SHR) model is recognized for human cardiovascular pathology, but discrepancies appeared in studies of arterial stiffness. We performed experiments using a robust analysis via echo tracking in 20‐week adult (n = 8) and 80‐week‐old SHR (n = 7), with age‐matched normotensive Wistar Kyoto rats  at basal and matched levels of blood pressure (BP). After anesthesia with pentobarbital, abdominal aortic diameter and pressure were recorded and BP was decreased by clonidine i.v. At basal BP, aortic pulse distension, compliance, and distensibility (AD) were reduced and stiffness index increased with age and hypertension and further altered with age + hypertension. When BP was adjusted in SHR to that of normotensive rats (130 mmHg), there was no difference between 20‐week‐old SHR and WKY. Importantly, the age effect was maintained in both WKY and SHR and accentuated by hypertension in old rats. At 130 mmHg, with similar pulse pressure in the four groups, AD (kPa−3) = 24.2 ± 1 in 20 weeks WKY, 19.7 ± 1.4 in 20 weeks SHR, 12.4 ± 1.3 in 80 weeks WKY and 6.6 ± 0.6 in 80 weeks SHR; distension = 7.6 ± 0.4%, 6.7 ± 0.6%, 3.7 ± 0.3%, and 1.8 ± 0.2% in the same groups. In conclusion, reduced distensibility, that is, stiffening due to age is clearly shown here in both WKY and SHR as well as a synergistic effect of age and hypertension. This technique will allow new studies on the mechanisms responsible and drug intervention.Age and hypertension are major causes of large artery remodeling and stiffening, a cardiovascular risk factor for heart and kidney damage. The aged spontaneously hypertensive rat ( Increased large central artery stiffness is now recognized as a predictor of all‐cause mortality, fatal and nonfatal coronary event, and fatal strokes in not only disease populations such as essential hypertension  and normotensive rats. In adult SHR, Labat et al.  describeWe previously evaluated aortic distensibility in a model of severe hypertension and aortic remodeling, the SHR‐LN, using the three methods, PWV  and 80 weeks . The animals had ad libitum access to both standard rat chow and water for the duration of their housing. The animals were housed together in their distinct groups with up to four animals per cage in a temperature‐controlled room (20–21°C) with a 12:12 h light:dark cycle.This study was conducted in accordance with the European Community Guidelines for the use of experimental animals and was approved by the ethical committee on Animal Experiments of the Servier Research Institute. All animals were provided by Charles River . Male Wistar Kyoto rats (WKY) and male spontaneously hypertensive rats (SHR) were age matched at 20 weeks (WKY 2O. Body temperature was maintained at 38°C with a homeothermic blanket (Harvard) connected to a rectal probe. A microtip pressure catheter (Millar 1.2F) was inserted into the abdominal aorta via the right femoral artery. The blood pressure signal was visualized and analyzed with Biopac 4.2 Acknowledge acquisition and analysis system (CEROM). Aortic diameter was simultaneously measured with pressure using ultrasound. An ultrasound probe (L10‐5 40 mm 10 Mhz) was placed on the shaved skin on the side of the animal and was manipulated until a clear B‐mode image of the abdominal aorta and the intra‐arterial catheter was seen. A section of artery adjacent to the catheter was selected and subsequently analyzed in M‐mode. Vessel wall tracking technology  was used to measure the changes in arterial diameter for 6 sec (~30 cardiac cycles). The blood pressure signal was split and sent to a second computer containing Art.Lab to allow for blood pressure and diameter synchronization . The jugular vein was cannulated for constant administration of anesthesia and the penile vein was cannulated for administration of other drugs. The trachea was cannulated and ventilation was maintained with a pressure controlled respirator  at a frequency of 60–70 cycles per minute and a pressure of 9–12 cmHion Fig.  and the ion Fig.  have preD); mean distension (in μm); compliance (ΔA/ΔP) in mm2/kPa, where A is the transsectional area of the vessel calculated from the diameter, and P is pressure; distensibility (ΔA/ΔP × A) in 1/kPa; and beta stiffness index {[dDln(SAP/DAP)]/(sD − dD)},where sD is systolic diameter, SAP is systolic arterial pressure, and DAP is diastolic arterial pressure. Aortic distension was expressed in percent versus diastolic diameter (ΔD × 100/dD). The local pulse wave velocity (PWV) was calculated from √⌈(A/ΔP/ρΔA), ρ = blood viscosity.The parameters automatically calculated to determine the dynamic properties of the aortic wall are as follows: mean diameter and diastolic diameter (d3) to avoid heart rate differences between groups  were calculated. For the pressure wave and the distension (%) wave, the AUC values were adjusted for heart rate (AUC/msec = AUC × heart rate/60 × 10μg/kg) which decreases blood pressure by inhibiting α2‐receptors in the brainstem, thereby decreasing peripheral sympathetic tone. A measurement was made at baseline blood pressure for each animal and again as blood pressure was slowly decreasing due to the action of clonidine. The discrete blood pressure chosen (after a measurement at baseline blood pressure) was: 130 mmHg for the SHR. The baseline blood pressure for an anesthetized WKY is approximately 130 mmHg, which allowed for a simple comparison with the SHR.In order to gain a greater understanding of the pressure‐dependent changes in arterial stiffness in the rat models used, blood pressure was changed using intravenous administration of clonidine .All data were expressed as the mean ± the standard error of the mean (SE). The coefficient of variation measurement (%) was calculated. Then, each hemodynamic parameter was analyzed with a two‐way ANOVA of raw data followed by a Dunnett post hoc comparison on age and hypertension, first at basal blood pressure and again at matched blood pressures across all groups. The raw data residuals followed a normal distribution and the variances were homogeneous. Three parameters, Correlation analysis was performed for blood pressure, distensibility, stiffness index, and distension; Pearson r and p value were determined (GraphPad Prism software version 6.03).β‐stiffness index compared to the adult SHR. WKY showed an increase in aortic stiffness with age as determined by all measures of aortic stiffness. Similarly, hypertension at both ages induced an increased β‐stiffness index and decreased distensibility.Body weight in adult rats were similar (WKY: 340 ± 7 g and SHR: 334 ± 7 g). Old WKY had as expected a higher body weight 628 ± 14 g) than adult rats and old SHR (396 ± 7 g). Table 4 g than b‐index = 6.7 ± 0.5, local PWV = 7.9 ± 0.3 m/sec) D = 15.6 ± 1.3 kPa*10−3, C = 19.4 ± 1.2 and distension = 5.7%.Because of this difference in SHR groups, the first BP level analyzed in adult SHR after clonidine injection was 151 ± 3 mmHg. At this similar level of pressure, the old SHR have higher stiffness parameters and decreased distensibility parameters. The values for adult SHR at such blood pressure value were: β‐stiffness index and local PWV) compared to the adult WKY; however, there was still a slight decrease in distensibility and compliance. The old SHR retained its previously observed increase in stiffness as compared with both the adult SHR and the old WKY with all parameters , we observed that the adult SHR no longer showed a difference in stiffness parameters , however, β‐stiffness index and distensibility were correlated (Pearson r = −0.8). Distension was correlated with MAP (Pearson r = 0.34) across all groups except in old SHR.Correlations were calculated across all blood pressure values. MAP was correlated with distensibility, but not with Figure By measuring aortic stiffness at isobaric blood pressure, this study has quantified the contribution of age, hypertension, and age combined with chronic hypertension on aortic arterial stiffness. The stiffness measurements taken at basal blood pressure indicated both an effect due to different operational pressures and putative remodeling. Since these measurements were taken again at isobaric pressure, the changes remaining in arterial stiffness could only be accounted for by vascular remodeling. Specifically, we have found that aging leads to an increase in aortic stiffness and this stiffening is made worse when coupled with chronic hypertension in rats.While the stiffening effects of aging and hypertension have been well described in humans as reported with aortic PWV  show that hypertension leads to a decrease  as a function of total energy throughout the cardiac cycle as stated previously , the structural data were completely in agreement with the functional results obtained in this study. Moreover, we also showed that endothelial dysfunction, the other crucial component of arterial aging was significantly reduced in 55‐week‐old SHR and not in 20‐week‐old SHR Marque et al. in 1999 (Marque et al. Ultimately, an assessment of the morphological changes of the arteries is essential for understanding the in vivo effects of aging and hypertension. Analysis of aortic morphology was not carried out during this study which focused on in vivo evaluations because our team and others previously conducted these assessments. When assessing the presence of aortic remodeling and fibrosis, we previously showed (Isabelle et al. In conclusion, we have shown that aging leads to an increase in aortic stiffness in the rat and this stiffening is made worse when coupled with chronic hypertension. These results reflect the values typically obtained when assessing human aortic PWV under the same conditions. Therefore, the aged rat model may be considered as a viable surrogate for human aortic stiffness when assessing novel drugs to reduce arterial stiffness.None declared.Table S1. Hemodynamic values and arotic properties expressed as mean and coefficient of variation.Click here for additional data file. Click here for additional data file.


Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary kidney diseases that frequently result in renal failure. In this cross-sectional observational cohort study, we evaluated urinary angiotensinogen (AGT) as a potential biomarker to assess renal function in ADPKD.Urinary AGT was measured in 233 ADPKD patients and its association with estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV) were evaluated. The localization of AGT and other renin-angiotensin system (RAS)-related molecules were identified using immunohistochemistry in human ADPKD tissues.r2 = 0.162, P < 0.001) and positively correlated with htTKV . Both urinary AGT/Cr and plasma renin activity levels were significantly elevated in hypertensive ADPKD patients. Among hypertensive subjects, urinary AGT/Cr was significantly increased in the advanced CKD stages (III-V) compared to early CKD stages (I-II) . Immunohistochemical study showed strong expression of AGT along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells.Baseline urinary AGT/Cr was negatively correlated with CKD-EPI eGFR  contains supplementary material, which is available to authorized users. Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary kidney diseases with the prevalence of 1 per 1000-4000 . Renal fADPKD patients develop hypertension earlier than the essential hypertensive patients and it is also well known that early-onset hypertension is the major predictor of renal outcome in ADPKD . IntrareFrom January 2011 to February 2012, a total of 304 ADPKD patients above 18 years regularly visiting our ADPKD clinic were enrolled in the study. ADPKD was clinically diagnosed according to the Unified Criteria for Ultrasonographic Diagnosis of ADPKD proposed by Pei et al . Among t2), stage II (60-90 mL/min/1.73 m2), stage IIIA (45-60 mL/min/1.73 m2), stage IIIB (30-45 mL/min/1.73 m2), stage IV (15-30 mL/min/1.73 m2), and stage V (<15 mL/min/1.73 m2) [Upon enrollment, the demographic information and laboratory parameters were investigated. Systolic and diastolic blood pressures were measured at every visit and the number and types of anti-hypertensive medications were also reviewed. Upon enrollment, blood samples were withdrawn and serum Cr was measured by Jaffe method. The eGFR was calculated using chronic kidney disease epidemiology (CKD-EPI) equation , 19. The1.73 m2) . To evalOf 233 patients, 200 patients underwent CT within 1 year from their enrollment time points. Thirty-three patients were excluded from the analysis because they underwent CT scans apart from urinary biomarker measurement (>1 year). Among them, 189 patients had available height information to calculate htTKV (mL/m) . We haveUrine samples were separately collected for the measurement of urinary AGT, mixed with 1 mL of 10 mM Tris buffer, centrifuged at 3000 g for 10 min, and stored at -80 °C until measurement. Urinary AGT was measured by commercial sandwich enzyme-linked immunosorbent assay (ELISA) . Urine samples were diluted 10 times before the measurement. To evaluate whether urinary AGT is a better biomarker for renal function in ADPKD, we also measured urinary NAG and β2MG. The activity of urinary NAG was measured by a spectrophotometric assay under a 340-nm wavelength using a TBA 200 FR biochemical analyzer  . The uri2O2 for 10 min at room temperature to block endogenous peroxidase. The slides were rinsed three times with PBS and then blocker with universal blocking buffer. The primary antibodies were added at the dilution indicated in Table One normal kidney specimen and two polycystic kidney specimens were collected from radical nephrectomized kidneys Table . Each kiwww.spss.com). The variables that did not follow normal distribution were log-transformed before analysis. To investigate whether urinary biomarkers were correlated with either eGFR or htTKV, linear regression analyses were performed. To adjust for potential confounders, multiple regression analysis was performed. We also performed independent t-test and the analysis of variance (ANOVA) test to compare continuous variables between groups. The P-value < 0.05 was considered statistically significant.Statistical analyses were performed using SPSS, version 19.0 . The procedures for the use of the human kidney specimens were approved by Seoul National University Hospital Institutional Review Board (H-0701-033-195). All participants provided written informed consent before the study in accordance to the Declaration of Helsinki.2, respectively. The median value of urinary AGT/Cr was 13.7  μg/g. The CT scan was taken in 189 subjects. Measured htTKV at baseline was 705 mL/m  and the mean time gap between urinary biomarker measurement and CT scan was 4.7 ± 4.0 months.A total of 233 ADPKD patients were selected for this study. Baseline clinical characteristics are summarized in Table r2 = 0.162, P < 0.001)  than urinary NAG/Cr and β2MG/Cr   . Among hypertensive subjects, urinary AGT/Cr was significantly increased in the advanced CKD stages (III-V) compared to early CKD stages (I-II) . This remained statistically significant when we compared urinary AGT/Cr among the subgroup population who were not taking RAS blocker medications . On the other hand, PRA could not differentiate those with decreased renal function from those with normal renal function . In concordance to previous studies, our results suggest that local RAS (represented by urinary AGT/Cr) as well as systemic RAS (represented by PRA) are activated in hypertensive patients. However, urinary AGT/Cr showed better association with CKD stages among hypertensive subjects compared to PRA. Meanwhile, RAS blockers, ACEi and/or ARB, did not affect either urinary AGT/Cr levels or PRA/aldosterone levels , AGT was strongly expressed in proximal tubules and cyst-lining epithelial cells Fig. . Of noteExpression levels of other intrarenal RAS components such as AngII, Ang-(1-7), ACE, ACE2, and chymase were investigated using immunohistochemical staining Fig. , Table 5AGT is a 52- to 64- kD peptide molecule that has a limited glomerular permeability and tubular degradation. Because of these properties, urinary AGT has been studied as a marker for the intrarenal RAS activity among other RAS related proteins . As a noOur study is the largest study to demonstrate urinary AGT/Cr as a useful clinical parameter associated with renal dysfunction and underlying pathophysiology. In this study, urinary AGT/Cr demonstrated a better association with concurrent eGFR, htTKV, and hypertension compared to other biomarkers including urinary NAG/Cr and β2MG/Cr. In addition, our immunohistochemical staining results showed that most of RAS components including AGT were highly expressed in the polycystic kidney tissues compared to normal kidney. These results suggest that intrarenal RAS activation may play an important role in blood pressure elevation and renal dysfunction. Indeed, high blood pressure often manifests far earlier than cyst growth and replacement of renal parenchyma. It suggests that not only mechanical compression by cysts but also paracrine hormonal action will be crucial for developing hypertension in ADPKD.In our study, urinary AGT/Cr was well correlated with concurrent eGFR and htTKV even in the early CKD stages. In the previous study, urinary AGT/Cr measured from healthy volunteers ranged from 5.0 to 30.0 μg/g  than that in case II  suggesting that urinary AGT/Cr may be more useful in the early stage of renal disease. Previous studies support our results, clearly showing that all the intrarenal RAS components are highly expressed in the proximal tubules in the pathologic condition [However, our immunohistochemical study suggests AGT may be produced and secreted vigorously in the early CKD stages. In concordance to previous study results, AGT was highly expressed in proximal tubular epithelial cells and cyst-lining cells of ADPKD . Notablyondition , 28, 29.ondition . Intraluondition .Unravelling the mechanisms involving intrarenal RAS activation in ADPKD is beyond the scope of this study since this study aims to investigate the clinical usefulness of urinary AGT/Cr as a biomarker of renal insufficiency. However, it is worthy to note that the expression levels of the counterpart molecules, ACE2 and Ang-(1-7), were also elevated in the polycystic kidneys. Two possible explanations can be given. First, since the subjects were taking ARB to block the action of AngII, the feedback mechanism would increase the production of upstream molecules, AGT and AngII. Ang II is then further converted to Ang (1-7) directly by ACE. Another possible mechanism is that the dose of RAS blocker was insufficient to decrease intrarenal RAS activity hence the counterpart pathway was activated to compensate the deleterious effects of AngII. The functional effect of increased ACE2 and Ang-(1-7) should be demonstrated in the further study.The expression of ACE was universally decreased in ADPKD tissue compared to normal control. Previous study suggested that AngII production in organ or tissue may rely more on chymase rather than ACE in pathologic conditions . The othThis study has several limitations. This is a single-center, cross-sectional study that included only Korean patients. Second, we failed to show independent association between urinary AGT/Cr and eGFR. Third, patients in advanced CKD stages were largely excluded. Lastly, TKV was measured using a modified ellipsoid method from CT images. The modified ellipsoid method was originally developed to measure kidney volumes from ultrasonographic images . In addiWe found that high urinary level of AGT/Cr was associated with lower eGFR, larger htTKV, and hypertension. Immunohistochemical results demonstrated the possible link between ischemic insult by cyst growth and subsequent activation of intrarenal RAS in the progression of ADPKD. Further long-term studies should reveal the usefulness of urinary AGT/Cr in the prediction of faster renal function deterioration.


The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome by cellular stress leads to activation of the inflammasome, and NLRP3 gene polymorphisms have been associated with autoinflammatory diseases. Inflammasomes have also been implicated in the initiation or progression of metabolic disorders such as atherosclerosis, type 2 diabetes and obesity. The association of NLRP3 genetic variant rs7512998 with blood pressure and hypertension was studied in a 50-year-old Finnish cohort with a subpopulation who had available data on blood pressure measurements also at the age of 45 years.p = 0.006) and diastolic (p = 0.011) blood pressure compared to the TT-genotype carriers in 50-year-old subjects. In addition, by analysis of variance for repeated measures between ages of 45- and 50 years there was a significant time by genotype interaction; blood pressure increased more in subjects with the C-allele both in systolic (p = 0.035) and diastolic (p = 0.012) values. However, no association with diagnosed hypertension was found.NLRP3 gene polymorphism rs7512998 C-allele was associated with higher systolic (We report for the first time that NLRP3 gene polymorphism rs7512998 was associated with systolic and diastolic blood pressure in 50-year-old subjects. In addition, an effect of this variation upon blood pressure was seen in these same subjects in a 5-year follow-up from a 45-year-old cohort to 50 years of age. There is increasing evidence that inflammasomes are involved in the initiation or progression of diseases including metabolic disorders such as atherosclerosis, type 2 diabetes and obesity . Inflammn = 16), 0.28 for TC (n = 216) and 0.70 (n = 537) for TT. These frequencies were in Hardy-Weinberg equilibrium (p = 0.287), and did not differ between cases and controls.Clinical characteristics of the cases (325) and controls (444) at the age of 50 years are presented in Table p = 0.006) and diastolic (p = 0.011) blood pressure at the age of 50 years than those homozygous for the T allele. The difference between subjects with the C allele and genotype TT was 3.4 mmHg in systolic blood pressure and 1.9 mmHg in diastolic blood pressure. This difference in blood pressure was not seen at the age of 45 years. At the ages of 45 and 50 years there were no differences between the genotype groups in prevalence of hypertension, blood pressure medication, BMI, serum cholesterol or glucose levels. Multivariate analysis confirmed NLRP3 gene rs7512998 genotype as an independent predictor of both systolic  and diastolic (p = 0.012) values.When the 45- and 50 year follow-up data of blood pressure measurements in Table We report that C-allele of the NLRP3 gene polymorphism was significantly associated with higher blood pressure compared to genotype TT at the age of 50 years. To our knowledge, there are no previous studies showing such an association. The C-allele of rs7512998 has previously been shown to be more common in gout patients compared with controls, although 16 other NLRP3 gene polymorphisms showed no such association . In the The observed increase in blood pressure in subjects with the NLRP3 gene rs7512998 C-allele with aging may be linked to modified activation of NLRP3 by aging-related reactive oxygen species (ROS) production by damaged mitochondria. This process of inflammasome activation through NLRP3 is present in many age‐related conditions, such as obesity, and type 2 diabetes . An antiThe toll-like receptors (TLR) are transmembrane proteins that are important for immune surveillance at the cell surface and endolysosomal compartments, recognizing a wide range of microbial structures and endogenous danger signals. In most cell types inflammasome activation commonly includes priming with a TLR agonist, such as lipopolysaccharide (LPS), which induces elevated expression of NLRP3 . Once prThere was a gender bias since in multivariate analysis male gender was a predictor of both systolic and diastolic blood pressure. However, multivariate analysis also showed that C-allele of the NLRP3 rs7512998 gene polymorphism was significantly associated with higher blood pressure, independently of gender and BMI. Life-style factors such as smoking and exercise contribute to inflammation, metabolic syndrome and blood pressure increase. However, in regard to smoking and BMI, there were no differences between genotype groups.The study group was restricted to residents of a large city in Finland, posing a challenge to how broadly one can apply the findings. Since the study subjects are from a restricted genetic pool (Finnish Caucasian), the findings might not be extrapolated to different genetic populations. Replication studies should be called for to explore more fully the findings with further consideration of the molecular mechanisms. In addition, each registration of blood pressure was made at one examination visit only, and most of the subjects with hypertension were already on medication by the age of 50 years. It is also clear that information on medication had not been provided by some of the participants with hypertension, since the percentage of these with recorded blood pressure treatment was only 73 %.In conclusion, our results indicate that NLRP3 gene polymorphism rs7512998 is associated with systolic and diastolic blood pressure in 50-year-old subjects in the TAMRISK study. Between ages of 45- and 50 years blood pressure increased more in subjects with the C-allele. Age-related increase in blood pressure could have an inflammatory background where NLRP3 inflammasome action may be involved.TAMRISK study data was collected from periodic health examinations (PHE) done for 50-year-old men and women living in Tampere, a city in southern Finland with 220 000 inhabitants . Basic en = 325) were subjects who had hypertension at the age of 50 years (as diagnosed by a physician) and for each case, at least one normotensive control subject (n = 444) with the same sex and similar smoking habits, was chosen in order of admission from a PHE cohort (n = 6000). The present study population at the age of 50 years thus included 769 subjects. Of these same individuals, we also analyzed the subpopulation of men and women who had available previous PHE data from the age of 45 years (n = 678), Both 50- and 45 year PHEs were conducted in a similar fashion by the same organization.Cases . The samples were transferred into 96-well plates and genotyped for NLRP3 gene polymorphism rs7512998 at the KBioscience Institute (UK) using Competitive Allele Specific PCR (KASP) technique.http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/). The C-allele frequency of NLRP3 gene polymorphism rs7512998 was 0.1599 reported by National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/snp/?term=rs7512998). Using 80 % power, a type I error rate of 0.05 and a two-sided statistical test, the required sample size per group was calculated to be 99. A total of 325 cases and 444 controls with successful genotyping were included in the final study population.Sample size was calculated by Quanto 1.2.4 , with a choice of gene-only model. According to the World Health Organization a prevalence ratio of raised blood pressure in adults aged over 25 is about 40 % .


Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult. Statins effectively decrease cardiovascular risk, and cholesterol lowering with statins has become a cornerstone of cardiovascular disease prevention for a wide range of patients . DespiteDespite the existence of statin intolerance having been widely acknowledged, a large degree of variability remains as to what is considered to be statin intolerance. In addition, there is significant uncertainty regarding the actual incidence, and there is insufficient knowledge concerning the best therapeutic approaches to the problem. Most cases of statin intolerance are related to muscle complaints –7, with It should be noted that all of the mentioned symptoms can stem from a number of different causes and are often unrelated to actual statin use. However, even among patients with true statin-related symptoms, many can tolerate lower doses of the same statin, or perhaps a different statin. Establishing a diagnosis of statin intolerance is therefore less straightforward than it might appear, and an adequate therapeutic approach is more complex than simple discontinuation of statin therapy.As a result of these complexities, statin intolerance is currently gaining increased attention and several guidelines , 11, 12 In general terms, statin intolerance can be defined as the occurrence of (1) adverse symptoms perceived by the patient to be unacceptable, and/or (2) laboratory abnormalities suggesting undue risk, which are attributed to statin therapy and lead to its discontinuation. For practical purposes, descriptions regarding acceptability of symptoms, attributability to statin therapy, and the degree of intolerance, need to be better defined.Most cases of statin intolerance are related to patient complaints; the discontinuation of therapy due to laboratory abnormalities is far less common. Thus, in most cases, decisions pertaining to statin intolerance are patient decisions. In this context, it is important to note that some degree of adverse symptoms might be tolerated by patients and it does not necessarily imply intolerance of therapy. Statin intolerance is not simply the occurrence of symptoms in general, but rather those symptoms that are perceived to be unacceptable. Hence, the patient’s subjective assessment of perceived risks and inconveniences, versus the benefits of therapy, are at the core of an effective approach to the issue of statin intolerance.Identifying true cases of statin intolerance is, therefore, of great practical importance in order to avoid unnecessary discontinuation of statins from patients who would otherwise benefit from them. However, evaluating the likelihood that the adverse symptoms are causally related to statins is often a difficult task (Table http://www.acc.org/StatinIntoleranceApp).When experienced during the course of statin therapy, myalgia and other adverse symptoms are often unrelated to treatment, and most patients with a history involving episodes of these symptoms are able to tolerate adequate statin therapy , 18. Idesk Table . It is adefinition of statin intolerance for use in clinical practice:Given the specifications mentioned above, we propose the following Statin intolerance is the occurrence of (1) adverse symptoms perceived by the patient to be unacceptable, and/or (2) laboratory abnormalities suggesting undue risk, which are attributed to statin therapy and lead to its discontinuation.symptoms or abnormalities should be temporally associated with the initiation of statin therapy, improve upon discontinuation, and reoccur after the readministration of therapy, andknown precipitating factors and conditions with similar presentations should first be excluded. These primarily include musculoskeletal diseases, hypothyroidism, vitamin D deficiency, strenuous exercise, intercurrent illness, or drug interactions .To be attributed to statins:Regarding the degree of statin intolerance, it can be classified as partial or complete .Mild symptoms should not be considered intolerance, provided they are deemed acceptable by the patient.we propose two degrees of statin intolerance for consideration:complete statin intolerance: the inability to tolerate a minimum of three statins at their usual lowest daily starting doses, andpartial statin intolerance: the inability to tolerate statin therapy in the form and dosages required to achieve treatment goals .Among patients presenting with statin intolerance, there is great variability regarding the number and doses of statins they are unable to tolerate. Some patients are intolerant of virtually all statins, even in low doses; others only experience adverse symptoms with a particular statin, or only with the highest doses of particular statins. With this in mind, For the purposes of this definition, the lowest daily starting doses of statins are proposed as rosuvastatin 5 mg, atorvastatin 10 mg, simvastatin 20 mg, lovastatin 20 mg, pravastatin 40 mg, fluvastatin 40 mg, and pitavastatin 2 mg.Inability to tolerate some statins, or some doses, should not be considered as statin intolerance, provided it does not interfere with the achievement of treatment goals.Partial intolerance is pragmatically defined with respect to the therapeutic needs of individual patients. statin therapy remains the mainstay of lipid-lowering treatment for most of these patients  supplementation is frequently used for statin myalgia, but the evidence in support of its use has, thus far, been contradictory. Recently, a well-designed trial , in conjIn patients with partial statin intolerance , lower doses, or less potent statins, should be used.For patients unable to tolerate any statin at the usual starting daily dose, there is emerging agreement that very low doses, and/or less-than-daily dosing, should be attempted , 13. SinIn terms of a practical approach to statin intolerance, listening to the patient’s complaints and fears is crucial to encourage greater receptivity and willingness to try various statins and dosing schedules, some of which may be associated with adverse symptoms , 26. TheIn order to prevent unnecessarily intense symptoms of statin intolerance and improve patient adherence to statin therapy in the general population, it may be wise to initiate statin therapy in statin-naive patients with low or moderate (rather than high) doses in the majority of cases, except for patients at highest cardiovascular risk. Patients who previously tolerated lower doses are much more willing to return to them in cases where they experienced problems with higher doses, compared to those who were intolerant to a higher starting dose. It is also advisable to perform both creatine kinase and liver tests prior to commencing statin therapy in order to establish reference baseline values in case the patient develops elevations in these tests during therapy.Other lipid-lowering drugs may be needed to achieve appropriate targets, either in combination with statins, or alone, if statins are not tolerated at all. A combination of these drugs and low-dose statin therapy can provide reductions in LDL-C similar to those obtained with high doses of statins.Ezetimibe decreases LDL-C by 15–20 % (either in combination with statins or as monotherapy) and is widely used in patients with statin intolerance. Ezetimibe is well tolerated, but the evidence of cardiovascular benefit is limited to one trial that demonstrated a modest 6 % reduction of cardiovascular events .Fibrates are primarily used to lower triglycerides and increase high-density cholesterol; they also decrease LDL-C levels, but to a lesser extent. The effect on LDL-C is more pronounced in patients with hypertriglyceridemia. Accordingly, the reduction of cardiovascular risk with fibrates is only 10 % in unselected patient population, but is substantially greater (≈30 %) in patients with hypertriglyceridemia . As suchBile acid sequestrants (resins) provide LDL-C reduction that is comparable to that observed with ezetimibe, and they have been proven to reduce cardiovascular events. Resins are safe, but poorly tolerated, due to gastrointestinal side effects. The recently developed colesevelam has fewer side effects and better patient compliance.Niacin is similar to fibrates relative to its effect on blood lipids, but its use in clinical practice has dropped substantially after two clinical-endpoint trials failed to demonstrate cardiovascular benefits of niacin therapy , 30.PCSK9 inhibitors are a novel class of lipid-lowering drugs; they were approved quite recently in the USA and Europe. They reduce LDL-C levels by ≈ 50 %. Meta-analyses of phase 2 and 3 trials demonstrated a >50 % reduction of cardiovascular events with evolocumab and alirocumab , 32, andMuscle problems and other adverse symptoms associated with statin use are relatively frequent reasons for non-adherence and discontinuation of statin therapy, which can contribute to adverse cardiovascular outcomes. However, most patients who experience objectionable symptoms during statin use are still able to tolerate at least some degree of statin therapy. The clinician’s challenge is therefore to help their patients find their way back to statins.In essence, this task comprises only a few steps: First, identify patients with unlikely statin intolerance, and who can therefore probably continue with some type of adequate statin therapy. A pragmatic definition of statin intolerance, as outlined above, may be useful in this respect. Second, in cases with statin intolerance, consider very low doses of statins and/or altered dosing regimens. In addition, other lipid-lowering drugs may be needed, in conjunction with changes in lifestyle and better control of other cardiovascular risk factors. With this cautious and multifactorial approach, reasonable improvement in blood lipid levels, as well as a marked reduction in global cardiovascular risk score, can be achieved in most patients.As simple this approach may appear, it may prove difficult in practice. Listening to patients’ complaints and fears, explaining the benefits of therapy, and motivating patients to try various therapeutic schedules (some of which may be associated with adverse symptoms) are often difficult and time-consuming tasks. From a clinician’s perspective, a successful approach to statin intolerance primarily entails the art of successful communication with the patient.


Objective. Central blood pressure (BP) and vascular indices estimated noninvasively over the 24 hours were compared between normotensive volunteers and hypertensive patients by a pulse wave analysis of ambulatory blood pressure recordings. Methods. Digitalized waveforms obtained during each brachial oscillometric BP measurement were stored in the device memory and analyzed by the validated Vasotens technology. Averages for the 24 hours and for the awake and asleep subperiods were computed. Results. 142 normotensives and 661 hypertensives were evaluated. 24-hour central BP, pulse wave velocity (PWV), and augmentation index (AI) were significantly higher in the hypertensive group than in the normotensive group , whereas reflected wave transit time (RWTT) was significantly lower in hypertensive patients (126.6 versus 139.0 ms). After adjusting for confounding factors a statistically significant between-group difference was still observed for central BP, RWTT, and peripheral AI. All estimates displayed a typical circadian rhythm. Conclusions. Noninvasive assessment of 24-hour arterial stiffness and central hemodynamics in daily life dynamic conditions may help in assessing the arterial function impairment in hypertensive patients. In recent years, great emphasis has been placed on the role of arterial stiffness and central blood pressure (BP) as independent predictors of the development of cardiovascular (CV) diseases –3. ConseRegional and local arterial stiffness may be measured directly and noninvasively, at various sites along the arterial tree, by assessing pulse wave velocity (PWV) and augmentation index (AI) . CentralThe most widely employed methods for evaluating pulse waveforms are those based on applanation tonometry and transfer functions, although recently oscillometric ambulatory blood pressure monitoring (ABPM) devices using specific algorithms for pulse wave analyses have been proposed for assessing arterial stiffness –9. At prIn the present study we aimed at assessing the feasibility of determining central BP and various indices of arterial stiffness over the 24 hours by a noninvasive, clinically validated technology of pulse wave analysis based on oscillometric BP measurements, integrated in an ambulatory BP (ABP) monitor , 12. PotTreated or untreated hypertensive outpatients and untreated healthy volunteers, aged 18 years or more, were included in the study. Healthy individuals were eligible for inclusion into the study in absence of arterial hypertension , blood test abnormalities , obesity, and other major cardiovascular risk factors. Both healthy subjects and hypertensive patients were excluded in case of previous or current cardiovascular disease or any other concomitant significant systemic condition. All individuals were submitted to an ABPM, preceded by an office automatic BP measurement with the same device used for ambulatory monitoring. Office BP was measured in the sitting position after 5-minute rest: three measurements were obtained at 2 min intervals and the average of the three measurements was taken as the reference for office BP.Hypertensive patients were recruited among consecutive patients with a known history of high BP presenting at the outpatient clinic of the Cardiology Research Complex, Moscow. Healthy volunteers were recruited among the staff and personnel at the Russian Railroad and at the Russian Navy. The study was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki, and the protocol was approved by the ethics committees of the centers involved. Written informed consent was obtained from all patients and controls prior to their inclusion into the study. All individuals were recruited and studied between September 2008 and December 2012.ABPM was performed noninvasively over the 24 hours by the BPLab electronic, oscillometric, automated BP monitor . The device accuracy in measuring BP has been previously successfully tested in a validation study . AdditioCurrent international guidelines were followed for proper ambulatory recording performance . The optThe BPLab BP monitor makes use of brachial oscillometric BP waves for a noninvasive estimation of central BP and arterial stiffness , 12–14. The following indices were derived. The reflected wave transit time (RWTT) represents the transit time of pulse wave along a corresponding artery and is the reciprocal of PWV . In caseThe analysis of 24-hour BP recordings was preceded by removal of artifacts according to the previously described editing criteria . Recordir) was determined. The level of statistical significance was kept at 0.05 throughout the whole study. Data are shown as mean ± SD or as mean and 95% confidence interval for continuous variables and as absolute (n) and relative (%) frequencies for discrete variables.Mean values obtained in each individual subject were averaged for the whole study population, separately for the healthy normotensive and hypertensive group. Differences in hemodynamic indices were assessed by analysis of variance, without adjustment (crude estimate) and after accounting for age, gender, body mass index (BMI), antihypertensive drug treatment, and mean ABP (adjusted estimate). Adjustment for mean ABP was not applied to normalized RWTT and normalized PWV, because these measures were already normalized to a SBP of 100 mmHg and to central BP. Comparison of categorical variables was made by a Chi-square test. To check the relation between the studied parameters, Pearson's correlation coefficient (n = 10) or office or ABP were elevated. In the hypertension group valid ABP recordings could not be obtained in 73 patients. Thus, in summary, 803 subjects were included in the analysis, of which 142 were controls and 661 were patients with arterial hypertension. The average percentage of valid readings obtained over the 24 hours was 93.9% in the healthy control and 93.1% in the hypertensive group. The average number of valid readings available during the day was 32.9 ± 9.4 in the control group and 26.7 ± 5.6 in the hypertension group, while the corresponding figure for the nighttime period was 7.6 ± 2.6 and 8.2 ± 2.6.Overall, 916 people were recruited and performed an ABP recording, of which 182 were healthy volunteers and 734 were hypertensive patients. In the control group, 40 subjects were not considered eligible for inclusion in the analysis because either of ABP recordings did not meet quality criteria , statistically significant between-group differences were still observed for central BP, RWTT, and AI, only. This suggests that these indices may be unaffected by intrinsic subjects' characteristics and/or BP levels and may thus represent a more sensitive index for evaluating arterial function, at least in ambulatory conditions.Our paper also provides additional findings which are worth being discussed in detail.The different indices displayed a typical circadian pattern, regardless of the normotensive or hypertensive status. In particular, central BP followed a diurnal course similar to that of peripheral brachial BP and thus decreased during nocturnal sleep. Conversely, AI increased overnight, likely because this index is inversely related to heart rate, which decreases at night, and it is strongly affected by the body posture, with absolute values increasing during recumbency , 21 and Standardization of the AI to heart rate removed the diurnal profile, in case of being peripheral but not aortic AI. RWTT and PWV both depend on BP and were, respectively, higher and lower at night than at day. As in the case of peripheral AI, circadian pattern of RWTT and PWV both disappeared after correction for SBP and HR, suggesting that standardized parameters may be more robust as compared to uncorrected ones. All these findings are in line with and confirm those obtained in healthy volunteers or hypertensive patients with other oscillometric devices; although such studies were based on a different technology, they were carried out in smaller groups of subjects and the majority of them evaluated central BP only , 24–26. We also examined the correlation between the different central and peripheral hemodynamic and arterial stiffness indices. A close relation was found between age and 24-hour arterial stiffness, in both healthy individuals and hypertensive patients, confirming previous evidence collected in resting conditions , 29. ABPThe results of the present study must be interpreted also in the context of its limitations. First of all, we assessed arterial parameters noninvasively by applying transfer function analysis to an oscillometric reconstructed waveform rather than via a direct measurement. Indeed, several authors have questioned the goodness of the principle of one-site central BP, PWV, and AI measurements by oscillometry , 40, 41.Our results suggest that noninvasive assessment of ambulatory arterial stiffness and central hemodynamics may be feasible and help in assessing the degree of impairment of the arterial tree in hypertensive subjects in daily life dynamic conditions. Such an approach may help unraveling subclinical organ damage or functional changes, for instance, due to an increased sympathetic tone, which are typically associated with hypertension. However, further observations in diverse populations are required before ambulatory assessment of the central hemodynamic variables can make it to the clinical practice. Future studies should validate whether the assessment of noninvasive 24-hour central hemodynamics can provide further information regarding CV risk stratification and target organ damage beyond the 24-hour brachial BP. Additionally, reference values specifically obtained by the BPLab monitor, ideally in prospective studies, are needed. Nevertheless, our data may be used as preliminary diagnostic values of BPLab ABPM additional indices in adult healthy normotensive and hypertensive subjects.


The airway remodeling in asthma is associated with increased amount of matrix metalloproteinase (MMP)-9. High levels of MMP-9 were found in mucosal biopsies, sputum and in exhaled breath condensates (EBC) of asthma patients. However, there are no data concerning real in vivo activity. Inhaled corticosteroids are effective in asthma control, but it is unclear, whether they only attenuate inflammation, or also protect against progressive remodeling of respiratory tract. Therefore, the aim of the study was to assess the amount and activity of MMP-9 in context of pro-inflammatory cytokines , measured in EBC of asthma-suffering children, treated with inhaled steroids. The study involved 27 children with asthma, continuously treated with inhaled fluticasone propionate, and 22 healthy controls. In addition to routine clinical screening, the selected cytokines in EBC were analyzed using Ultrasensitive ELISA, whereas activity of MMP-9 was assessed using a novel immunozymography method. Despite chronic treatment with inhaled steroids mean MMP-9/EBC activity in asthma group was significantly higher than in healthy controls. Moreover, high MMP-9/EBC in asthma-suffering children significantly correlated with IgE serum levels. The IL-6 and IL-8 concentration was below the detection limit in all EBC samples. TNF/EBC levels were similar in both, asthma and healthy children. We hypothesize that MMP-9 hyperactivity in asthma may be closely related to high IgE serum levels. Our results suggest that inhaled steroids may be ineffective to prevent asthma-associated airway remodeling. Finally, we emphasize the necessity of further research focused on MMP-9 inhibition in asthma treatment. Matrix metalloproteinases (MMPs) belong to the family of zinc-dependent proteases, which are necessary for physiological turnover of extracellular matrix and tissue repair . The children from study group have been receiving inhaled glycocorticosteroids with a daily dose 500 µg of fluticasone propionate for at least 6 months. They were allowed to take second-generation H1 antihistamines and inhaled β2-mimetics (upon request).Our study involved 27 children  with chronic allergic asthma. The asthma recognition was based on the recommendations of “GINA”—the Global Initiative for Asthma, Strategy for Asthma Diagnosis and Prevention , attending the outpatient clinic of the Department of Paediatrics, Pneumonology and Allergology, at the Warsaw Medical University, for routine healthcare control visits.All individuals and their parents signed the informed written consent to participate in the study. The protocol of this experiment was formally approved by the local bioethics committee .According to the inclusion and exclusion criteria, all children were subjected to a routine clinical examination and laboratory tests. The peripheral blood morphology was analyzed using flow cytometry, with determination of total leukocyte count and main leukocyte subpopulations. To confirm the allergic background of asthma, the total IgE serum level and specific IgE or skin tests were performed. The asthma control was verified by the presence of clinical symptoms, spirometric assessment and exhaled nitric oxide (eNO) level . The results of assessment of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) were calculated as the FEV1/FVC ratio (Tiffeneau–Pinelli index). After adjustment to the patients age, the data were shown as the standard deviation score. The reference values were based on data from large multicenter population studies , according to protocol described previously . The absorbance of analyzed samples was measured using the Microplate Reader 550 . The OD results were converted to the specific cytokine concentrations (expressed in pg per ml of EBC), based on the respective standard calibration curves. For all tested cytokines the assay sensitivity, corresponding to the lowest points of the standard calibration curves, was 0.1 pg/ml.0) and then after 2 h of incubation at 37 °C (T2). The MMP-9 concentrations in EBC, both, active and total, were calculated based on the standard calibration curve of APMA-activated human recombinant MMP-9 and expressed in ng/ml. The assay sensitivity (0.01 ng/ml) corresponded to the lowest point of the standard calibration curve.The MMP-9 activity and concentration were estimated in EBC samples using QuickZyme Human MMP-9 activity assay. This novel immunozymography method allowed an assessment of both, the specific protein level, as well as its actual enzymatic activity. The test was performed according to detailed protocol provided by the manufacturer . All EBC samples were run in two series, each of them in duplicates. The first series reflected the actual amount of active MMP-9 in exhaled air. The second group of samples was pretreated with p-aminophenyl mercuric acetate (APMA) to ensure the assessment of the entire MMP-9 concentration  in tested sample. The baseline absorbance of analyzed samples was measured with the Microplate Reader 550 (BIO-RAD) immediately after addition of substrate  was 16.1 ± 10.9 ng/ml in asthmatic patients vs. 2.1 ± 1.1 ng/ml, in control individuals  with the total IgE serum levels  and levels of exhaled nitric oxide (The concentrations of IL-6 and IL-8 in all EBC samples of both, patients and control groups, were below the detection limit, i.e., <0.1 pg/ml. In contrast to them, TNF was detectable in all tested samples. The mean concentrations of TNF/EBC were 3.45 ± 0.87 pg/ml in asthma group and 3.74 ± 0.71 pg/ml in control individuals, but they did not differ statistically.Our study has shown for the first time that children with stable asthma, when compared to healthy controls, had significantly elevated active form of MMP-9 in their EBC. This observation may have practical value, as a noninvasive measurement of MMP-9/EBC activity is easy to perform even in very young children. Therefore, it may potentially be useful to assess current state of disease. Interestingly, the activity of MMP-9/EBC in our patients was higher than in health controls, despite relatively mild symptoms of asthma, possibly due to prolonged treatment with inhaled corticosteroids. It has been proven that the allergic asthma may be well controlled pharmacologically in majority of patients Kroegel . In factIt is well known that neutrophils and macrophages are main source of MMP-9 in inflammatory reaction (Delcaux et al. The mentioned above results may suggest that inhaled steroids, although effective to satisfactorily control clinical symptoms of asthma, do not normalize the initial high activity of MMP-9 in respiratory tract. Thus, inhaled steroids seem to have limited influence on natural course of asthma in children and, as shown by other authors, do not protect against airway remodeling (Bisgaard et al. It is noteworthy that some authors have reported decrease of MMP-9 concentration following the inhaled steroid treatment (Wang et al. Although MMP-9 is recognized as key factor involved in asthma-associated structural changes of airway, detailed mode of its action remains unclear. The well-known mechanism concerns proteolytic degradation of extracellular matrix components and basement membrane, which facilitate the active leukocyte passage and their accumulation in respiratory tract wall. However, MMP-9 may also modulate inflammatory reaction by interference with cytokine/chemokine network, e.g., via catalytic activation of IL-8, release of latent transforming growth factor-β1 and, possibly, IL-13 (Atkinson and Senior Finally, in addition to the usefulness of MMP-9/EBC measurement as a risk marker, the confirmation of pivotal role of MMP-9 in asthma-associated remodeling may have another potential benefit. It strongly supports the need for further research focused on implementation of modulators of MMP-9 activity also in asthma treatment. That approach was already demonstrated to be clinically effective in vascular diseases associated with MMP-9 hyperactivity—aortic aneurysm and chronic wounds healing (Curci et al.


The study aimed to examine the effect of gastric bypass on diabetic nephropathy (DN) in Chinese patients. A retrospective study of 101 samples with DN stages I to IV underwent Roux-en-Y gastric bypass. Anthropometric and biochemical parameters were assessed during a 1-year follow-up. Binary logistic regression analysis was used for predictors and ROC for cutoff points. There was significant reduction of medication for diabetes and hypertension. Overall remission of T2DM was 80.2 %. Preoperative albumin/creatinine ratio (ACR) and serum creatinine (SCr) levels could be predictors for DN remission, and the cutoff points were 126 mg/g cr and 57 μmol/L, respectively. Gastric bypass showed improvement of T2DM and DN. Gastric bypass may be more beneficial for those with lower preoperative ACR and SCr.The online version of this article (doi:10.1007/s11695-015-1666-y) contains supplementary material, which is available to authorized users. The incidence of diabetes mellitus has risen rapidly in the past few decades, and its prevalence has increased from less than 1 % in the Chinese population in the 1980s . Even moDiabetic nephropathy (DN), also known as diabetic glomerulosclerosis or diabetic kidney disease, is one of the major microvascular complications of type 2 diabetes mellitus (T2DM) , and is Metabolic surgery has been approved as an effective and potentially useful treatment for T2DM with obesity, especially the Roux-en-Y gastric bypass (RYGB) –10. SeveThough the evidence suggests that RYGB might be a potential treatment for DN, it remains unclear whether the surgery improves progression or provides remission for incipient and overt nephropathy. Therefore, the aim of our study was to investigate whether the RYGB is appropriate for DN.2, (3) a diagnosis of T2DM based on the criteria of the American Diabetes Association (ADA), and (4) a fasting C-peptide by the oral glucose tolerance test >1 ng/mL and a ratio of peak to fasting value >2 ng/mL. Those with established diagnoses of type 1 diabetes, latent autoimmune diabetes in adults, malignancy, debilitating disease, unresolved psychiatric illness, or substance abuse were excluded from the study.A retrospective study was made between February 2011 and December 2013. A total of 157 patients had RYGB during this period, and 101 T2DM patients with different DN stages were enrolled. The inclusion criteria included (1) age from 18 to 65 years, (2) BMI over 28 kg/mDN is divided into five stages according to the Morgenson standard : (I) hypMedical history, current medications, anthropometric evaluations including weight, BMI, percent of excess weight loss (%EWL), waistline, and hipline were recorded before and after bypass surgery. Biochemical parameters were evaluated by obtaining blood samples after an overnight fast and included fasting glucose, postprandial glucose followed by OGTT, fasting C-peptide, glycated hemoglobin (HbA1c), glycosylated serum protein (GSP), lipid profile , and renal function profile . In addition, the screening of DN with GFR, urine albumin/creatinine ratio (ACR), and 24-h microalbuminuria were evaluated. Insulin resistance level and β-cell function were measured by the homeostasis model assessment insulin resistance (HOMA-IR) using the formula mIU/mmol/L2 = fasting insulin (mIU/L) × fasting glucose (mmol/L) / 22.5 and the homeostasis model assessment β-cell (HOMA-β) using % = 20 × fasting insulin (mIU/L) / fasting glucose (mmol/L) − 3.5) (%).Remission of T2DM was defined as an HbA1c level <6.5 % and a fasting glucose concentration <7.0 mmol/L for 1 year or more without active pharmacologic intervention . Plasma Of the 101 patients, 45 (44.6 %) were female. The mean age of all participants was 47.6 ± 11.9 years, and the mean duration of T2DM was 7.63 ± 4.84 years. Hypertension was diagnosed in 40 (39.6 %). All patients were divided into four groups according to their DN stage diagnosis.Nearly 50 % were treated with insulin and more than 60 % with oral diabetes medications in each group preoperatively. Patients in DN stage I with hypertension (25.8 %) had the least proportion of antihypertensives 12.9 %). Most of the antihypertensives taken were angiotensin-converting enzyme inhibitor (ACEI) or/with angiotensin receptor blocker (ARB). Antihyperlipidemia medication was taken by 61.9 and 60 % separately in DN stages III and IV while in DN stages I and II, it was 48.4 and 35.3 %, respectively (Table 2.9 %. MoAll patients had laparoscopic Roux-en-Y gastric bypass (LRYGB) by the same surgical team with over 50 cases of experience. The patient was placed in reverse Trendelenburg position and the surgeon positioned between the patient’s legs. Five trocars are inserted under direct laparoscopic vision. A gastric pouch of approximately 30 mL is created with mechanical sutures preventing the transection of the left gastric artery. The angle of Treitz is then identified, and a 100-cm-long jejunal loop (biliopancreatic limb) is ascended anterior to the colon and anastomosed to the gastric pouch with mechanical linear suture (30 mm). A lateral jejuno-jejunal anastomosis adjacent to gastro-jejunal anastomosis is made 100 cm away from the previous nastomosis  with a mechanical linear stapler.t tests were used to compare variables before and after the study. Contingency tables of categorical variables were analyzed by Fisher’s exact test (grade and gender in remission of DN stages III and IV). Correlations between clinical parameters and MAU were analyzed by partial correlation analysis. Multiple stepwise logistic regression analysis was performed to assess the independent predictive effects of the variables on remission of DN. The measure index was set as blood pressure, albumin/creatinine ratio and serum creatinine, and the remission standard as MAU <30 mg/day. The predictors’ cutoff point was evaluated by Youden’s Index with the receiver operating characteristic (ROC) curve. Data are presented as the mean ± SD. Statistical significance was defined as P < 0.05.All statistics were calculated with SPSS statistical software . Paired F = 1.529, P = 0.212), patients in DN stage II were older  and longer T2DM duration . One year after surgery, there was a significant reduction of each type of medication used in each group , serum creatinine, Homa-IR, Homa-β, fasting C-peptide, and cholesterol levels Table . AnalysiRecently, there have been many encouraging reports suggesting that gastric bypass is an effective, stand-alone procedure for T2DM with obesity. However, before discussing DN remission, the primary concern should be about safety. In our study, all surgeries were performed by one team with experience of over 50 cases of LRYGB. An important aspect in the learning curve for successful metabolic surgery, according to Huang , is haviThe primary aim of DN treatment is currently focused on delaying its progression by improving the control of T2DM and of hemodynamic abnormalities . EvidencThe present study advocates that vascular endothelial dysfunction leads to changes in the renal vascular system and contributes to the development of DN. Good glycemic control is effective in reducing diabetic microvascular complication . HemodynA recently described mechanism of proximal tubule injury that involved the formation of advanced glycation end-products (AGE) by nonenzymatic binding of glucose to proteins, lipids, and nucleic acids can lead to alteration of protein structure and function, oxidative stress, and expression of proinflammatory cytokines and growth factors , which cThis study confirms the remarkable efficacy of gastric bypass for treatment of T2DM with obesity. The percentage of female patients participating was 44.6 %, which is lower than in other studies. The overall remission of T2DM after 1 year was 80.20 %. The central obesity status, hypertension, and lipid levels were significantly improved in all DN groups. Further analysis showed that patients in DN stage I were younger with shorter diabetes duration, less insulin resistance, and better blood pressure control compared with those in DN stages III and IV before surgery. Despite the differences in the four groups, the 1-year follow-up showed that gastric bypass can also lead to similar recovery of metabolic disorder. Although HOMA-IR and HOMA-β in DN stage IV showed impressive improvement, they were significantly higher than in the other three groups 1 year following surgery, which represents greater insulin resistance and poor β-cell function indicating progression of DN. Furthermore, the medication used for diabetes, hypertension, and hyperlipidemia was reduced significantly in all groups after surgery.Most patients with hypertension in our study used ACEI and/or ARB, which could reduce the risk of albuminuria to control blood pressure . After sThe renal function index including serum creatinine, blood urea nitrogen, uric acid, and GFR had no significant changes. However, microalbuminuria and albumin/creatinine ratio were significantly reduced in DN stages I, II, and III, but not in patients in stage IV. The mean level reduced continuously. The microalbuminuria reflects the glomerular filtration function due to the change in endothelial cell permeability and glomerular basement membrane. The GFR is affected by several factors including the glomerular filtration function, glomerular hydrostatic pressure, and colloid osmotic pressure. Therefore, we speculate that gastric bypass could improve the capillary membrane permeability, but the complex connection between capillary hemodynamics and gastric bypass still needs further research.Patients with DN at the time of T2DM diagnosis can go unrecognized for years. Albuminuria is common among patients with established diabetes, and becomes more prevalent with worsening glucose tolerance . DN stagOur study found that patients in DN stage III are more likely to get remission compared with stage IV, but gender, age, and diabetic duration were not correlated. The renal function index including microalbuminuria, albumin/creatinine ratio, serum creatinine, and blood urea nitrogen had a significant difference in both patients with and without remission before surgery. Further analysis shows significant correlation with albumin/creatinine ratio, serum creatinine, systolic blood pressure, cholesterol and insulin sensitivity, and insulin resistance. This result confirms the relationship between DN and metabolic disorder.In our study, patients with increased baseline of systolic blood pressure, serum creatinine, or albumin/creatinine ratio are less likely to achieve remission of DN, and the ROC curve revealed that serum creatinine and albumin/creatinine ratio are potential predicators for remission failure of incipient and overt DN. Youden’s Index showed that the cutoff point for serum creatinine and albumin/creatinine ratio were 57 μmol/L and 126 mg/g cr, respectively. As a normal value of the serum creatinine cutoff point with less applicability, the albumin/creatinine ratio cutoff point may have greater clinical value. Although most patients in stage IV did not reach the remission standard, the reduction of microalbuminuria helped to stabilize DN.Our study has several limitations such as retrospective design, small population size, and the limited follow-up duration which may have interfered with the results. The study by Alexander et al. showed that loss of excess body weight had the most positive effect in patients with obesity-related focal segmental glomerulosclerosis , which dIn conclusion, the beneficial results observed in our study demonstrate that gastric bypass should be considered in Chinese patients with T2DM and obesity. The RYGB shows the possibility of slowing down progression of diabetic nephropathy. Furthermore, albumin/creatinine ratio could help predict the remission of DN.ESM 1(GIF 136 kb)High resolution image (TIFF 163 kb)


The angiotensin converting enzyme inhibitors (ACEIs) are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in some cases as the drugs of first choice. The renin-angiotensin system is activated in response to hypotension, decreased sodium concentration in the distal tubule, decreased blood volume and in renal sympathetic nerve stimulation. This study examines the effects of angiotensin converting enzyme inhibitor (Lisinopril) on blood pressure (BP) 131±2.4 and proteinuria 0.198±0.005 in Kurd hypertensive patients, mean arterial blood pressure and proteinuria excretion were measured weekly along the period of 12 weeks. Lisinopril significantly reduced mean arterial blood pressure, and attenuated proteinuria level in patients subjected to this study in lisinopril 10mg dose dependent manner . In conclusion, lisinopril is of beneficial of renoprotection and in lowering BP Elevated blood pressure and severe proteinuria are important predictions of progressive renal injury . How proThe excretion of protein in the urine (proteinuria) is generally thought to be an indicator of deteriorating kidney function. While drugs which lower high blood pressure (hypertension) may all contribute to the preservation of kidney function, experiments in diabetic rats with hypertension have shown that the drugs which function by inhibiting angiotensin-converting enzyme are more effective in reducing proteinuria than other antihypertensive drugs .Urinary excretion of albumin is a sign of mild kidney disease . There iIntervention in the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEIs) is the therapy of choice for proteinuric renal disease, since these drugs lowered blood pressure (BP) and proteinuria and preserve renal function in the long term . It is gThis research was performed on randomly chosen hypertensive patients , the treatment period lasted three months, during which 24 patients; 11 males and 23 females were taking lisinopril 10mg/day. Baseline measurements of BP, is taken, and at 1, 3, 5, 7, 9, and 11 weeks of treatment. Urine samples were collected from patients on day 1 prior to first dosing with antihypertensive therapy (baseline) and at 2, 4, 6, 8, 10, 12 weeks of the treatment period of time. Serum creatinine level was measured before treatment and after one week of it, the result was within the normal range: patients on (ACEÍs) or (ARBs), their serum creatinine and after one week of starting treatment should not be exceeding more than 30% of their baseline value, otherwise it may precipitate unilateral and/or bilateral artery stenosis which lead to its exclusion .BP was determined according to Riva Rocci , by two 24-hr urine samples were collected by spontaneous voiding urineprotein excretion was determined by spectrophotometer , Autoanalyzer t-test for dependent samples.Statistical Analysis was performed using the ANOVA with respect to mean arterial pressure (MAP), and proteinuria. Differences between two measurements within one group were tested by First part of the results is revealing the effect of lisinopril on MAP in patients with essential hypertension. It is evident from the The second part is the effect of lisinopril on proteinuria in patients with essential hypertension. Residual proteinuria is a strong modifiable risk factor for renal failure progression . HyperteThe remaining risk of progression of hypertension kidney disease to end-stage renal disease (ESRD) is still high despite introduction of diverse categories of new drugs . The preThe role of blockade of the rennin-angiotensin system has been explored in many clinical contexts with positive results . A numbeBy contrast, positive effects were observed in a trial of four weeks duration in normotensive subjects with nephropathy .We evaluated the antihypertensive and renoprotective effects as reflected by short-term changes in blood pressure and in proteinuria. Across past two decades ACEIs expressed powerful effects in lowering blood pressure by inhibiting production of angiotensin II and impeding breakdown of bradykinin to which the cough is attributed after administration of lisinopril .The results in this study show that inhibition of the rennin-angiotensin system is particularly effective in lowering mean arterial pressure to about normal values 97±0.9 in Kurdish patients after one week of the treatment. This work provides evidence of an important role for lisinopril therapy in Kurd patients with hypertension as this remedy is effective at reducing mean arterial blood pressure and has beneficial effect on proteinuria in Kurd patients after 8, 10, and 12 weeks of medication, a result which is parallel to that documented by many other researchers . This st


In most cases, initial volume expansion does not requiremore sophisticated or invasive measures. Clinical history data and clinical signs of lowflow may suggest the likelihood of a response to the initial fluid infusion. As suggestedby Vincent and Weil, “the concept of volemic expansion parallels that of feeding a cryingbaby who may be thirsty or hungry. The baby’s response to feeding is rapidly apparent as aneed is satisfied”.Most critically ill patients in intensive care units (ICU) require fluid administration forvolume expansion at some point during their hospital stay.These findings suggest that the fluid challenge frequently depends on a “proof of faith”,which is more strongly based on the belief of the possibility of a clinical response to afluid challenge than on objective parameters.Unfortunately, this basic principle is not frequently used in practice. A recent analysisof more than 2,000 fluid challenges showed that critically ill patients tend to be treatedin the same manner, regardless of the initial response to volume expansion. Half of thepatients who were responsive to the initial fluid challenge did not receive additionalfluid and were subjected to hypoperfusion, and half of the non-responsive patients receivedfluid and were subjected to fluid overload. In addition, the initial clinical evaluation ofthe cardiovascular response of approximately 1/3 of the patients was uncertain. Even inthese cases, additional fluid tended to be administered to more than half of the patientswithout a more thorough evaluation.,5It is essential to use monitoring methods capable of quickly and precisely identifyingvolume deficits to minimize tissue damage related to hypovolemia and avoid iatrogenic fluidoverload.pulsus paradoxus or ‘paradoxicalpulse’. In 1899, Otto Frankdeveloped an experimental model consisting of air chambers that simulated the heart-vesselinteraction, which helped to define the relationship between arterial tone, stroke volume,and arterial pulse pressure.,8 Mechanical ventilation with positivepressure reverses the intrathoracic pressure and increases arterial pressure duringinspiration, which was defined as reversed pulsus paradoxus in1973. In 1978, researchers beganto evaluate the relationship between the volemic state and systolic arterial pressurevariation,-17 until 2000, when Michard et al. demonstrated the high accuracy of the clinical use of ∆Ppin the evaluation of fluid responsiveness in septic patients. The pressure changes observedin the arterial bed match those found in the venous bed. Thoracic pressurization acts onthe right heart and vena cava, influencing blood return to the heart resulting in changesof the central venous pressure during ventilatory movements.-22Several invasive and noninvasive methods, known as dynamic parameters for the evaluation ofthe cardiovascular responsiveness to volume, have been suggested to improve volumereplacement. Among these measures, the respiratory change in arterial pulse pressure (∆Pp)is likely the most well-known method; its first historical reference was in 1669, whenLomer reported a pathological intensification of blood pressure changes in a case ofpericarditis, defined by Kussmaul as  This constrictiongenerated in the intrathoracic portion of the venous bed during mechanical inspirationfunctions as a flow resistor, engorging and distending the extrathoracic portions of thegreat venous vessels, such as the intradiaphragmatic portion of the inferior vena cava(IVC) and the jugular veins. Therefore, responsive patients tend to present with anincrease in the inspiratory collapse index of the superior vena cava (SVC) and in thedistensibility indices of the inferior vena cava (IVC) and the internal jugular veinsduring mechanical ventilation.,23In an individual’s responsive to volume, the pressure around the intrathoracic veins exceeds the internal vessel pressure, and the vascular structuretends to collapse.reinforce the idea that the respiratory variation in the internal jugular vein diameter(ΔDRIJ) is correlated with the respiratory variation in the inferior vena cavadiameter (ΔDIVC), suggesting that the internal jugular distensibility may be aneasy, noninvasive alternative to evaluate fluid responsiveness in mechanically ventilatedpatients. IVC imaging can be difficult in obese patients and patients with abdominaldistension and ascites, and SVC imaging requires transesophageal echocardiography, whichlimits its application. Becauseinternal jugular vein imaging does not require transesophageal echocardiography and istechnically more simple than visualizing the IVC, this technique seems to be a simple andpromising bedside method for the evaluation of fluid responsiveness. However, thelimitations of the study should be considered when interpreting the results. Broilo etal. evaluated the correlationbetween ΔDRIJ and ΔDIVC without testing the capacity of ΔDRIJ topredict fluid responsiveness to volemic expansion based on the cardiac output behavior. Inaddition, recent studies have questioned the accuracy of ΔDRIJ in predicting theresponse to volume infusion.,26 Thus, as the authors themselves forewarn,the results should be interpreted with caution until new studies are published. We alsohighlight that the method is applicable for sedated and mechanically ventilated patients.Additionally, data on patients with conditions that lead to an increase in venous pressure as well as to jugular vein engorgement due tothe inadequate position of the head of the bed should be interpreted withcaution.,24In this issue of RBTI, Broilo et al.


To describe our results of protective ventilation and negative fluid balance strategy in potential multi-organ donor patients.A descriptive, retrospective study. We describe the results of a small series of potential donors (including older than 70 years) treated in single tertiary level center, from January to September 2013, in accordance with a strict protocol of protective ventilation, recruitment maneuvers, postural changes and negative fluid balance.® system (Pulse Contour Induced Cardiac Output).The collected variables were: Ventilatory parameters, central venous pressure, 24 hours fluid balance and information related to hemodynamic monitoring by transpulmonary thermodilution with Picco13 potential donors were included. Mean age average was 46 years, 46,15% were male. Mean values of central venous pressure (CVP), extravascular lung water indexed (ELWI), a global diastolic volume indexed (GEDI) and stroke volume variation (SVV) at baseline were 7,08 cmH2O; 10,67 ml; 795,22 ml / m2 and 12,38% respectively. After application of the protocol, the mean values were: PVC 6,67 cmH2O; ELWI 8,13 ml; GEDI 683,38 ml / m2 and VVS 16,83%. Mean 24 hours fluids balance was -466,33 ml, mean ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen (PaFiO2) improved of the initial value from 256,24 to 365,40 mmHg. Postural changes were made in 91,7% and alveolar recruitment in 83.3% of the patients, diuretics were required in 83.3% of them.Of the 13 potential donors, 4 patients were lung donors. Within this subgroup, the final CVP decreased to 5,75 cmH2O; the ELWI to 7,33 ml and the GEDI to 660 ml / m2. 24 hours fluid balance was -1167,50 ml and PaFiO2 improved to 424,50 mmHg .Moreover of the 13 cases, there were also other donations: 3 hearts, 10 livers, 1 pancreas and 9 kidney donor.The depletion of fluids and adequate ventilation management is sure, improves lungs function and probably improves multi-organ donation results.These measures allow rescue 4 lung donors which initially gasometric criteria contraindicates a possible donation.


Background. The Cardiovascular Risk Reduction Clinic (CRRC) in Perry County, Alabama, provides free pharmacist-led services. Clinic goals include improving health outcomes and reducing cardiovascular risk factors. Objective. To investigate the effectiveness of the CRRC in rural Perry County, Alabama. The reduction of the modifiable cardiovascular risk factors, blood pressure and body mass index, was evaluated to measure a decrease from baseline to last clinic date. Methods. This retrospective chart review identified 130 patients with at least two blood pressure and BMI measurements from baseline to June 30, 2010. The patients' paper files were used to collect baseline data and most recent measurements, which were recorded on a data collection sheet. Results. There was a statistically significant reduction in systolic blood pressure of 4.08 mmHg, 3.25 mmHg reduction in diastolic blood pressure, and 0.42 kg/m2 reduction in mean BMI. At their last visit prior to June 30, 2010, 59% of hypertensive patients and 35% of diabetic patients were meeting their blood pressure goals. Conclusion. Pharmacist-led management of patients with cardiovascular risk factors significantly reduced blood pressure and allowed more patients to meet their hypertension treatment goals. Despite being modest, reductions in blood pressure and BMI help reduce overall cardiovascular risks. Perry County, Alabama, is geographically located approximately 75 miles southwest of Birmingham. It is a rural community of about 10,373 residents, with a majority African American population 68%) . Hyperte8% . HypeIn 2004, the Cardiovascular Risk Reduction Clinic (CRRC) was established in Perry County as a collaboration between the nonprofit organization Sowing Seeds of Hope, the Perry County Health Department, and Samford University's McWhorter School of Pharmacy. The CRRC provides free pharmacist-led services at the Perry County Health Department. Population surveys indicate that only 52% of adults in the United States with hypertension actually achieve blood pressure target levels . InvolvePatients are encouraged to attend the weekly clinic where they receive free health screenings and medication therapy management. Medication therapy management (MTM) focuses on the assessment and evaluation of the patient's complete medication therapy regimen to optimize and improve therapeutic outcomes for patients . PatientThe purpose of this study is to investigate the effectiveness of the pharmacist-led CRRC in rural Perry County, Alabama. More specifically, this retrospective chart review looked at the impact of the CRRC on reducing modifiable cardiovascular risk factors in patients utilizing the clinical services provided. Uncontrolled hypertension and obesity are two of the modifiable risk factors related to cardiovascular disease –14 and aThe Cardiovascular Risk Reduction Clinic (CRRC), located in the Perry County Health Department, provides free health screenings, disease state management services, and patient counseling to residents of Perry County, Alabama. The CRRC is staffed by a board certified ambulatory care pharmacy specialist, senior pharmacy students completing Advanced Pharmacy Practice Experience (APPE) rotations, licensed registered nurses, and premedical students. While most patients are self-referred, they can be referred to the pharmacist-led clinic by their primary care provider for education and medication management. Data is unavailable to determine the number of patients who have been referred to the clinic but chose not to use the services. Typical patients include elderly patients needing assistance with medication organization and uninsured patients who are in need of help acquiring their prescription medications, therefore presenting with adherence issues.During the initial visit, a complete medical history is obtained from the patient, a medication list is compiled, and patients receive a health screening including measuring weight, body mass index (BMI), blood glucose, and blood pressure. Patients are also interviewed about their dietary and exercise habits and receive ongoing counseling about proper diet and exercise to help manage their chronic disease states. Participants are provided with assistive materials such as caloric restriction meal plans, information on adopting the Dietary Approaches to Stop Hypertension (DASH) lifestyle eating plan, Healthy Plate for a Healthy Weight placemats with portion control counseling, and information on reducing sodium/salt intake. They are also encouraged to work with CRRC providers to develop measurable and realistic weight loss and exercise goals, along with developing reminders for taking medications, and provided assistance with obtaining medications through patient assistance programs or discounted medications at specific pharmacies to improve access to medications and adherence. During each follow-up visit, the providers assess the patient's medication adherence, weight loss, dietary and exercise habits, and disease state control according to the latest guidelines. If additional information is needed, patients' primary care providers are contacted to access laboratory results and to request information about prescribed medications. Medication recommendations are also forwarded to the primary care providers if CRRC staff believes there is a need to adjust, change, or add an additional medication to optimize therapy for patients not reaching their Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) or American Diabetes Association (ADA) blood pressure or blood glucose goals.A chart review of 253 patients who had an encounter with a pharmacist or pharmacy student in the Perry County Cardiovascular Risk Reduction Clinic was performed by reviewing the paper charts of every individual patient who had been seen in the clinic and had a clinic file. Files were evaluated to identify patients who had at least two clinic visits . Baseline data measurements were collected for the earliest encounter on file. Most recent data measurements for comparison were collected for the latest encounter on record prior to June 30, 2010. The patient's most recent visit must have been at least one month after their initial visit to be included in the study. We decided on an interval between the first and the last visit of at least one month based on guideline recommendations to reevaluate blood pressure within one month when modifying or changing antihypertensive therapies. Baseline demographic data included sex, age, weight, body mass index, blood pressure, blood glucose, and A1c if available. Charts were reviewed for medical history, diagnosis of hypertension including systolic and diastolic blood pressure measurements, diagnosis of diabetes, body mass index (BMI), and weight status . Patients were considered to have hypertension or diabetes if it was self-reported, if it was documented in the medical chart, or if there was current use of antihypertensive or antihyperglycemic medications. Patients were considered to be at a healthy weight, to be overweight, or to be obese based on their BMI measurements related to their height and weight. BMI classifications can be found in All patients included in the study were at least 19 years of age or older and had been seen in the CRRC at least twice during the study period to compare their baseline data to their blood pressure, BMI, and weight. There were 130 patients identified who met this criterion. Patients were excluded from the study if they were under 19 years of age, if they only had one clinic visit, or if their subsequent clinic visit was less than one month after their initial visit. Patients were also excluded if they began utilizing the clinic services after June 30, 2010. Demographic data including race, gender, age, and diagnosis of hypertension or diabetes was gathered on all included patients.During the time period of the study, every patient chart was reviewed for possible inclusion. All patients meeting the abovementioned criteria were included in the study and a patient list was formulated. Patient information was recorded on data collection sheets (Appendix). The data collection sheet allowed for the assignment of an arbitrary patient number to be used instead of patient names. Each patient received a unique number used specifically for this study. The list of patient names and corresponding numbers was kept separate from the data collection sheets in a locked file cabinet used to store patient files. The primary investigator and senior pharmacy students trained on how to collect the needed information from patient charts were the only ones extracting data for the review. All charts were reviewed on the premises of the CRRC within the Perry County Health Department and were kept confidential in file cabinets currently used to house clinic documents.t-test. The paired samples were assessed for normal distribution by employing the 2-tailed t-tests. Statistical significance was recognized as a p value less than or equal to 0.05. This study underwent review and received approval from the Samford University Institutional Review Board (IRB).We used statistical software SPSS  for data analyses. Clinical value changes from baseline to the last recorded follow-up were analyzed using a matched pair Patient characteristics of the study population are depicted in t-test was used to measure significant differences in systolic blood pressure and the diastolic blood pressure of the study population during pre- and postintervention periods. The t-test assumes that the data is distributed symmetrically. In order to check the violation of the above assumption, we conducted a Wilcoxon Rank Sum test which requires no parametric assumption and showed that the data was distributed symmetrically. At baseline, patients had higher mean systolic/diastolic blood pressure (p < 0.05). Mean reduction in systolic blood pressure at the end of the study period was significantly lower from baseline [4.08 ]. Also, at the end of the study period, the mean diastolic blood pressure significantly changed from baseline [3.25 ]. There was also a significant reduction in the mean of BMI during the study period. BMI decreased by 0.42 kg/m2 (p < 0.05)  .We found that the pharmacist-enabled services in the CRRC in Perry County made a significant difference in the blood pressure control of patients. We used the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines to determine whether patients were meeting their blood pressure goals . The JNCWe did see small decreases in both systolic and diastolic blood pressure, showing that clinic efforts are making a difference in blood pressure control. There was a statistically significant drop in SBP of 4.08 mmHg and diastolic blood pressure decreased by an average of 3.25 mmHg. The reduction in SBP moved some patients from being above the 140 mmHg goal to being below it at their last clinic visit. While the average BMI remained constant among patients using the CRRC, six patients moved from the obese category to the overweight category, and six patients moved from the overweight to the normal category. This weight reduction, while being modest, is an improvement in risk since obesity is a modifiable risk factor associated with cardiovascular disease, hypertension, myocardial infarction, and stroke.During each clinic visit, patient parameters were measured along with the provision of education related to reduction of cardiovascular risk factors, meal planning, weight management, and counseling on medication compliance and utilization. When necessary, patient's providers were contacted with recommendations on changing or augmenting therapy based on the clinical guidelines if patients are not meeting the goal. All of these factors probably have played a role in improving the outcomes of patients using the CRRC.Centers for Disease Control and Prevention (CDC) statistics show that the stroke death rate in Perry County declined by 37.4% between 1991 and 2010 from 190 to 153 per 100,000 people [While many Americans gain weight each year, participants in the CCRC are controlling and maintaining their weight. While only six participants moved from the obese category to the overweight category, the same number of patients moved from being overweight to being in the healthy/normal weight category according to their BMI. Acquiring a normal weight significantly reduces cardiovascular risk factors.There were limitations to our study. First, there were inconsistencies in documentation in the patient charts. More than 200 charts were reviewed, but, due to documentation errors, omitted information, and incomplete SOAP notes, many patients had to be omitted from the study. Patients were also excluded because they had only one office visit. This loss to follow-up was most concerning to investigators as patients often came to the initial office visit due to symptoms of uncontrolled hypertension or diabetes. These patients may have been referred to their primary care physicians or the emergency room for follow-up but did not return to our clinic for disease state management. Second, there was a lack of a control group for comparison. The lack of a control group prevented us from being able to determine whether clinic efforts were fully responsible for the decreases in blood pressure and weight. Third, we had limited comparison data parameters. We originally wanted to determine whether we had made a difference in diabetes control among patients; however, there was not enough blood glucose data to compare among diabetic patients. Ideally, hemoglobin A1c is a clinical marker used in guidelines and its measurements would be compared to give a more definitive evaluation of blood sugar control.The residents of rural Perry County, Alabama, are working to close the gap in cardiovascular health disparities by taking charge of their health and utilizing the CRRC at the Perry County Health Department. The CRRC aims to increase awareness about disease states among patients and to teach patients how to control their risk factors along with taking charge of their comorbid disease state. In summary, the Perry County CRRC model may be an innovative model that is effective in screening patients with hypertension and narrowing the health disparity gap among patients in a rural area. Questions remain as to whether this model is replicable in other areas and whether further improvement in blood pressure control has been realized in patients beyond the study period. The study has also shown the need for more consistent documentation, periodic measurements for hemoglobin A1c and lipids, and an electronic medical record for clinic staff.