic BP difference of −0.6 ± 10.2 (p = 0.5)). In the 67 patients who had in-clinic measurement performed first on that day, mean systolic blood pressure differences  were −3.7 ± 10.1 mmHg (p = 0.002) and mean diastolic differences were 0.7 ± 8.2 (p = 0.4) mmHg. Corresponding numbers were −5.8 ± 14.3 (p = 0.004) for systolic blood pressure and −0.4 ± 12.2 (p = 0.5) for diastolic blood pressure in the remaining 57 patients who had same-day BP assessments but in whom in-clinic measurement was performed second.Results were similar in the subgroup of 124 patients who underwent same-day in-clinic and trial visit assessments (systolic BP difference of −4.7 ± 12.3 (p < 0.0001).In terms of potential treatment thresholds and clinical decision-making, 38 (28.4%) of patients in our cohort had a blood pressure greater than 140/90 mmHg when evaluated by casual in-clinic measurement compared with 36 (26.9%) of those when evaluated using the standardized approach that we considered the “reference” standard . Thus, accuracy in the severely obese is not guaranteed and further validation of this (and other) device specifically in this population is necessary.What are the potential explanations for our findings? We postulate that clinic providers, knowing that the arm circumference is likely to be high, may be using the extra large (thigh sized) BP cuff routinely in most patients. Arm circumference is not routinely measured in the clinic and we are also unsure to what extent the clinic providers are using the arm circumference guide imprinted on the cuff. Thus, the possibility of systematic overcuffing, rather than the undercuffing commonly found in nonobese patients, is raised. This may be specific to bariatric clinics as opposed to other primary care or speciality clinics, as bariatric clinics are probably more likely to have and use extra large sized equipment. Another possibility is that the standardized trial visit induced a greater “white coat” response than the in-clinic visit, although this seems unlikely given that the patients are more often anxious in the clinic environment  and because they were left alone in a quiet room when the standardized trial measurements were taken. A third possibility is that, in this severely obese study population with very high mean BMI levels, the Watch BP Office device readings are high. We note that the extra large (32–52 cm) cuff has met validation criteria, passing all three phases of the international protocol of the European Society of Hypertension . HoweverThe present study has several limitations. First, we did not measure arm circumference. Second, in-clinic measurements were collected as part of routine clinical care and not according to a study protocol. In addition, although the in-clinic measurements were almost certainly not performed in standardized fashion , these measurements were not observed and, as such, we could not systematically catalogue the protocol deviations  that may have occurred. Third, a comparison of two different oscillometric devices was performed; differences in proprietary algorithms may cause differences in blood pressure readings between these two devices . FinallyIn summary, we unexpectedly found that casual in-clinic blood pressure measurements were, on average, lower than standardized measurements in severely obese patients. This raises the possibility of overcuffing as a potential explanation for our findings . Based upon these findings, an increased risk of overdiagnosis and overtreatment of hypertension in patients seen in this bariatric clinic was not found. However, we do recommend that providers caring for severely obese patients be vigilant about potential “default overcuffing” and take care to ensure that the proper sized cuff is used for blood pressure measurement.


Estimating kidney glomerular filtration rate (GFR) is of utmost importance in many clinical conditions. However, very few studies have evaluated the performance of GFR estimating equations over all ages and degrees of kidney impairment. We evaluated the reliability of two major equations for GFR estimation, the CKD-EPI and Schwartz equations, with urinary clearance of inulin as gold standard.2. A linear mixed-effects model was used to model the bias (mean ratio of estimated GFR to measured GFR). Equation reliability was also assessed using precision (interquartile range [IQR] of the ratio) and accuracy (percentage of estimated GFRs within the 10% [P10] and 30% [P30] limits above and below the measured GFR). In the whole sample, the mean ratio with the CKD-EPI equation was significantly higher than that with the Schwartz equation . At GFR values of 60–89 ml/min/1.73 m2, the mean ratios with the Schwartz equation were closer to 1 than the mean ratios with the CKD-EPI equation whatever the age class . In young adults (18–40 y), the Schwartz equation had a better precision and was also more accurate than the CKD-EPI equation at GFR values under 60 ml/min/1.73 m2  and also at GFR values of 60–89 ml/min/1.73 m2. In all patients aged ≥65 y, the CKD-EPI equation performed better than the Schwartz equation . In children and adolescents (2–17 y), the Schwartz equation was superior to the CKD-EPI equation . This study is limited by its retrospective design, single-center setting with few non-white patients, and small number of patients with severe chronic kidney disease.The study included 10,610 participants referred to the Renal and Metabolic Function Exploration Unit of Edouard Herriot Hospital . GFR was measured by urinary inulin clearance  then estimated with isotope dilution mass spectrometry (IDMS)–traceable CKD-EPI and Schwartz equations. The participants’ ages ranged from 3 to 90 y, and the measured GFRs from 3 to 160 ml/min/1.73 mThe results from this study suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults with mild to moderate kidney impairment up to age 40 y. In this retrospective cross-sectional study, Luciano da Silva Selistre and colleagues compare Schwartz and CDK-EPI equations for estimating glomerular filtration rate in patients of different ages and degrees of renal impairment. Throughout life, our kidneys filter waste products  and excess water from our blood to make urine. If our kidneys stop working for any reason, the rate at which they filter the blood  decreases, and dangerous amounts of creatinine and other waste products build up in the blood. Kidneys can stop working suddenly, but in chronic kidney disease (CKD), a condition that affects more than 10% of the world’s population, kidney function declines gradually over many years. The symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, especially at night. CKD cannot be cured, but its progression can be slowed by controlling high blood pressure and diabetes and by adopting a healthy lifestyle; the same interventions also reduce the chance of CKD developing in the first place.CKD is linked with an increased risk of end-stage renal (kidney) disease and cardiovascular disease. Early identification of CKD can prevent these life-threatening complications, so clinical practice guidelines have been proposed for the diagnosis and management of CKD in the general population. The assessment of GFR is central to these guidelines. GFR can be measured by infusing inulin, a compound that is eliminated from the body by glomerular filtration, into the blood and measuring its rate of appearance in the urine. However, in routine clinical practice, GFR is usually estimated from blood creatinine levels using a GFR estimating equation . Examples of creatinine-based GFR estimation equations include the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Schwartz equation, which were developed in middle-aged adults and children, respectively. Few studies have evaluated the performance of such equations over all ages and levels of kidney impairment, so here the researchers assess the reliability of the CKD-EPI and Schwartz equations for estimating GFR in children, adolescents, and adults.In 10,610 individuals referred to a single French hospital because of suspected or established kidney disease or before kidney donation, the researchers compared GFR measured by inulin clearance with GFR estimated using the CKD-EPI and Schwartz equations. They evaluated the reliability of each equation by calculating the average (mean) ratio of estimated GFR to measured GFR  and by assessing the precision and accuracy of the estimated GFR values: the precision of a measurement indicates its reproducibility and reliability; the accuracy of a measurement indicates its closeness to the true value of a quantity. Across all the participants, the mean ratio of estimated GFR to measured GFR with the Schwartz equation was nearer to 1 than the mean ratio for the CKD-EPI equation. Among participants of all ages with measured GFR values indicating mild loss of kidney function, the mean ratio obtained with Schwartz equation was also nearer to 1 than that obtained with the CKD-EPI equation. Among young adults (18–40 years old) with measured GFR values indicating mild to moderate loss of kidney function, the Schwartz equation had better precision and was more accurate than the CKD-EPI equation, but, in all patients aged ≥65 years, the CKD-EPI equation performed better than the Schwartz equation. Finally, in children and adolescents, the Schwartz equation performed better than the CKD-EPI equation.Several aspects of this study  may limit the accuracy and generalizability of its findings. However, these findings suggest that the Schwartz equation may be more reliable than the CKD-EPI equation for estimating GFR in children and adolescents and in adults up to 40 years old with mild to moderate kidney impairment. Up to now, there has been no consensus about when physicians should switch from using the Schwartz equation (which was developed in children) to using the CKD-EPI equation (which was developed in middle-aged adults) to estimate GFR in their patients. The findings of this study might therefore help physicians decide when to make this switch, thereby improving clinical decision-making and possibly helping to reduce the global burden of CKD.http://dx.doi.org/10.1371/journal.pmed.1001979.This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at chronic kidney disease, including information on screening for and diagnosing CKD and some personal stories about the diseaseThe UK National Health Service Choices website provides information for patients on chronic kidney disease and about the estimation of glomerular filtration rates (in English and Spanish)The US National Kidney Foundation, a not-for-profit organization, provides information about kidney disease and information on creatinine-based GFR estimation equations; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)The US National Institute of Diabetes and Digestive and Kidney Diseases provides links to information about all aspects of World Kidney Day, a joint initiative of the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney diseaseClinical guidelines for the evaluation and management of CKD produced by the Kidney Disease Improving Global Outcomes not-for-profit foundation are availablekidney diseasesMedlinePlus provides links to additional resources about  In the past decade, kidney disease has been recognized as a major public health burden. The prevalence of chronic kidney disease (CKD) currently exceeds 10% of the general population . The twoThe assessment of GFR is currently the accepted surrogate marker of nephron endowment and a surveillance tool to monitor the progression of renal disease. Ideally, GFR should be measured by renal clearance of an exogenous marker that is exclusively eliminated by glomerular filtration . However, for practical reasons, GFR measurement cannot be performed in routine clinical practice. Instead, serum levels of endogenous filtration markers, such as plasma creatinine (PCr), have traditionally been used to estimate GFR, along with urinary measurements in some cases . EffectiThus, despite some drawbacks, isotope dilution mass spectrometry (IDMS)–calibrated PCr determination is now widely used as a noninvasive method for GFR measurement ,4–6. IndAmong several GFR estimating equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has been recommended in adults, and the Schwartz equation in children ,4,7,8 T. VariousIn clinical practice, equation use in middle-aged individuals is a daily issue, and priority should be given to easy-to-use equations. Thus, there is a need for a comprehensive examination of the reliability of the most recommended PCr-based equations according to age ,10. The The study considered a cross-sectional retrospective sample of 10,610 individuals. It included all eligible individuals 3 to 90 y old referred between 22 July 2003 and 7 July 2014 to a single university department  to undergo GFR measurement for suspected or established renal dysfunction or renal risk, or before kidney donation.2; (4) GFR measurement by iohexol clearance.The exclusion criteria were as follows: (1) treatment by dialysis at the time of the study; (2) taking cimetidine, trimethoprim, or intravenous injections of albumin or diuretics before GFR measurement; (3) GFR >160 ml/min/1.73 mThe data were extracted from a database that included urinary clearance of inulin as measurement of GFR. In addition, the data included the clinical indication for the test, demographic data from a standardized interview, and measurements of blood pressure, pulse, and body mass index (BMI). Other blood and urine laboratory results were available in the hospital laboratory database.During the study period, some participants had several GFR measurements, but, for the present study, only the first GFR measurement in each participant was kept for analysis. . Based on previous studies on kidney physiology ,18, the z-score according to the height-for-age and height-for-sex growth charts in France ..2 and waAlbuminuria was expressed as the ratio of urine albumin to urine creatinine, and the participants were separated into three categories: (i) normal: <3 mg/mmol (<30 mg/g), (ii) increased: 3–30 mg/mmol (30–300 mg/g), and (iii) high: >30 mg/mmol (300 mg/g).t-test in the linear mixed-effects model. In a second step, two models were built: a first model that included the variables “equation type” and “age class” and a second model that included an interaction between the variables “equation type” and “age class.” The second model allows quantification of the change of the effect of the equation type according to age. An ANOVA was used to compare the two nested models and draw conclusions regarding the statistical significance of the interaction. This analysis was carried out on the entire sample and on each category of renal function.The bias, precision, and accuracy of the Schwartz and CKD-EPI equations were estimated for each age class and each category of renal function. Bias was defined as the mean of the eGFR/mGFR ratio. In a first step, the eGFR/mGFR ratio was modeled according to a linear mixed-effects model with random intercept to quantify the effect of the equation type (CKD-EPI or Schwartz equation) on the bias. The mean ratios according to the two equations were compared by a Precision was defined as the interquartile range (IQR) of the eGFR/mGFR ratio. Following the KDIGO guidelines, accuracy was defined at two levels: P10, the percentage of eGFR values within the 10% percent limits above and below the mGFR, and P30, the percentage of eGFR values within the 30% percent limits above and below the mGFR . The 95%http://cran.r-project.org/). The nominal p-value used to determine statistical significance was p < 0.05.  had a BMI ≥35 kg/ m2.The clinical characteristics of the 10,610 participants are shown in 2. Within the mGFR range of 3–160 ml/min/1.73 m2, 37.6% of the participants had values <60, 32.7% had values from 60 to 89, and 29.7% had values ≥90 ml/min/1.73 m2. The participants with mGFR values < 60 ml/min/1.73 m2 were older and had higher albuminuria values than the others. In the whole sample 1,793 participants (16.9%) had a ratio of urine albumin to urine creatinine > 30 mg/mmol (300 mg/g).The population consisted of three major groups of indication for GFR measurement: 193 candidates for living kidney donation, 8,867 cases of native CKD, and 1,550 kidney transplant recipients. The mean ± standard deviation of mGFR was 72.0 ± 32.0 ml/min/1.73 mp < 0.001, t-test). The interaction between the type of equation and age class was statistically significant . This indicates that the mean ratios given by the two equations have different changes with increasing age class   . In the mGFR category 60–89 ml/min/1.73 m t-test) .In children and adolescents (<18 y), the Schwartz equation performed better than the CKD-EPI equation regarding precision  and accuracy  . In patients aged 65 y and older, the CKD-EPI equation performed notably better than the Schwartz equation regarding precision and accuracy  . In contrast, in the adult (≥18 y) population with mGFR ≥ 90 ml/min/1.73 m2, the CKD-EPI equation was more accurate than the Schwartz equation . Finally, in adults ≥65 y of age, the CKD-EPI equation performed better than the Schwartz equation whatever the mGFR category.At mGFR < 60 ml/min/1.73 mThis study compared CKD-EPI and Schwartz equation estimations of the GFR in 10,610 participants referred to a single university hospital. In this cohort, the Schwartz equation was more reliable and accurate in children and adolescents (2–17 y) and in young adults (18–40 y) with mild to moderate kidney impairment. These results may help in determining a cutoff age for switching from a pediatric to an adult equation. Up to now, the CKD-EPI equation, recommended in adults, has assumed that GFR decline starts at the age of 18 y, which may not be accurate.GFR is currently considered the best indicator of kidney function. Direct GFR measurement being complex, PCr-based estimating equations have been proposed. KDIGO recommends using the Schwartz equation in children and the CKD-EPI equation in adults ,4. DevelNumerous studies have demonstrated the validity of GFR-predicting equations in middle-aged adults and in children ,7–11,13,Age-associated changes in renal function have been under study for over half a century ,19. GFR Most GFR estimating equations have been developed using a combination of demographic and clinical variables ,4. In faWe hypothesized that the better reliability of the Schwartz compared to the CKD-EPI equation was due to the choice of height as a surrogate for muscle mass and renal volume, and thus for GFR, which would confirm previous studies ,25. In t2 could not be independently examined because of the small number of participants with severe CKD.Despite its large scale, the present study has some limitations. First, the study population included few non-white participants and could not assess the effect of ethnicity; however, recent studies have reported that GFR is independent of ethnicity and that the use of population-specific corrections for PCr provide robust adjustments for standard eGFR equations ,26. Seco2. These people are exposed to increased risks of all-cause and cardiovascular mortality and to other traditional risk factors. However, the effect of more precise GFR estimates at lower mGFR values on clinical management should be assessed to identify and prevent the risks of CKD [The present analyses show that the Schwartz equation is less biased than the CKD-EPI equation in almost all subgroups. In particular, bias was low in subgroups at mild and high risk of CKD, in which an overestimation of eGFR may have led to an underestimation of CKD prevalence, including people aged less than 65 y. This has important clinical implications for eGFR reporting by laboratories and its interpretation by physicians. The better performance of the Schwartz equation should improve clinical decision-making in people with low mGFR, especially mGFR < 60 ml/min/1.73 mOne interesting extension of the present report would be to conduct the same study in individuals of other ethnicities. Another wider project would be to elicit the collaboration of several centers to develop an equation able to estimate GFR across all ages and all CKD stages.2. These results may help determine the cutoff age at which a physician should switch from the Schwartz to the CKD-EPI equation and suggest that the Schwartz equation can be an excellent alternative that does not need a computer.In this cohort, the Schwartz equation was less biased and showed higher precision and accuracy than the CKD-EPI equation in children and adolescents whatever the level of GFR and in adults aged 18–40 y with a GFR < 90 ml/min/1.73 mS1 Text(DOC)Click here for additional data file.S2 Text(DOC)Click here for additional data file.


Hypertension is a major public health problem, but measures to reduce blood pressure and thus cardiovascular risk are complicated by the high prevalence of treatment resistance, despite the availability of multiple drugs. Drug side-effects contribute considerably to suboptimal blood pressure control. Clinicians must often rely on empirical methods to match patients with effective drug treatment. Hypertension pharmacogenomics seeks to find genetic predictors of response to drugs that lower blood pressure and to translate this knowledge into clinical practice. In this review we summarise the current status of hypertension pharmacogenetics from monogenic hypertension to essential hypertension and discuss the issues that need to be considered in a hypertension pharmacogenomic study.  Blood pressure (BP) is chiefly determined by cardiac output and total peripheral resistance. Hypertension is defined as a clinically significant increase in blood pressure, often considered to be DBP ≥ 90 mm Hg or SBP ≥ 140 mm Hg. This cut-off is somewhat arbitrary, as there is evidence of a continuous relationship between blood pressure and cardiovascular risk . They coA combination of drugs and life-style interventions are the cornerstones of hypertension treatment and cardiovascular risk reduction. While many safe and effective antihypertensive drugs exist, blood pressure is controlled in <50% of the patients. A recent analysis of National Health and Nutrition Examination Survey (NHANES), showed that only 53% of participants being treated for hypertension achieved a reduction in blood pressure below 140/90 mm Hg . Prevaleet al. [per se, and BP response to various drugs are being reported with increasing frequency. The ability to identify patient characteristics associated with BP response to each drug class could increase control rates and improve on the current "trial-and-error" approach to selection of drug therapy for hypertension . Some ofet al.  showed tThe promise of pharmacogenomics is that it may present a more effective way of identifying responders and non-responders to antihypertensive medication and those susceptible to adverse effects. Antihypertensive drugs lower blood pressure by acting on specific targets in the pathway of blood pressure regulation, although the mode of antihypertensive action of many of the available drugs is complex and multifactorial. Obvious candidate genes that influence drug responses are those that code for components of a system targeted by the drug or components of the counter-regulatory systems opposing the drug-induced fall in blood pressure. Ethnic differences in response to beta blockers and ACE inhibitors suggest different pathways are involved in hypertension causation in different ethnic groups. Indeed, antihypertensive drugs were the first cardiovascular therapies for which there was wide recognition of clinical differences in response based on ethnicity. Blacks generally respond more favourably to diuretics or calcium channel blockers, whereas whites tend to respond similarly to all the drug classes. In comparisons between groups, blacks respond slightly better than whites to diuretics and calcium channel blockers, whereas whites respond slightly better than blacks to ACE inhibitors and β-blockers . If diffThis forms the basis of the theory underpinning the AB/CD algorithm ,15. HypeThe search for the genetic determinants of antihypertensive drug response follows the same strategy as the studies of the genetics of complex traits. Most of the genetic studies of complex traits follow from successful gene mapping of rare monogenic forms of the condition. Rare monogenic forms of hypertension or hypotension have all been associated with genes involved in the renal tubular electrolyte transport functions  Figure . There aCYP11B1, coupled with the structural region of the aldosterone synthase gene, CYP11B2. This results in aldosterone secretion in response to adrenocorticotrophic hormone (ACTH) in contrast to it usual agonists, angiotensin II and potassium. The specific treatment for hypertension in these individuals is low-dose glucocorticoids, amiloride, and spironolactone, which blocks binding of aldosterone to the mineralocorticoid receptor (MCR). Familial hyperaldosteronism type I (FH-I)—also known as glucocorticoid-remediable aldosteronism—was the first form of monogenic hypertension to be recognized as a single-gene hypertensive disorder . The genA leucine for serine substitution at codon 810 in the hormone-binding domain of the MCR has been recently described, which causes the receptor to be constitutively active and alters its specificity such that the steroid hormones, which lack a 21-hydroxyl group and are normally antagonistic (including progesterone and cortisone), act as agonists . FemalesLiddle syndrome is an autosomal dominant disorder caused by hyperactivity of the amiloride-sensitive sodium channel (ENaC) of the principal cell of the cortical collecting tubule ,24. MutaWNK1 and WNK4 (members of a family of serine–threonine kinases) have been shown to cause the rare familial autosomal dominant disease, Gordon's syndrome  [WNK1 and WNK4 inhibit the thiazide-sensitive Na–Cl co-transporter in the distal tubule. Mutations of these proteins are associated with gain of function and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion. Treatment consists of either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na+–Cl- co-transporter activity, respectively.Mutations of type II) . Wild-tyThere is considerable evidence supporting the presence of a modest genetic contribution to the common essential hypertension which poses the significant public health problem as described above. Studies of blood pressure in twins and familial aggregation of blood pressure indicate a heritable component to non-Mendelian hypertension. Hypertension is about twice as common in individuals who have one or two hypertensive parents, and blood pressure is more closely correlated in identical (monozygotic) than non-identical (dizygotic) twins ,27. In tACE I/D polymorphism in the pharmacogenetic substudy of ALLHAT, called GenHAT. This study tested the association of various outcomes in ALLHAT with the I/D polymorphism in 37,939 patients. No association was found between this polymorphism and BP lowering (with lisinopril or any other study drugs) nor with any of the study outcomes, either when considered in combination or stratified by drug therapy [AGTR1 1166A→C genotype and BP response [WNK1, ADRB2, and the epithelial sodium channel-subunit gene (SCNN1G) predicted interindividual differences in antihypertensive responses to hydrochlorothiazide [ADRB1)- Ser49Gly and Arg389Gly, suggest greater BP lowering in the Arg389Arg individuals. The commonly studied is the Arg389Gly polymorphism, for which many, but not all, studies show a significant association with antihypertensive response to beta-blockers and two independent studies have suggested an association between treatment related hypertensive outcomes and ADRB1 SNPs [ADD1) gene is another extensively studied candidate gene and one study showed differential outcomes  with thiazide treatment based on the Gly460Trp genotype [ADD1 gene remains an interesting candidate and recently ADD1 considered together with NEDD4L revealed a significant association with BP response to a thiazide, while neither gene alone showed such an association [KCNMB1, for which SNPs have been associated with BP response in three independent populations, and treatment-related outcomes in one [There are numerous small candidate gene association studies that have tried to determine if common polymorphisms in genes can predict response to antihypertensive agents. The candidate gene association study approach involves the selection of candidate genes based on a mechanistic understanding of the roles of the encoded proteins in blood pressure regulation, or drug target. However this will, at best, identify only a fraction of genetic risk loci even if the pathway is relatively well understood. Candidate genes studied fall into the following categories—the Renin-Angiotensin-Aldosterone-System, adrenergic system and genes involved in sodium transport in the kidneys. None of the candidate gene studies have so far shown reproducible associations. Some of the limitations of the candidate gene approach are as follows: first, the choice of candidate genes may be inappropriate. Second, the causative genes might be either upstream of the points of action or in the downstream signalling pathways of the selected candidates. Third, the SNPs selected for association studies may provide incomplete coverage of all the variants within the genes studied. Fourth, most studies are underpowered and problems due to population stratification, phenotypic and locus heterogeneity. Finally, candidate gene studies rely on prior hypotheses about disease mechanisms, so that discovery of genetic variants in previously unknown pathways is precluded . The mos therapy . Similarresponse . In an aRB1 SNPs . There iRB1 SNPs ,42. The genotype . But, sugenotype ,45. Howeociation . This sus in one ,49.Finally the first hypertension pharmacogenomics genome-wide association study (GWAS) showed promise by discovering and validating a region on chromosome 12 that was associated with the response to hydrochlorothiazide . With deet al. [SLCO1B1 gene, encoding the organic anion-transporting polypeptide OATP1B1, as a susceptibility factor for statin-induced myopathy involved a genome-wide association analysis of 85 individuals with definite or incipient statin myopathy (and 90 controls) from a trial involving over 12,000 subjects [There are important design issues to be considered in antihypertensive pharmacogenomics studies. Kurland et al.  have sugsubjects . Here, thttp://www.1000genomes.org), one can be confident of interrogating almost the entire genome in terms of common variants. However, these experiments are blind to rare variants and structural variants. Though GWAS has identified numerous validated SNPs for most common diseases and traits, these explain only a tiny proportion of the heritability of these traits suggesting that rare variants and structural variants may explain the remaining missing heritabilities [-8, however the gold standard of any study is multiple replications in independent studies followed by functional validation [The study design that is most likely to yield validated results would be GWAS but one should keep in mind the limitations of GWAS. All SNP chips used for GWAS genotype common variants and with the high coverage in newer chips which can genotype a million SNPs per sample along with imputation using data from the 1000 genome project (bilities . Howeverlidation ,55.etc. [Interpretation of the results of association studies is dependent on a narrow definition of the phenotype. For blood pressure this is difficult, in view of the variability of blood pressure, and a significant association result for blood pressure traits may in fact be an association between the factors that introduce variability in the measures . A multietc. . While tetc. . The aleetc. . Clinical trials which have shown blood pressure reduction on placebo treatments suggest that much of the apparent fall in blood pressure seen in clinical practice is regression to the mean . In otheGenetic predictive testing for antihypertensive dose adjustment of avoidance of adverse events require large scale studies taking into account the complexities of the blood pressure phenotype. Narrowing the phenotype by focussing on pathways will make this genetically tractable and lead to successful clinical translation. The discovery of new drug targets is no less important and the large scale efforts in whole genome mapping of hypertension and blood pressure traits will be key in this aspect.