Background. Allergic asthma is showed an increase in Th2-cytokine and IgE levels and an accumulation activation of Th2 cells, eosinophils and mast cells. However, recent studies focused on cell-based mechanisms for the pathogenesis of allergic asthma. Objectives. In this study, we compare the anti-IgE treatment modality in the dynamics of immune system cytokine levels in severe persistent asthma (SPA) patients who had no other any allergic disease, newly diagnosed allergic asthma patients and healthy volunteers. Study Design. The study population consisted of 14 SPA patients, 14 newly diagnosed allergic asthma patients and 14 healthy volunteers included as controls. Cytokine levels were measured. Total and specific IgE levels of anti-IgE monoclonal antibody treated patients, serum high-sensitivity C-reactive protein (hsCRP) levels, FEV1/FVC rates and asthma control test (ACT) were measured for the clinical follow-up. Results. We observed that SPA patients presented increasing levels of IL-8, IL-10, TGF-β and GCSF during the anti-IgE treatment in period of sampling times at 4 months and 18 months. However this increase was not correlated neither with serum hsCRP levels nor FEV1/FVC rates. Conclusions. Our study gives a different perspective for the SPA and anti-IgE immunotherapy efficacy at the cell cytokine-linked step. Asthma is the most common serious chronic lung disease that affects people of all ages with evidence for a growing prevalence in industrialized as well as in developing countries , 2. Withγ), and IL-12 reciprocally stimulate their production and function during cell-mediated immunity and development of naïve T lymphocytes into Th1 cells. Evidence suggests a contributory role of Th1 cells and their cytokines in asthmatic inflammation and airway hyper-responsiveness [α), and GM-CSF, which have been associated with asthma in murine models, in humans or with disease severity [Th2 cells secrete a panel of cytokines with several overlapping functions including Interleukin-4 (IL-4), IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF). By mediating differentiation of the Th2 subpopulation and eosinophils, as well as modulating B-cell proliferation and IgE switching, the Th2 cytokines are thought to play a prominent role in asthma . The sensiveness , 8. The siveness . Moreovesiveness , 11. Thiseverity .Asthma—probably the most heterogeneous lung disease—classification is based on severity and there is no universally accepted utility in diagnosis of asthma and certain subtypes. Current Global Initiative for Asthma (GINA) guidelines emphasize the need to evaluate asthma control to guide asthma management decisions. The Asthma Control Test (ACT) questionnaire—a simple, self-administered, and rapidly completed assessment tool—is also appropriate to assess the patients and has an advantage of can be applied at all levels of healthcare. Symptoms in the most severe form of asthma, also called ‘‘severe persistent allergic asthma”, are thought to be precipitated by allergens. In addition to allergens, environmental factors or infectious pathogens often trigger epithelial stress and altered innate immunity that induce different types of inflammation, thereby resulting in the heterogeneous forms of asthma.Most recent treatment modality—anti-IgE therapy—was developed for severe allergic asthma. Anti-IgE therapy affects by lowering free IgE and leading to downregulation of high-affinity IgE receptors on circulating basophils and mast cells. So that the early and late phase responses to inhaled allergens will be attenuated –22.β, and GCSF of the allergic asthma patients treated with anti-IgE therapy to investigate their roles in the pathogenesis of disease perpetuation, and anti-IgE therapy's impact on them.This study surveyed the levels of chosen serum IL-8, IL-17, TGF-Twenty eight allergic asthma—allergic rhinitis patients were included in the study and divided into two groups according to the severity. In the first group there were 14 patients of 5 male and 9 female, whom were suffering from severe persistent allergic asthma—allergic rhinitis and underwent anti-IgE therapy for 18 months within the product label  every 2 weeks. Assessment of clinical changes and adverse effects were evaluated at each bimonthly patient visit including vital signs, full physical examination, details of any allergy incidents, total and specific IgE levels, serum high-sensitivity C-reactive protein levels, pulmonary function test (FEV1/FVC rates), and asthma control test (ACT) . A spirometry was performed at each visit (once or twice a month depending on the patient's visit schedule). Reference values for the Mediterranean population were used . Need foThe other patients group included the newly diagnosed allergic asthma-allergic rhinitis patients (non-severe) (Group II).n = 14) had no history of allergy/atopy, family atopy, cardiac and pulmonary diseases or smoking.The healthy volunteers  in order to facilitate treatment control. Nonetheless, data for patients who came to the ER and discharge treatment were recovered, since the clinical histories at the hospital are computerized.Skin prick tests on the forearm were performed in all patients using standardized latex extract containing high ammonia natural rubber latex, and a full set of 35 common and 35 food allergens. In addition, venom SPT was performed on one patient based on the subject's clinical history. SPTs were performed by skilled nursing personnel. Positive tests were counted as wheals of 3 mm in diameter after 20 minutes. Tests were compared with positive histamine controls and negative saline controls. Commercial extracts used were manufactured by Allergopharma (Germany). No intradermal tests were performed.Best Standard Care (BSC) following the recommendations of the GINA included inhaled corticosteroids (fluticasone 500 mg bid), inhaled long-acting beta-agonists (LABA) , and oral methyl-prednisolone. Prior to starting omalizumab treatment, patients underwent a run-in period of at least 18 months. The protocol followed for decreasing oral steroid administration was as follows; the daily dose was decreased by 2 mg/day; if the patient remained stable, at the end of the two weeks the daily dose was decreased by a further 2 mg for the following weeks. Steroid dose was then increased to the previous level and the process was repeated.α, TGF-β, and GCSF in the serum samples were quantified using ELISA kits. The assays were performed according to the recommendations of the manufacturer using standard curve for every cytokine. The results were reported as means of duplicate measurements.Concentrations of IL-8, IL-10, IL-17, TNF-Total and specific IgE levels were enumerated by fluoroenzyme immunoassay (ImmunoCAP—FEIA) using an ImmunoCAP  kit. Values above 100 kU/L and 0.35 kU/L for total and specific IgE levels were considered abnormal.Serum hs-CRP levels were measured using a hs-CRP assay . The sensitivity of the assay ranged 0.04–5.0 mg/L.t-test with the statistical package for the Social Sciences 13.0 software for Windows . A P value less than 0.05 was considered to be statistically significant. GraphPad Prism version 5  were used to plot the data and perform correlation analyses. All correlation analyses used Spearman's Rho tests.All the data were analyzed by using student Main demographic and clinical characteristics of study participants were summarized in Tables β, and GCSF in the anti-IgE treated severe persistent asthma patients group, none of the cytokine concentrations in serum differ significantly between healthy and severe persistent asthma diseased patients . These values were also increased during the anti-IgE therapy and this difference is significant between the fourth/eighteenth month of anti-IgE therapy and control group and newly diagnosed allergic asthma patients. In contrast, the levels of IL-8, TGF-β, and GCSF did not differ between newly diagnosed allergic asthma patients, non-treated severe persistent asthma patients and control. Moreover, the mean serum IL-10 levels were lower than the control group in newly diagnosed allergic asthma patients and non-treated severe persistent asthma patients. Furthermore, IL-17 levels did not change between any groups and are not associated with any clinical parameters of asthma.In Results of serum cytokine measurements of the severe persistent asthma patients and distinct clinical parameters were then further analyzed. However, this increase was not correlated neither with any of the clinical follow-up markers and serum hsCRP levels. Even though, ACT score of the patients and serum hsCRP levels together with FEV1/FVC status were significantly different between two patient groups .In our study for this purpose we evaluated the cytokine levels of different T cell sub-types. However, no differences were observed in IL-8 levels between healthy and diseased individuals before anti-IgE therapy. IL-10 levels were higher in treated patients and healthy individuals than the newly diagnosed patients as it was previously reported that inhaled corticosteroid therapy restores the reduced IL-10 release  IL-17 leIt has been suggested that asthma is not necessarily associated with changes of serum cytokines . HoweverWe also evaluated serum cytokine levels in relation to clinical parameters, including total and specific IgE, asthma onset, pulmonary function tests, hsCRP level, and ACT. There was no clear pattern in the expression levels of circulating cytokines and clinical parameters of asthma. In this regard, our results are in accord with previous studies that indicate that serum cytokine levels reflecting activity of Th1, Th2, and Th17 cells and clinical symptoms are independent of one another , 40–42. β and GSCF in severe persistent asthma patients who were receiving anti-IgE therapy. Anti-IgE  treatment attenuates both the early- and late-phase responses to inhaled allergens in patients with asthma [β, and GCSF to this list.IL-8 is a pro-neutrophilic chemokine that is secreted by various cell types. It is thought to play an important role in asthma, with levels correlated with the severity of disease , 16, 18.h asthma . Furtherh asthma , 21. Othh asthma –46. Our Both local and systemic inflammation is associated with pathogenesis in asthma , 48. To In conclusion, the present study documents evidence for altered patterns in serum cytokines in severe persistent asthma patients following anti-IgE therapy. However, the basal serum cytokine profiles excluding the IL-10, patterns were not different between healthy and asthmatic individuals, regardless of whether the latter were newly diagnosed allergic asthma or non-treated severe persistent asthmatic patients. We believe this study provides a novel perspective on the mechanism of action of anti-IgE immunotherapy in severe persistent asthma patients and inflammatory mediators in defining clinical benefits.


The aim of the present study was to compare the responses of blood pressure, heart rate, and rate-pressure product of hypertensive women using beta-blockers with healthy controls during resistance exercise (by the end of the concentric phase of the contractions) and in the postexercise period (5 and 30 minutes after). Ten untrained normotensive women (N) and 10 mildly hypertensive females receiving 40 mg/day of propanolol (H) were selected. Three sets of 10 repetitions at 80% of 10 repetitions maximum with 30 s rest interval were performed on the leg press exercise. The H group exhibited lower systolic blood pressure after the second set compared with N. Heart rate and rate-pressure product were lower in H in all analyzed periods compared with N. Propanolol attenuates the cardiovascular response to a leg press resistance exercise in mildly hypertensive women. Resistance training (RT) is a noninvasive and nonpharmacological tool that improves specific health parameters and invokes benefits to both the cardiovascular and musculoskeletal systems. Health parameters such as muscle strength, flexibility, and body composition are intimately related with individual functional capacity and help to maintain quality of life by increasing the ability to maintain independent living with as one ages .On the other hand, hypertension alone is a risk factor for several cardiovascular diseases , such asRT is modality that has been shown to promote benefits on certain cardiovascular variables, both in sedentary and hypertensive individuals . The carResistance training progression and adaptation relies on the manipulation of training variables such as volume, frequency, velocity of muscle contraction, exercise order, and the rest interval length between sets . It has The magnitude of BP, HR, and RPP responses during RT are directly related to intensity, the number of repetitions and sets, and the rest interval . RecentlConsidering the relevance of HR, BP, and RPP in the controlling and prescription of RT in hypertensive individuals, the objective of the present study was to compare the cardiovascular response during and after multiple set RT with short rest intervals in mildly hypertensive women receiving 40 mg/day of propanolol with normotensive women. Our initial hypothesis was that women on beta-blockers would present an attenuated cardiovascular response during and after a RT session compared with healthy controls.Ten healthy women (N) and 10 mildly essential hypertensive women (H) receiving a daily oral morning dose of propanolol (40 mg/day) for at least six months before the intervention participated in the study. Before the drug treatment with propanolol, mildly hypertensive patients exhibited values of 140–159 mmHg for systolic blood pressure, and 90–99 mmHg for diastolic blood pressure. Hypertensive individuals were selected from the unit of hypertension treatment of Pelotas, Brazil. According to American College of Sports Medicine guidelines , particiParticipants did not ingest caffeine or alcohol during the 24-hour period prior to any of the testing protocols and did not perform any rigorous physical activity during the 48 hours prior to testing. All trials were performed at the same period of the day to avoid any influence of circadian rhythm on cardiovascular variables.All subjects underwent an anthropometric  and cardiac evaluation, including a resting 12-lead electrocardiogram. Following the resting electrocardiogram, all participants performed three orientation sessions to become familiar with the ten repetition maximal (10RM) test, with intervals between each session ranging from 48 to 72 h. Familiarization sessions were performed on the 45° leg press machine  using a training load corresponding to 15RM. The training load corresponding to 15RM was used to indirectly determine the load for the first 10RM test trial. The 10RM tests were then performed in two nonconsecutive days. The first 10RM test was performed, and, then after 48 h, the second 10RM test was repeated to determine test-retest reliability. The RT session was performed 72 h after the second 10RM test.t-test did not show significant differences between the 10RM tests . The heaviest load achieved was considered the 10RM.A light warmup with ten submaximal repetitions was instructed with a two-minute rest before the initiation of the tests. To obtain a reliable 10RM load, data was assessed during two nonconsecutive days in the 45° leg press (LP) . The 10RM load was determined by using the maximum weight that could be lifted for ten consecutive repetitions at a constant velocity of 3 seconds per repetition (1.5 s in concentric and 1.5 s in the eccentric phase). If the subject could not accomplish the 10RM in the first attempt, the weight was adjusted by 4–10 kg. Each subject performed a maximum of five 10RM attempts with 5-minute rest intervals between attempts. To minimize the error during tests, the following strategies were adopted according to Simão et al. : (a) staPrior to the RT session, volunteers rested quietly in a seated position for 20 minutes to facilitate baseline measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Before the session, a specific warmup with 1 set of 10 repetitions at 50% of 10RM was performed. Subsequently, the RT was initiated, and volunteers performed three sets, of 10 repetitions at 80% of 10RM in the 45° leg press, with 30 s rest interval between sets. No pauses between concentric and eccentric actions were allowed, and investigators were present to assure that standardized exercise technique was maintained. Volunteers were instructed to avoid the Valsalva maneuver during the RT session . This meP < 0.05) F ratio. The calculation of the effect size (ES) for the cardiovascular variables was performed according to the classification proposed by Rhea [P < 0.05. The data are presented as mean ± standard deviation of the mean. The sample size was calculated considering 1.8 mmHg as the minimum difference in the resting SBP value between the groups, the residual standard deviation was 0.75, and the statistical power was 0.80. All variables presented normal distribution and homocedasticity, and a 2 × 6 ANOVA with two independent variables  was computed. Bonferroni's posthoc test was applied in the event of a significant at ( by Rhea . StatistP = 0.02). There were no statistically significant differences in anthropometric variables between groups . Mean vaP = 0.001). Moreover, SBP dropped below resting 30 min after exercise. There were no significant changes in HR during the 3 sets of 45° leg press when only exercise conditions were compared . SBP, HR, and RPP were lower during the recovery period compared with the values found during the 3 sets of RT (P < 0.001). When only the exercise conditions were compared, no differences were observed among RT sets for SBP, DBP, HR and RPP responses. After five minutes of recovery, SBP and RPP exhibited lower values compared with resting and RT conditions (P < 0.05). Lower HR values were found after five and 30 minutes of recovery compared with the RT session, but not compared with resting values.Mean values for HR and BP before, during and after the RT session in the hypertensive group (H) are presented in H group exhibited a lower SBP during set 2 compared with N . No diff The present study reveals the important clinical role of 40 mg/day of propanolol in attenuating the cardiovascular responses to a RT session in mildly hypertensive individuals. In addition, these results have direct implications for RT prescription, highlighting the safety of this type of exercise for mildly hypertensive patients treated with propanolol. During three sets of RT, hypertensive women treated with propanolol exhibited lower values of HR and consequently of RPP compared with normotensive women. Additionally, propanolol modulated cardiovascular variables during resting and in the recovery period of a RT session. This indicates that beta-blockers, such as propanolol, are cardioprotective at rest and during a RT session in hypertensive individuals, who have a higher risk of developing coronary heart disease, cardiac ischemia, and acute myocardial infarction .While the intra-arterial method is considered the gold-standard for determining blood pressure , we chosIn the present study, normotensive individuals exhibited normal cardiovascular responses in the analyzed variables. The increases in SBP, HR, and RPP during RT were of a similar magnitude compared to previous studies which utilized low, moderate, and high intensity RT , 18, 19.Furthermore, it should be considered that the manipulation of training variables, such as number of sets and repetitions, intensity, and the rest interval between sets, can induce different cardiovascular responses. For example, Nery et al.  showed tIn the study of Nery et al. , there wIn the resting condition, individuals using propanolol presented a lower HR and this may be attributed to the attenuating chronotropic and inotropic effect of beta-blockers , 24. TheWhen compared with other antihypertensive medications, beta-blockers present an optimal effect in reducing BP, HR, and myocardial contractility, which are the three main determinants of oxygen consumption by cardiac muscle , 19. TheIn conclusion, 40 mg/day of propanolol attenuates the cardiovascular response to RT, mainly in HR, SBP, and RPP. Additional studies involving other RT variables such as: exercises for other muscle groups, single- and multiple-joint exercises, different intensity and volume are necessary to improve the understanding of the interplay between RT and beta-blocker use. The prescription of RT with different doses of beta-blockers should also be investigated.


Objectives. We planned to compare the impact of two beta blockers, metoprolol and nebivolol, on arterial blood pressure during exercise in patients with mild hypertension. Methods. A total of 60 patients  were enrolled in the present study. The patients were randomly selected to receive either nebivolol 5 mg/day (n = 30) or metoprolol 50 mg/day (n = 30) for 8 weeks. At the end of the 8th week, each of the patients received exercise stress test according to Bruce protocol and their blood pressures were remeasured after rest, exercise, and recovery. Results. Blood pressures were determined to be similar between metoprolol and nebivolol groups during rest, exercise, and recovery periods. Metoprolol and nebivolol achieved similar reductions in blood pressures during rest and exercise. However, five patients in nebivolol group and four patients in metoprolol group developed exaggerated BP response to exercise but the difference between metoprolol and nebivolol was not meaningful (P = 0.37). Conclusion. The results of the present study showed that metoprolol and nebivolol established comparable effects on the control of blood pressures during exercise in the patients with mild hypertensions. Development of exaggerated BP response to exercise is shown to be associated with increased cardiovascular morbidity and mortality –3. SuddeBeta blockers have been used in the treatment of hypertension for years and they are still the first line of drugs suggested , 11. MetWe aimed to evaluate the effects of nebivolol and metoprolol on arterial BP during exercise.We randomly included 30 patients for metoprolol group and 30 patients for nebivolol group. A total of 60 patients  were enrolled in the present study. The study was approved by the local ethics committee; the patients were informed and written consents from them were also obtained. All procedures were conducted in accordance with the Declaration of Helsinki (1964).The patients diagnosed newly with low-risk hypertensions at stage 1 were included in this study. The stage of hypertension was determined according to Guidelines for the Management of Arterial Hypertension approved by the European Society of Hypertension and by the European Society of Cardiology in 2007 . Stage 1The following patients were excluded from the current study: patients possessing middle or high-risk arterial hypertension, having hypertension beyond stage 1, showing fasting blood glucose of >126 mg/dL, previously taking any kind of antihypertensive medication, suffering from cardiovascular diseases, diabetes mellitus, chronic obstructive pulmonary disease, significant systemic disease, and atrial fibrillation, showing evidence of myocardial ischemia at exercise stress test, having concomitant diseases that might adversely impair his/her exercise capacity , or showing contraindications to b-blocker therapy .The patients were randomized at a 1 : 1 ratio to receive metoprolol succinate (50 mg daily)  or nebivolol (5 mg daily)  once a day in the morning for 8 weeks. The patients were carefully checked for the control of their BP and heart rate and for their compliance with medication at 2, 4, and 8 weeks of the treatment. The patients were asked not to use any kind of other drugs with known impact on the cardiovascular system throughout the study. Moreover, blood pressure was measured in the sitting position after 5 min of rest. The median value of two consecutive measurements taken at 2 min intervals on two different days was used for the study. The measurements of the BP were completed on the right arm of the patients using a sphygmomanometer with an appropriate cuff size . Successful antihypertensive therapy was defined as the establishment of blood pressure <140/90 (systolic/diastolic) at the end of the eight-week treatment.At the end of the 8th week, the patients received EST according to the standard Bruce protocol  . The patt-test was used to compare continuous variables showing normal distribution, Mann-Whitney U test was used to compare continuous variables not showing normal distribution. Categorical variables were compared using the chi-square test. A two-tailed paired t-test was used to compare continuous variables before and after drug therapy within the same group. For all the tests, a value of P < 0.05 was considered to be statistically significant. Statistical analyses were performed using the SPSS 16.0 Statistical Package Program for Windows .While continuous variables were expressed as mean ± SD, categorical variables were defined as percentages. While Student's Overall, 66 patients were enrolled in this study at the beginning; however, six patients were left out since two of them stopped taking metoprolol due to undesired side effects and two in metoprolol and two in nebivolol groups did not come to planned visits for their treatments. Consequently, 60 patients  with mean age of 54.3 ± 10.7 were included in the final analyses. On the whole, no significant differences were recorded between the metoprolol and nebivolol groups for their clinical and laboratory features. Main clinical and laboratory features of the patients are illustrated in P < 0.001) in metoprolol and nebivolol groups at the end of the eight-week treatment. The effects of metoprolol and nebivolol on the heart rates and systolic and diastolic blood pressures were comparable. The values of blood pressures and heart rates prior to and after the treatments with metoprolol and nebivolol are summarized in With regard to prior to therapy, heart rates and systolic and diastolic blood pressures were significantly reduced , and at 3rd and 5th minutes of recovery period were alike between metoprolol and nebivolol groups. The heart rates and systolic and diastolic blood pressures measured during rest, exercise stress test, and recovery periods are recapitulated in P = 0.65). The frequency of developing exaggerated blood pressure response in the two groups was similar. Five patients in the nebivolol group and four patients in the metoprolol group developed exaggerated BP response to exercise, but the difference between metoprolol and nebivolol was not meaningful (P = 0.37). The features concerning the patients developing normal and exaggerated BP response to exercise are summarized in We also compared metoprolol and nebivolol groups developing exaggerated BP rates in response to exercise. While successful antihypertensive treatments were achieved in 61.6% of the study population, antihypertensive treatment failed in 38.4% of the patients at the end of the eight-week treatment. In addition, while three of the patients (8.1%) with controlled hypertension developed exaggerated blood pressure, six of the patients (26.1%) with uncontrolled hypertension developed exaggerated blood pressure  developed exaggerated BP response to exercise.The balance between physiologically increased cardiac output and dilatation in peripheral vascular elements in muscles determines BP during exercise. If an increase in cardiac output during exercise is not balanced with peripheral vasodilatation, it causes a sharp rise in systolic BP . AwareneBeta blockers are shown to control exercise BP better with respect to other antihypertensive drugs, and few patients are shown to develop exercise-associated exaggerated hypertension against the use of these blockers . NeverthMetoprolol succinate (50 mg/day) and nebivolol (5 mg/day) similarly controlled BP response during rest and exercise in the present study. At the end of the eighth week, the treatment of the patients with these drugs achieved targeted BP response during rest and exercise in most of the patients. Our observations were consistent with other studies investigating the effects of metoprolol and nebivolol –28. AparWe think that the following elements could regulate comparable antihypertensive effects of metoprolol and nebivolol. Exercise increases adrenergic activity. Antiadrenergic activity of metoprolol is reported to be more potent than nebivolol . On the Moreover, the metabolic demand for many leisure and routine daily activities in middle-aged individuals is shown to be approximately 5 to 7 metabolic equivalents (METs) . Using BIn conclusion, the results of the present study demonstrated that metoprolol and nebivolol achieved comparable effects on the control of blood pressures during exercise in the patients with mild arterial hypertensions. Current observations suggest that metoprolol and nebivolol can reduce cardiovascular risk via reducing exaggerated BP response to exercise in hypertensive patients.


Reports have shown that normotensive offspring of hypertensive parents (OHP) are at increased risk of developing systemic hypertension (SH) and adverse cardiovascular events later in life. The pathological antecedents of this are thought to be alterations in the structure and function of left ventricle. Therefore, the present study aimed at determining left ventricular mass and geometry in OHP and compared with offspring without parental hypertension.Sixty-five OHP aged 15-25 years with 65-age and sex-matched offspring of normotensive parents (ONP) were studied for early makers of hypertensive cardiovascular disease. Those with heart murmurs, structural heart diseases and blood pressure ≥ 140/90 mmHg were excluded. Electrocardiography (ECG) and echocardiogram were done in standard positions.Mean left ventricular posterior wall thickness, left ventricular mass, left ventricular mass index (LVMI) and relative wall thickness (RWT) were significantly higher in the subjects than controls . LVMI correlated positively with systolic and diastolic blood pressure, waist circumference (WC), ECG voltage, and posterior wall diastolic dimension. Waist circumference was an independent predictor of LVMI in OHP.We concluded that normotensive OHP have alterations in left ventricular mass and structure; and should be considered as a special group that needs early dietary and lifestyle adjustments to prevent future cardiovascular events. Current approach to the management of systemic hypertension (SH) is early diagnosis and identification of individuals at risk through detection of early makers of the disease. The Writing Group of American Society of Hypertension considers left ventricular hypertrophy (LVH) as one of the early makers of hypertensive cardiovascular disease . The preA simple random sample (using random numbers) of patients who were hypertensive and attending Cardiovascular Clinic of the University of Ilorin Teaching Hospital, Ilorin was conducted. The selected patients were requested to bring one of their eligible children between the ages of 15–25 years for assessment (OHP group). The same procedure was employed to select age and sex-matched children without parental hypertension (ONP) from Medical Outpatient Department to serve as controls. Ethical approval was obtained from the Ethics and Research Committee of the hospital and informed consent was obtained from each participant.3−(LVIDd)3))+0.6. Left ventricular mass index (LVMI) was determined using formula: LVM/BSA, where BSA is the body surface area.Relative wall thickness (RWT) was calculated by the formula [All individuals who were pregnant, on cardio active drugs, had cardio-pulmonary disease; and those with organic heart murmur and renal bruit were not eligible to participate. Similarly, those with structural heart disease and poor echocardiographic windows were excluded from the study. A thorough history to exclude cardiovascular disease in the participants was taken and anthropometric parameters, blood pressure and other relevant clinical examination were performed on all subjects. Blood pressure was measured at the left arm in a comfortable position after about 10 minutes rest using an appropriate cuff. However, if the blood pressure was equal or greater than 10mmHg at the right arm, the latter blood pressure was used as the blood pressure of the subjects. An average of three measurements was used as the blood pressure. Individuals with blood pressure ≥ 140/90 mmHg or on anti-hypertensive drugs were also excluded. Electrocardiogram was done in standard position and subsequently echocardiogram. A long parasternal 2D guided M-mode echocardiogram was done and measurement taken according to the recommendations of the American Society of Echocardiography (ASE)  : 0.8× preceding onset of SH. The results showed that the LVMI as well as PWd were significantly higher in OHP than ONP (p<0.001 and 0.01 respectively). Similarly, prevalence of abnormal left ventricular geometric pattern was higher in the OHP compared with ONP . These rPublished observations had also shown mean 24-hour ambulatory systolic and diastolic blood pressure values to be an important determinant of LVM in hypertensive children and OHP –23. In oAssessment of left ventricular geometry further refined risk associated with LVH in individuals with systemic hypertension . This stThe results of the present study also showed that the parameters of left ventricular systolic function at rest were similar between the OHP and ONP groups. This is not surprising because prior investigations have shown that even in hypertensive individuals, alterations in the indices of left ventricular systolic function occur late in the course of the disease .In conclusion, normotensive offspring of hypertensive parents have alterations in left ventricular mass and geometry even before they have sustained elevation of blood pressure. OHP should be considered as a special group which needs early dietary adjustment and lifestyles modification in order to prevent future cardiovascular events.


In patients with metabolic syndrome, body iron overload exacerbates insulin resistance, impairment of glucose metabolism, endothelium dysfunction and coronary artery responses. Conversely, iron depletion is effective to ameliorate glucose metabolism and dysfunctional endothelium. Most of its effectiveness seems to occur through the amelioration of systemic and hepatic insulin resistance.BMC Medicine, Michalsen et al. demonstrated a dramatic improvement of blood pressure, serum glucose and lipids after removing 550 to 800 ml of blood in subjects with metabolic syndrome. This effect was apparently independent of changes in insulin resistance, in contrast to previous cross-sectional and cohort studies investigating the association between iron overload, insulin resistance and cardiovascular disease.In a study published by Despite drawbacks in the study design, its findings may lead the way to investigations aimed at exploring iron-dependent regulatory mechanisms of vascular tone in healthy individuals and patients with metabolic disease, thus providing a rationale for novel preventive and therapeutic strategies to counteract hypertension.http://www.biomedcentral.com/1741-7015/10/54Please see related article:  Metabolic syndrome (MetS) is a clustering of cardiovascular disease risk factors . Both insulin resistance (IR) and low-grade inflammation underlie the syndrome . The preet al. [Other strategies are also possible. Michalsen et al.  observedet al. [The beneficial effects of phlebotomies have been repeatedly observed in the past and documented in 1867 by Brunton, who observed that "Small bleedings of three or four ounces, whether by cupping or venesection, were (...) beneficial", and recommended that a few ounces of blood be removed every few weeks from patients with angina. He attributed the relief of angina to the diminution of "arterial tension" . In 1970et al. .Puzzlingly, the beneficial effect on blood pressure observed by Michalsen  was indeHowever, the results from this trial generate a number of questions regarding the lack of effect on IR and the early and consistent effects on blood pressure.A relationship between iron stores and IR has been reported, but with some inconsistencies. The risk of diabetes was significantly lower in frequent blood donors from the Health Professionals Follow-up Study when compared with non-donors after 10 years of follow-up . HoweverSerum ferritin, a surrogate marker of iron status as it accurately reflects body iron stores in healthy individuals , was assNone of these aforementioned studies provided information on insulin resistance, which has been explored in cross-sectional investigations. Frequent blood donors had improved insulin sensitivity and decreased insulin secretion when compared with sporadic blood donors or non-donors . In an uet al. [Concerning the relationship between iron stores, MetS and IR, a number of epidemiological studies showed a relationship -24. Hencet al. , who demSeveral epidemiological studies have investigated the effect of iron depletion on atherosclerosis, cardiovascular risk, mortality and morbidity . Blood pBy stratifying men from the Health Professionals Follow-up Study according to lifetime number of donations , no difference was observed in the risk for hypertension . The Kuoet al. [Thus, one of the main questions is how two phlebotomies worked to reduce blood pressure. Improvement of IR is not a nominee, at least at a first glance. Michalsen et al.  argue thet al. . Serum fet al. . Alternaet al.  speculatOn the other hand, as blood volume was not replaced following phlebotomies, patients on multi-drug therapy or with type 2 diabetes might also have a dysfunctional endothelium and sympathetic response to relative hypovolemia. They might be unable to compensate for hypovolemia as healthy donors do. Indeed, most previous evidence were from cohort and cross-sectional studies of healthy donors , and frode novo analyses of much larger cohorts of healthy donors and patients with an appropriately long-term follow-up and tight monitoring of dietary iron intake.The strength of Michalsen's study is that for the first time an effect of iron depletion on blood pressure is recognized. Like other evidence from clinical studies, the effectiveness of iron depletion on hypertension needs to be proved with further studies. The focus of the research should move toward two different fronts: i) investigation of the effect of reducing body iron stores through graded phlebotomy, preferably using solid measures of insulin sensitivity, vascular resistance, viscosity and oxidative damage; ii) meta-analysis of data from published cohorts or In conclusion, findings from Michalsen's study give new perspectives for prevention and treatment of the metabolic syndrome demonstrating that repeated phlebotomies, a low-cost and minimally invasive technique, are effective in reducing blood pressure with a mechanism that is independent of insulin resistance. Routine phlebotomies in these patients may enormously reduce health care costs related to the epidemic metabolic syndrome and, importantly, also contribute to increase the rate of blood donations.HOMA: homeostatic model assessment; IR: insulin resistance; MetS: metabolic syndrome; T2DM: type 2 diabetes mellitus.The authors have no conflict of interest in relation to this work.Both authors contributed equally to the drafting and revising of the manuscript, and both authors approved the final version to be published.MM, MD Ph.D FACN, is responsible for the research unit for multifactorial diseases at the Scientific Directorate of the Bambino Gesù Children's Hospital, Rome. She has devoted her entire research activity to obesity and type 2 diabetes.JMFR, MD, PhD, is Chief of the Section of Diabetes. Department of Endocrinology. Hospital de Girona Dr Josep Trueta and CIBERobn. Avinguda de França s/n. 17007 Girona, Spain.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/10/53/prepub


Haemodialysis is a form of renal replacement therapy used to treat patients with end stage renal failure. It is becoming more appreciated that haemodialysis patients exhibit higher rates of multiple end organ damage compared to the general population. There is also a strong emerging evidence that haemodialysis itself causes circulatory stress. We aimed at examining haemodynamic patterns during haemodialysis using a new model and test that model against a normal control.We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs , the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations during HD. Using a non-invasive cardiac output monitoring device (Finometer®) we compared various haemodynamic parameters using the above model between a haemodialysis patient during a dialysis session and an exercised normal control after comparison at rest.Measurements yielded 29,751 data points for each haemodynamic parameter. Extrema points frequency of mean arterial blood pressure was higher in the HD subject compared to the normal control . Similarly, extrema points frequency of systolic blood pressure was significantly higher in haemodialysis compared to normal. In contrary, the frequency of extrema points for TPR was higher in the normal control compared to HD  with significantly higher amplitudes.Haemodialysis patients potentially exhibit an aberrant haemodynamic behaviour characterised by higher extrema frequencies of mean arterial blood pressure and lower extrema frequencies of total peripheral resistance. This, in theory, could lead to higher variation in organ perfusion and may be detrimental to vulnerable vascular beds. Patients with end stage renal failure (ESRF) require renal replacement therapy (RRT). Haemodialysis (HD) is a form of RRT in which the blood is pumped from the patient into an extracorporeal circuit through an array of semipermeable membranes called the dialyser. The blood in the dialyser is separated from a fluid called the dialysate by a semipermeable membrane; and the plasma biochemistry changes towards that of the dialysate due to diffusion of the molecules according to their concentration gradients. Traditionally the treatment is given in three sessions a week each session lasting for three to four hours.It is becoming more appreciated that HD patients exhibit higher rates of multiple end organ damage compared to the general population. HD patients for example have hugely elevated cardiovascular mortality which is estimated to be at least thirty times greater than aged matched population . There iThere are multiple factors that contribute to this abnormal cardiovascular function and complicate the HD treatment. On macrovascular level, vascular calcification is predominant in HD patients . This reAll the above factors result in abnormal haemodynamic behaviour during HD that has not been fully characterised or correlated to measures of end organ damage. We aimed at examining the haemodynamic pattern during HD and at rest using a new model and test that model against a normal control.Each heart beat generates a pressure pulsation expressed as systolic and diastolic pressures. These are largely dictated by the stroke volume and the compliance of the arterial tree. It is this compliance and distensability that lead to the damping of the pulse pressure in smaller arteries allowing tissue blood flow to be continuous throughout diastole . From thThe body uses several mechanisms such as local chemical and autonomic feedback to keep the perfusion pressure within the limits that are best for organ viability. We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs , the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations in HD patients.When measuring blood pressure by oscillometry using an inflatable cuff to occlude the brachial artery the measured systolic and diastolic pressures belong each to different heart beats. Hence, the use of such method would not provide sufficient resolution and the use of a continuous beat to beat cardiovascular monitoring device is needed to examine the above hypothesis.The Finometer  is a tool for blood pressure and haemodynamic monitoring. It is particularly useful due to its non-invasive nature and ability to provide continuous readings over a period of several hours. The Finometer works by continuous pulse-wave analysis at the digital artery and utilises the finger-clamp method, in which changes in digital arterial diameter are detected by means of an infrared photoplethysmograph  and oppoEthical approval was obtained from Nottingham research ethics committee (09/H0408/71).Using the Finometer we recorded the above haemodynamic parameters in a HD patient and compared them with those of a healthy volunteer. The data was first recorded at rest for a period of 25 minutes for the HD patient and 30 minutes for the normal control (NC). Then the data was collected during a three hours HD session for the HD patient and to mimic the circulatory stress, the data for the healthy volunteer was collected during exercise using a cycling pedal for a similar period to the HD session. This yielded a total of 29,751 data points for each haemodynamic parameter measured between the two subjects for analysis.P) to qualify as an extrema it has to be either larger than both of its neighbouring points (maxima) or smaller than neighbouring points (minima) Figure The analysis of each haemodynamic parameter was done by identifying the local extrema points then calculating their frequencies and amplitudes using Matlab and Simulink . At first local extrema points were defined . For the points (t). This was then used to calculate the time elapsed between each consecutive extrema.The extrema indices were also used to enable pairing with their time points (F) of the change between extrema points was then calculated.The frequency (a) between two consecutive extrema points was also computedFinally, the amplitude . Statistical analysis was performed using SPSS version 19 . An alpha error at 0.05 was judged to be significant. All continuous variables were tested for normality using their histograms and normality tests. Parametric data are presented by mean and standard deviation (SD), while non-parametric are presented as median and interquartile range (IQR). Between group differences were tested using the Independent Characteristics of both HD and NC subjects are demonstrated in Table Extrema points frequency of MAP was higher in HD compared to that of NC in the resting state . The same was noted for SBP and DBP as demonstrated in Table Table On comparison with the resting data, circulatory stress seems to cause a large increase in the frequency of TPR extrema points in NC to a level that is higher than that of the HD subject . A similar but modest response in the frequency of TPR extrema points is noted in HD . Although there was an increase in the MAP extrema frequency when exercising in the NC  the frequency remains much lower than the HD patient which did not demonstrate a significant increase in the MAP extrema frequency during dialysis .In this proof of concept study we propose the use of frequencies and amplitudes of extrema points to analyse various haemodynamic parameters during HD. Testing the model during HD against an exercised normal control and at rest revealed multiple abnormalities in the haemodynamic behaviour of the HD subject. Firstly, we found that in the resting state the frequency of extrema points for MAP, SBP and DBP was higher in HD compared to NC. On the other hand, TPR extrema points frequency at rest was lower in NC but with higher amplitudes. As a response to circulatory stress the NC subject seems to have the ability to increase the frequency of TPR extrema points and maintain a much lower extrema frequency of MAP than the HD subject. This quicker change in TPR with higher amplitudes would in theory provide a better control and stability of blood pressure in the NC and the lack of this process in HD subject could be representative of autonomic dysfunction. HD patients as previously demonstrated have reduced baroreflex sensitivity which correlates with higher vascular calcification scores and increased arterial stiffness -16,21 an1, P2) is one of the determinants of blood flowAs MAP is considered the perfusion pressure for organs; in the HD subject the variation of MAP over one minute is higher than that of the normal volunteer. According to Ohm’s law the pressure difference between two ends of a vessel (P1 and a lower variation in resistance (R) in theory would results in higher variation in blood flow to that organ, assuming that the venous pressure P2 is constant. Hence, in theory HD patients can experience a higher variation per minute in blood flow compared to normal exercised healthy volunteer. This haemodynamic behaviour could theoretically be detrimental to vulnerable vascular beds.Therefore, a higher variation in PPrevious studies that analysed haemodynamic parameters during HD used periodic averaging methodologies -24. In tWe have shown using this model a marked difference in the haemodynamic behaviour at rest and in response to circulatory stress between the HD and the exercised NC subjects. The determinants of this haemodynamic behaviour in HD patients are still to be explored. Although these differences in haemodynamic performance could be attributed to differences in age and cardiovascular comorbidities between the two subjects; it is important to demonstrate the model’s ability to detect differences from two ends of the cardiovascular spectrum. The hypothesis that higher extrema frequencies of MAP and lower extrema frequencies of TPR during HD produces higher variability in organ perfusion; which could contribute to its damage is still to be tested. Studies that correlate between this haemodynamic model and measures of structural and functional organ damage are currently being undertaken.The authors declare that they have no competing interests.MTE designed the model and its computational implementation, conceived the study, collected and analysed the data, and drafted the manuscript. AO conceived the study, collected and analysed the data, and drafted the manuscript. CWM conceived the study, critically reviewed the data analysis and drafted the manuscript. All authors read and approved the final manuscript.


Differentiation of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH) often requires right heart catheterization (RHC). We sought to determine whether a combination of clinical and echocardiographic variables could predict the pulmonary diastolic to wedge (PAd-PWP) gradient and thus differentiate patients with PAH and PVH.We prospectively enrolled 108 patients presenting for PH evaluation. We developed a multivariate model to predict PAd-PWP gradient and validated this model using bootstrapping technique.PAH patients had worse hemodynamics and were more likely to have evidence of right ventricular dilation and dysfunction whereas patients with PVH were older and more likely to have features of the metabolic syndrome. PAd-PWP gradient of ≥ 6mmHg accurately discriminated patients with PAH compared to PVH. Our model including clinical and echocardiographic variables was highly accurate for the prediction of PAd-PWP gradient with a slope 0.89 (slope of 1 represents perfect prediction).In this prospective study of patients referred for PH evaluation, a model of readily available clinical parameters and simple echocardiographic measurements accurately predicted the PAd-PWP gradient, allowing discrimination of patients with PAH and PVH. This model requires validation in a larger cohort, but may afford clinicians more parsimony with referral for invasive testing in the evaluation of PH. Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the pulmonary arterioles, elevated pulmonary vascular resistance (PVR) and eventual right heart failure. PAH confers a poor prognosis compared to other causes of pulmonary hypertension (PH), but is often difficult to differentiate from other etiologies –3. EchocThere are limited data on how to differentiation of PAH from PVH clinically, with most prior literature focusing on the hemodynamic differences . EchocarThe transpulmonary gradient , is thought to be a reflection of the underlying etiology of PH; TPG is low in PVH due to passive upstream transmission of elevated left-sided pressure and high in PAH due to pre-capillary vasoconstriction or structural changes. However, TPG is influenced by stroke volume, arterial compliance, and elevated left atrial pressure (LAP) and may therefore misclassify the etiology of PH in some patients ,11. The We hypothesized that a combination of clinical and simple echocardiography-based variables could be used to predict the PAd-PWP gradient. We used an existing prospectively collected dataset to develop and internally validate a statistical model using these variables to predict hemodynamic differences in PAH and PVH and patients with no pulmonary hypertension.This prospective, single-center study was approved by the Vanderbilt Institutional Review Board and all subjects signed informed consent.All new or returning patients aged >18 years who were evaluated in the Vanderbilt University Center for Pulmonary Vascular Disease from August 2009 through March 2010 were eligible for enrollment. Right heart catheterization was performed by either of two cardiologists using a standard protocol. PH was defined as mean pulmonary artery pressure (mPAP) of ≥ 25 mm Hg by cardiac catheterization. PAH required a pulmonary artery wedge pressure (PWP) measured at end-expiration of ≤ 15 mm Hg . PatientDemographic data, results of blood tests, 6MWT, and pulmonary function testing were extracted from the medical record. RHC data were manually reviewed by two authors with extensive experience in the evaluation and management of PH (I.M.R. and A.R.H.). The 6MWTs were performed according to American Thoracic Society criteria , althougWe pre-specified several clinical variables which would indicate a likely pulmonary venous etiology of PH: history of coronary artery disease (CAD), prior cardiac surgery, history of percutaneous coronary intervention (PCI), history of atrial fibrillation (AF) or flutter, and prior AF ablation. In addition, we pre-specified several echocardiographic variables which would indicate likely PVH  or PAH , or paradoxical septal motion). We also pre-specified several risk factors  to be included in the model in conjunction with the echocardiographic variables, clinical variables, or both 1.χ² test for nested models to assess whether echocardiographic variables add predictive value to a model that includes clinical variables and whether clinical variables adds predictive value to a model that includes echocardiographic variables. The adequacy index is the fraction of the total LR χ² explained by a set of variables that could be explained by omitting the competing variables. The prediction model was internally validated and calibrated using bootstrapping technique with 300 bootstrap resamples. Model validation estimates the model’s future performance. Model calibration estimates the accuracy of the model’s predicted outcome compared to the observed outcome, which can be demonstrated using a smooth nonparametric calibration curve or plot of predicted versus observed outcome. Bootstrap samples were created by drawing random samples with replacement from the original sample with same size. A model was derived in each bootstrap sample and was applied without change to the original sample. Optimism was then calculated as the accuracy index from the bootstrap sample minus the index computed on the original sample. This process was repeated for 300 times and the average optimism was used to obtain the overfitting-corrected estimate.Descriptive statistics were presented as mean ± standard deviation, median (interquartile range [IQR]), or percentage (N) as appropriate. Continuous variables were compared between groups using Wilcoxon rank sum test and Person’s chi-squared test for categorical variables. Clinical variables and echocardiographic variables which indicate the same clinical aspects were grouped into clusters. We used linear model with least squares to assess the association between PAd-PWP and the clinical/echocardiographic variables with adjustment of age, sex, BMI, diastolic blood pressure, DM, HTN, beta blocker use and RVH on EKG. All the continuous variables were modeled as linear trend due to the limited sample size. To test for a difference in the predictive value of clinical factors and echocardiographic factors, we used the LR All analyses were done with the statistical programming language R, version 2.15.1 . The level of statistical significance was set at p<0.05.The composition of the study population has been previously reported . For thiAs shown in In order to allow our prediction model to be easily integrated into clinical practice we chose echocardiographic parameters easily assessed on any patient with adequate image quality and excluded highly quantitative, load-dependent, or Doppler-based parameters. Echocardiographic variables for PAH and PVH patients are shown in Detailed hemodynamic data for the PAH and PVH groups are shown in χ² test for nested models, clinical factors did not add predictive value to a model that includes echocardiographic factors , whereas echocardiographic factors added clinically and statistically significant predictive value to a model that includes clinical factors . The adequacy index for clinical factors model and echocardiographic factors model were 0.802 and 1, respectively. The influence of each of the risk factors and echocardiographic variables in the final model on the predicted PAd-PWP is shown To study the ability of the pre-specified clinical and echocardiographic variables to predict PAd-PWP, we fit three linear models: clinical variables, echocardiographic variables, and combined. All 3 models included an identical set of other risk factors, which were: age, sex, BMI, diastolic blood pressure, diabetes mellitus (DM), hypertension (HTN), beta-blocker use, and RVH on electrocardiography. Using the LR 2 = 0.507, with adjusted R2 = 0.427. We used bootstrapping to validate and calibrate the model. The bias-corrected R2 was 0.35. The slope shrinkage factor was 0.89. Echocardiographic factors were more predictive than the clinical factors; we therefore chose the model with echocardiographic variables and risk factors to predict PAd-PWP. The proportion of variation explained by the model is RAs an example of practical clinical application, In this prospective study of new and returning patients referred for PH evaluation, we have shown that a combination of readily available clinical parameters and simple echocardiographic measurements is able to accurately predict the PAd-PWP gradient. We found that a combination of clinical risk factors and imaging parameters better predicted PAd-PWP than either group alone, which may explain some of the limitations of imaging-only models. Finally, we demonstrated that our model has good internal validity using a bootstrapping technique.Both PAd-PWP and TPG were significantly different between the PAH and PVH cohorts. However, the mean value of TPG for the PVH group (15.7 mmHg) was elevated. Based on that value, according to current guidelines, the average PVH patient in our cohort may be considered by some physicians to have mixed etiology PH or even for PAH-specific therapy . HoweverWe deliberately chose echocardiography variables that can easily be assessed in any patients with adequate image quality and avoided highly-quantitative or Doppler-based measurements. Quantitative measurements such as the tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC) reflect RV function and predict outcomes in PAH but cannot differentiate PAH and PVH. Doppler parameters such as notching of the right ventricular outflow tract or pulmonary acceleration time (PAT) better reflect underlying physiology but are limited by subjective interpretation (notching mid- versus late systole) and vary based on acquisition technique (placement of pulse Doppler sample). Visual assessment should not be the only method for determining RV function, but is reliable when performed by an experienced reader . RV dilaThe cluster of echocardiographic variables was by far the most influential element in the prediction model. The inclusion of several other pre-specified risk factors  provided additional predictive value. Surprisingly, the clinical variables we chose  or flutter, and prior AF ablation) did not provide incremental value and were thus excluded from the final model. It is likely that the predictive value inherent in the clinical variables was accounted for in the risk factors included in the model.Our model appears to be least accurate at the extremes of predicted PAd-PWP; however, in the range of PAd-PWP that presents a diagnostic dilemma, > 5mmHg to < 15mmHg, the model is highly accurate. Patients with predicted PAd-PWP > 15mmHg could be confidently assessed to be high risk for PAH and be referred for invasive hemodynamics to confirm the diagnosis and perform vasodilator testing. Conversely, patients with predicted PAd-PWP < 5mmHG are highly likely to have PVH and further diagnostic work-up could focus on underlying causes of elevated LAP and may not necessitate RHC.Several echocardiography-based prediction models to differentiate PAH and PVH have been described. Opotowski et al developed a prediction rule using left atrial dimension, presence or absence of systolic notching of the RVOT Doppler signal, PAT, and lateral mitral E/e’. The prediction rule performed quite well inpatients who clearly had hemodynamic evidence of PAH or PVH, but did not reliably differentiate patients with hemodynamic evidence of “mixed PH” (i.e. elevated PASP and PWP). The score presented is easy to use but may fail to accurately classify patients with ambiguous hemodynamics. Willens et al examined the ability of various LV diastolic parameters to differentiate PAH and PVH. The variables studied, especially E/e’ , performed very well. The mean TPG in the patients with PVH (13.8±7.2mmHg) was above the conventional cutoff of 12 whereas the PAd-PWP was essentially zero, again indicating the limitations of TPG and likely superiority of PAd-PWP as a discriminator between PAH and PVH . DespiteThe treatment and prognosis of PAH and PVH differ dramatically, underscoring the need for accurate diagnosis. The ability to predict PAd-PWP gradient and thus differentiate PAH and PVH has a number of potential advantages over routine referral for invasive hemodynamics. RHC cannot practically be performed in the increasing number of patients with PH due to left heart disease. A model that accurately predicts the underlying physiology of PH would maximize identification of high-risk patients for PAH to select for confirmatory RHC. Patients predicted to have PVH would be considered for further or alternative diagnostic testing and therapy directed at left heart disease. Patients likely to have PVH based on clinical factors but with a predicted PAd-PWP > 7mmHg may have developed a reactive component or “out-of-proportion” PH. Our cohort included 2 such patients, both of whom were found to have very high PWP. Therefore, this model does not discriminate patients with “out-of-proportion” PH, but these patients should be referred for RHC as they may require evaluation by a specialist for appropriate classification of PH . A retroThese findings are from a single center; an independent validation cohort would be needed to confirm the utility of this model. The number of patients with PVH is small because we included both new referrals and returning patients, most of whom have PAH. Therefore, our cohort is heavily skewed toward PAH patients which have influenced the accuracy of our prediction model. In addition, we excluded patients with LV systolic dysfunction. Our model incorporates more variables than some other prediction models, but all the variables we included are routinely collected as part of a clinical evaluation of PH. The determination of RV function was based on visual assessment without any confirmatory quantitative measures as recommended by the American Society of Echocardiography . HoweverWe have shown that a combination of clinical and simple echocardiographic variables can accurately predict the pulmonary artery diastolic pressure to wedge pressure gradient in patients with PAH, PVH, and NoPH. The PAd-PWP gradient is a better physiologic reflection of underlying etiology of PH compared to the TPG and reliably discriminated between PAH and PVH in our cohort. The model presented is most accurate in the range of PAd-PWP that may present a diagnostic dilemma (5-20mmHg) reinforcing its potential clinical usefulness. Our model requires further testing and independent validation, but may allow clinicians to be more parsimonious with referral for invasive testing in the work-up of pulmonary hypertension.


The aim of this study was to explore the correlation of erythropoietin (EPO) with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hs-CRP) in patients with chronic heart failure (CHF) or CHF complicated with anemia, in addition to its correlation with the prognosis of the patient. A total of 217 CHF patients were enrolled in this study. The patients were graded according to the cardiac function criteria of the New York Heart Association (NYHA). The serum EPO, NT-proBNP and hs-CRP levels of the patients were determined. The patients were followed up for ≥24 months. The EPO expression level in patients with NYHA II–IV CHF was significantly higher compared with that in the control group (P<0.05). EPO expression increased with the aggravation of CHF, exhibiting significant differences amongst the various NYHA graded groups (P<0.05). The EPO expression level increased significantly with an increase in NHA grade in addition to the severity of the anemia in the patients with CHF complicated by anemia (P<0.05). In the patients who succumbed , the expression level of EPO was significantly higher and the hemoglobin level was significantly lower compared with those of the survival group (P<0.05). The EPO expression levels were elevated in CHF patients and patients with CHF and anemia. The level of expression correlated positively with the severity of CHF as well as that of anemia. Serum EPO measurements were successful in predicting the mortality and re-hospitalization rates of CHF patients at the end point, within two years of follow-up. The treatment of chronic heart failure (CHF) is currently an area of interest in the field of cardiovascular disease. Numerous factors such as neurohormonal activation, inflammation and oxidative stress may lead to a poor prognosis of CHF and a one-year mortality rate as high as 30–40% ,2. AlthoNeurohormonal and inflammatory activation may trigger CHF and scholars have long sought serological markers capable of reflecting the effectiveness of CHF treatment and predicting its long-term prognosis –18. The EPO, which is produced by the kidneys, promotes the proliferation and differentiation of erythroid progenitor cells in the spinal cord. Recently, with a deepened understanding of its action mechanisms and its potential actions as a multifunctional cytokine, EPO has attracted an increasing amount of attention. EPO has anti-apoptotic and anti-oxidative properties and promotes the activation of endothelial precursor cells for angiogenesis. Due to its multiple properties, EPO has been assumed to be a stress hormone; EPO is highly expressed under aggravated CHF conditions –23. A clTherefore, in the current study, the EPO levels of patients with CHF were determined in order to explore the correlation between EPO expression and the severity of CHF and CHF complicated with anemia. The results were analyzed further using known neurohormonal and inflammatory activation markers used for CHF prognostic prediction. The findings of this study may provide theoretical references for the early intervention and prognostic prediction of CHF.A total of 217 CHF patients who received treatment at Shandong Provincial Hospital  between January 2007 and December 2010 were recruited for this study. All patients met the Framingham diagnostic criteria of CHF  and wereThe study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Shandong Provincial Hospital. Written informed consent was obtained from all participants.Patients who met any of the following criteria were excluded from the study: age, <18 years; currently pregnant; diagnosed with a malignant tumor; presented with a systemic infection; exhibited gastrointestinal bleeding; and had undergone a cerebral vascular accident, major surgery, or recombinant EPO treatment within the previous three months.The patients received clinical examinations and were subsequently NYHA-graded. All patients were consulted further, every 1–3 months or dependent on the pathogenic condition. The control group comprised 50 non-CHF patients who were admitted to hospital during the same period exhibiting symptoms of palpitations and chest pain. No significant differences in age or gender were observed between the groups.The end point of this study was the time to mortality due to any cause or re-hospitalization due to CHF. All patients were followed-up for 24 months.Fasting ulnar venous blood (3 ml) was extracted in the morning for all participants and subsequently centrifuged at 730 × g for 10 min. The serum was separated and stored at −20°C. Serum EPO levels were determined using an radioimmunoassay.® full-automatic hematology analyzer  using the cyan-methemoglobin method. The serum level of NT-proBNP was determined by ELISA. hs-CRP levels were determined using a latex particle-enhanced turbidometric immunoassay.Hb content was determined using a CoulterData were analyzed using SPSS 10.0 software . Enumeration data were presented as the mean ± SE. The Student’s t-test was performed for pairwise comparisons and one-factor ANOVA was performed in order to compare the EPO levels among groups with different NYHA grades. P<0.05 was considered to indicate a statistically significant difference.The mean age of the 217 CHF patients was 69.7±10.4 years. According to the NYHA criteria, 74 patients (34.1%) were grade II, 96 (44.2%) were grade III, and 47 were grade IV (21.7%). Of all the patients, 69 (31.8%) had CHF accompanied by anemia. The clinical features and medications of the patients are summarized in In total, 69 of the 217 patients were diagnosed with CHF accompanied by anemia, which corresponded to an incidence of 31.8%. The EPO level increased with an increase in the NYHA grade in addition to the severity of anemia, demonstrating significant differences among the various groups (P<0.05). The results are summarized in All patients were followed-up through phone calls, clinical visits or hospitalized medical records. During the follow-up period, 34 of the 217 patients succumbed, and 183 survived with an average follow-up time of 3.5±1.3 years. The EPO expression level of the mortality group was significantly higher, compared with that of the survival group, whereas the Hb level was significantly lower, (P<0.05). The results are summarized in Of the 217 patients, 34 (15.6%) succumbed, 67 (30.9%) were re-hospitalized due to CHF and 42 (19.4%) were hospitalized due to severe CHF. The mean levels of EPO, NT-proBNP, and hs -CRP at the various end points are summarized in In this study, the serum EPO levels of patients with CHF of various NYHA grades were determined, and compared with those of non-CHF patients who were recruited as controls. The results show that the EPO levels in patients with NYHA II-IV CHF are significantly higher than those in observed in non-CHF patients (P<0.05). In addition, EPO levels significantly increase with an increase in NYHA grade (P<0.05). Furthermore, this study demonstrates that with an increase in NYHA grade, Hb levels decrease significantly. These results demonstrate that EPO is important in the development of CHF. As anoxia is a vital regulatory factor of EPO, patients with CHF presumably suffer from tissue hypoperfusion, which causes internal environmental hypoxia and subsequently leads to the overexpression of EPO. Alternatively, tissue hypoperfusion may lead to other types of stimulation that upregulate the expression of EPO, such as oxidative stress leading to the production of oxygen radicals ,25.Epidemiological data have indicated that being female, increased age, kidney insufficiency, low body weight and severe cardiac dysfunction are high risk factors for CHF complicated by anemia . The incIn addition, this study reveals that serum EPO expression levels correlate with the severity of CHF predicted using NYHA grading. The two years of follow-up in this study further demonstrates that NT-ProBNP expression is an independent predictor of the mortality and re-hospitalization rates of patients with CHF. Furthermore, this study demonstrates that serum EPO expression may serve as a predictor in this respect, whereas hs-CRP levels do not successfully predict the mortality rate.In conclusion, EPO expression is increased in patients with CHF and in those with CHF complicated by anemia, and the increase correlates with the severity of CHF. Thus, EPO levels may successfully predict the prognosis of CHF, and serum EPO expression performs an important role in the progression of CHF. Furthermore, EPO, NT-ProBNP and hs -CRP correlate with one another. These findings indicate that neurohormonal activation and inflammation are clinical responses to late CHF. Therefore, the determination of serum EPO expression is clinically significant for the prediction of the development, outcome and prognosis of CHF.


The behavior of arterial blood pressure in postpartum of women with hypertension and pregnancy and the best treatment for very high blood pressure in this period still need evidence. The Cochrane systematic review assessing prevention and treatment of postpartum hypertension found only two trials (120 patients) comparing hydralazine with nifedipine and labetalol for the treatment of severe hypertension and did not find enough evidence to know how best to treat women with hypertension after birth. Although studies have demonstrated the effectiveness of treatment with captopril, side effects were reported. Because of these findings, new classes of antihypertensive drugs began to be administered as an alternative therapy. Data on the role of clonidine in this particular group of patients, its effects in the short and long term are still scarce in the literature.To determine the effectiveness of clonidine, compared to captopril, for the treatment of postpartum very high blood pressure in women with hypertension in pregnancy.The study is a triple blind randomized controlled trial including postpartum women with diagnosis of hypertension in pregnancy presenting very high blood pressure, and exclusion criteria will be presence of heart disease, smoking, use of illicit drugs, any contraindication to the use of captopril or clonidine and inability to receive oral medications.Eligible patients will be invited to participate and those who agree will be included in the study and receive captopril or clonidine according to a random list of numbers. The subjects will receive the study medication every 20 minutes until blood pressure is over 170 mmHg of systolic blood pressure and 110 mmHg diastolic blood pressure. A maximum of six pills a day for very high blood pressure will be administered. In case of persistent high blood pressure levels, other antihypertensive agents will be used.During the study the women will be subject to strict control of blood pressure and urine output. This proposal has already obtained approval of the local Institutional Review Board of the coordinating center  and of the National Council for Ethics in Research (CONEP) of the Brazilian Ministry of Health.NCT01761916.Clinical Trials Register under the number  Hypertension complicates approximately 10% of pregnancies  and the Although the true prevalence of postpartum hypertension is unknown, it is important to monitor blood pressure levels after delivery, because they can continue to increase in women with previous diagnosis of hypertension or hypertensive crisis can develop only postpartum . AccordiIt has been shown that blood pressure increases progressively over the first five days after birth, peaking on three to six days after delivery  It is beHypertension, proteinuria and biochemical changes caused by pre-eclampsia may persist for six to 12 weeks postpartum . AlthougThe effectiveness of different antihypertensive medications in the postpartum period has not been adequately assessed. In the Cochrane systematic review specifically evaluating prevention and treatment of postpartum hypertension, nine trials were included, four of those evaluating prevention furosemide, nifedipine and L-arginine compared to placebo, three studies evaluated timolol, oral hydralazine, or oral nifedipine compared with methyldopa and only two studies (120 patients) evaluated the treatment of severe hypertension with intravenous hydralazine, labetalol intravenous or sublingual nifedipine. In these last studies, there were no maternal deaths or hypotension. Use of additional antihypertensive therapy did not differ between groups , but the trials were not consistent in their effects. The reviewers conclude that there are no reliable data to guide management of women who are hypertensive postpartum. Any antihypertensive agent used should be based on a clinician's familiarity with the drug .Captopril is an inhibitor of angiotensin I converting enzyme and is used for treating hypertensive crisis . AlthougThe use of captopril postpartum was tested in an open clinical trial with 79 patients with a diagnosis of pre-eclampsia and eclampsia. Of these, 71 received captopril at a dose of 25 mg at intervals of 30 minutes up to three doses and the remaining eight received hydralazine intravenously at a dose of 5 mg, maximum of four doses with an interval of 20 minutes. Of the mothers who received captopril, 52 (73.3%) responded satisfactorily to the drug with a reduction of up to 25% of blood pressure levels. Regarding the number of doses administered, 20 patients (38%) required one dose, 26 (50%) two doses and six (11%), three doses. No adverse maternal effects were observed. There were also no changes in diuresis and creatinine levels in the neonate. Given these findings, the authors recommend the use of captopril for the management of hypertensive crisis in the puerperium . Low levClonidine belongs to the class of alpha-2-agonist with central action  and begaThere were no reports in the database searched , neither randomized controlled trials that prove the effectiveness of clonidine for the treatment of hypertensive crisis in this particular group of patients or studies comparing this drug with captopril.The objective of this study is to determine the effectiveness of clonidine compared to captopril for treatment of very high blood pressure in postpartum women in a randomized controlled trial.The overall objective is to determine the effectiveness of clonidine compared to captopril, for treatment of postpartum women with very high blood pressure.Analyzing postpartum patients with very high blood pressure randomized to receive clonidine or captopril, the specific objectives are to compare:• Mean arterial blood pressure• Need of another antihypertensive agent for very high blood pressure;• Need to maintain the antihypertensive therapy;• Daily mean systolic blood pressure• Daily mean diastolic blood pressure• Number of days with hypertensive peaks• Daily mean of hypertensive peaks• Number of days until blood pressure control• Number of days using antihypertensive drugs for treatment of hypertensive peaks• Number of antihypertensive drugs associated• Need for sodium nitroprusside to control hypertension• Number of days of obstetric ICU stay.In postpartum patients with postpartum very high blood pressure randomized to receive clonidine compared to the women receiving captopril:• Mean blood pressure is lower• Need of other antihypertensive agents for very high blood pressure is lower• Need to maintain other antihypertensive agents is lower• Daily mean systolic blood pressure is lower• Daily mean diastolic blood pressure is lower• Number of days with hypertensive peaks is lower• Number of days until blood pressure control is lower• Number of days using antihypertensive drugs for treatment of hypertensive peaks is lower• Need of association with other antihypertensive drug for treatment of hypertensive peaks is lower• Number of antihypertensive drugs associated is lower• Need for sodium nitroprusside to control hypertension is lower• Number of days of obstetric ICU stay is lower.The present study is a triple blind randomized controlled trial. The SPIRIT guidelines were used to prepare this protocol .The study population will include all eligible women with hypertension in pregnancy admitted to the obstetrical ICU in the postpartum period.The inclusion criterion is the presence of very high blood pressure in postpartum women with hypertension in pregnancy receiving magnesium sulfate for prevention or treatment of eclampsia (which includes both severe and superimposed preeclampsia or eclampsia cases). Exclusion criteria are: other associated maternal diseases ; smoking; use of any antihypertensive agent for very high blood pressure before admission to ICU or illicit drugs that may interfere with maternal hemodynamics; contraindications to the use of captopril  and contraindications to the use of clonidine .Eligible patients will be invited to participate and those who agree will be included in the study and receive clonidine or captopril according to a random list of numbers generated by the Random Allocation Software (Ispharan Iran), version 1.0. This list of randomization will be provided by the statistician to the pharmacist who will be responsible for preparing the packages containing either the clonidine or captopril, both in an identical presentation, with the identification number of list labeled. This procedure will be followed in order to guarantee the concealment of allocation of patients in both arms. Considering both drugs have rare identifiable immediate effects, either patients and medical staff should be blind of the intervention condition in each case. Study medication, after delivered by the pharmaceutical industry to the pharmacy of the coordinating center, will be packed as previously described and according the random list. The drugs will be kept at the ICU under the responsibility of the nurse, and when included the patient will receive the drug in the package corresponding to the inclusion. The subjects will receive the study medication at the moment of the inclusion (very high blood pressure) and the drug will be repeated after 20 minutes if the blood pressure levels have not responded to the administered drug, to a maximum of six doses. Other episodes of very high blood pressure during the day will be managed likewise, respecting the maximum of six doses of the study medication a day.If attending physicians observe that the blood pressure levels do not improve or if the 6 doses of medication for very high blood pressure where used, another drug for very high blood pressures  will be used, according to the physicians’ choice and judgment. During the study period other anti hypertensive agents used for maintenance may be initiated according to the physicians’ choice and judgment.During the observation period the women will be subject to the ICU routine which includes strict control of blood pressure and urine output . Laboratory tests will be performed at regular intervals of 24 hours .To calculate the sample size, as there were no studies evaluating the use of clonidine for the treatment of hypertensive crisis in the puerperium, nor a comparison with captopril for this purpose, we conducted a pilot study with 30 postpartum women with hypertensive disorders, 15 of each group (captopril vs. clonidine) in order to obtain the most suitable calculation of the sample.After completion of the pilot study and through statistical calculator Open Epi 3.01 , the daily mean of hypertensive peaks in each group  was used to calculate the sample with a power of 90% and a confidence level of 95%. Considering a mean of 2.8 hypertensive peaks/day in group A, with a standard deviation of 2.0 and a mean of 6.2 hypertensive peaks/day with a standard deviation of 6.2 in group B, a total of 90 patients was estimated already predicting eventual losses or differences between the groups .• Use of clonidine or captoprilMean arterial blood pressure, need of another antihypertensive agent for very high blood pressure, need to maintain the antihypertensive therapy, daily mean systolic blood pressure, daily mean diastolic blood pressure, number of days with hypertensive peaks, number of days until blood pressure control (absence of episodes of very high blood pressure), number of days using antihypertensive drugs for treatment of hypertensive peaks, need of association with other antihypertensive drugs for treatment of hypertensive peaks, number of antihypertensive drugs associated, need for sodium nitroprusside to control hypertension and number of days of obstetric ICU stay.• Hypertensive disorders of pregnancy: defined according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy .• Very high blood pressure episode: systolic blood pressure (SBP) ≥ 180 mmHg and/or diastolic blood pressure (DBP) ≥ 110 mmHg ; in case of adverse effects the number needed to harm (NNH) and its 95% confidence will also be calculated.The data analysis will be performed using the public domain software Epi Info version 7 , or the newest available version under the intention to treat principle. The statistician and the investigators will remain blind to the treatment groups until the tables will be prepared and the analysis concluded. The approach for analysis will be that showed in Figure rson’s χ  test or The local researchers will maintain a record of problems occurred during the study and any doubt should be solved with the project's coordinators and the Steering Committee.http://clinicaltrials.gov/ct2/show/NCT01761916?term=CLON+CAP&rank=1). Postpartum patients with hypertension and very high blood pressure will only be included if they agree to participate and sign the informed consent. All principles related to research in human beings established by the Brazilian National Health Council according to the Declaration of Helsinki will be followed. The confidentiality on women's data and medical care will be ensured regardless of whether they participate in the study or not.The original protocol of this research proposal has already obtained approval of the local Institutional Review Board from the coordinating center , and of the National Committee for Ethics in Research (CONEP) of the Brazilian Ministry of Health, under the number 3079–12. The protocol also was published in the Clinical Trials Register under the number NCT01761916 (Postpartum hypertension is still an understudied theme and may represent either the continuation of a pre-existing hypertension and new onset hypertension after delivery. Evidence of good quality evaluating the treatment of hypertensive crisis during this period are not yet available. Very high blood pressure may be associated with increased risk of stroke, eclampsia, congestive heart failure, acute pulmonary edema, renal failure and other morbidities, but the best drug for its treatment in the postpartum period remains to be established. Both captopril and clonidine have been proposed for this purpose, being both therapeutic options widely available, inexpensive and compatible with lactation. However, their effectiveness and safety have not been demonstrated in randomized controlled trials. This study is important because it can bring substantial information on antihypertensive treatment in the postpartum period with affordable medicines which are available in poor countries, especially those where hypertension remains a major cause of maternal death and labetalol is not available. The study may also determine which antihypertensive drug is safer and more effective for treatment of postpartum very high blood pressure, which can reduce maternal complications and length of hospital stay.ICU: Intensive care unit; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; IRB: Institutional review board; NNH: Number needed to harm; NNT: Number needed to treat; RCT: Randomized controlled trials.The authors declare that they have no competing interests.The first version of this protocol was drafted by MA and LK. All authors have made substantive intellectual contributions to the manuscript and read and approved its final version.