The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Treatment of Hypertension, Resistant to Conventional Antihypertensives, in Patients on Maintenance Hemodialysis

Background: Hypertension (HTN) is present in up to 90% of end stage kidney disease (ESRD) patients irrespective of the etiology of their kidney disease. Moreover, it is an important modifiable risk factor for progression to ESRD and its overall cardiovascular morbidity and mortality. Objective: to evaluate, prospectively, the role of Renin-Angiotensin-Aldosterone System blockade (RAAS) in HTN, resistant to 3 conventional antihypertensives, in patients on maintenance hemodialysis (MHD). Patients and methods: A total of 52 such patients were treated with Ramipril and 5 with Losartan after intolerable cough/shortness of breath following Ramipril-use. None of the patients had fluid depletion, renal artery stenosis and primary endocrinopathy. The study group was compared to a matched control group of MHD patients with normal blood pressure following 3 drugs-combination therapies. Results: All patients, with resistant HTN, had significant activation of RAAS system prior to treatment compared to inactive one in the control group. In those with resistant HTN, control of HTN, was established within 2 weeks of therapy and was associated with suppression of the RAAS. Such therapy was associated with minor side effects. Conclusion: Our study has shown that RAAS blockade is safe and effective in controlling such resistant HTN in MHD patients.

Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

BACKGROUND A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension(aTRH)and risk of cardiovascular disease(CVD).AIM To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association.METHODS We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT).ALLHAT recruited participants(n=25516)from 625 primary care settings throughout the United States,Canada,Puerto Rico,and United States Virgin Islands,aged 55 and older with hypertension and at least one additional risk factor for heart disease.aTRH was assessed from the year 2 visit.CVD event was defined as one of the following from the year 2 follow-up visit:Fatal or non-fatal myocardial infarction,coronary revascularization,angina,stroke,heart failure,or peripheral artery disease.Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk.Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction.RESULTS Of the total study participants(n=25516),5030 experienced a CVD event during a mean of 4.7 years follow-up.aTRH was associated with a 30%increase in risk of CVD compared to non-aTRH[hazards ratio(HR)=1.3,95%CI:1.19-1.42].Sex and age modified this relationship on both multiplicative and additive scales independently.Stratified by sex,aTRH was associated with a 64%increase in risk of CVD(HR=1.64,95%CI:1.43–1.88)in women,and a 13%increase in risk of CVD(HR=1.13,95%CI:1.01–1.27)in men.Stratified by age,aTRH had a stronger impact on the risk of CVD in participants aged<65(HR=1.53,95%CI:1.32–1.77)than it did in those aged≥65(HR=1.18,95%CI:1.05–1.32).Significant two-way interactions of sex and aTRH,and age and aTRH on risk of CVD were observed(P<0.05).The observed joint effect of aTRH and ages≥65 years(HR=1.85,95%CI:1.22–2.48)in males was less than what was expected for both additive and multiplicative models(HR=4.10,95%CI:3.63–4.57 and 4.88,95%CI:3.66–6.31),although three-way interaction of sex,age,and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance(P>0.05).CONCLUSION aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age.Further studies are warranted to test these mechanisms.

Development of pulmonary hypertension remains a major hurdle to corrective surgery in Down syndrome

Down syndrome is the most common chromosomal abnormality encountered in clinical practice with 50%of them having associated congenital heart disease(CHD).Shunt lesions account for around 75%of all CHDs in Down syndrome.Down syndrome patients,especially with large shunts are particularly predisposed to early development of severe pulmonary hypertension(PH)compared with shunt lesions in general population.This necessitates timely surgical correction which remains the only viable option to prevent long term morbidity and mortality.However,despite clear recommendations,there is wide gap between actual practice and fear of underlying PH which often leads to surgical refusals in Down syndrome even when the shunt is reversible.Another peculiarity is that Down syndrome patients can develop PH even after successful correction of shunt.It is not uncommon to come across Down syndrome patients with uncorrected shunts in adulthood with irreversible PH at which stage intracardiac repair is contraindicated and the only option available is a combined heartlung transplant.However,despite the guidelines laid by authorities,the rates of cardiac transplant in adult Down syndrome remain dismal largely attributable to the high prevalence of intellectual disability in them.The index case presents a real-world scenario highlighting the impact of severe PH on treatment strategies and discrimination driven by the fear of worse outcomes in these patients.

Non-interventional management of resistant hypertension

Hypertension is one of the most popular fields of re-search in modern medicine due to its high prevalence and its major impact on cardiovascular risk and con-sequently on global health. Indeed, about one third of individuals worldwide has hypertension and is under increased long-term risk of myocardial infarction, stroke or cardiovascular death. On the other hand, resistant hypertension, the "uncontrollable" part of arterial hy-pertension despite appropriate therapy, comprises a much greater menace since long-standing, high levels of blood pressure along with concomitant debilitating entities such as chronic kidney disease and diabetes mellitus create a prominent high cardiovascular risk milieu. However, despite the alarming consequences, resistant hypertension and its effective management still have not received proper scientific attention. As-pects like the exact prevalence and prognosis are yet tobe clarified. In an effort to manage patients with resis-tant hypertension appropriately, clinical doctors are still racking their brains in order to find the best therapeutic algorithm and surmount the substantial difficulties in controlling this clinical entity. This review aims to shed light on the effective management of resistant hyper-tension and provide practical recommendations for cli-nicians dealing with such patients.

Renal sympathetic denervation in resistant hypertension

Resistant hypertension remains a major clinical problem despite the available multidrug therapy.Over the next decades,its incidence will likely increase given that it is strongly associated with older age and obesity.Resistant hypertension patients have an increased cardiovascular risk,thus effective antihypertensive treatment will provide substantial health benefits.The crosstalk between sympathetic nervous system and kidneys plays a crucial role in hypertension.It influences several pathophysiological mechanisms such as the central sympathetic tone,the sodium balance and the systemic neurohumoral activation.In fact,studies using several animal models demonstrated that the renal denervation prevented and attenuated hypertension in multiple species.Large reductions in blood pressure were also observed in malignant hypertension patients submitted to sympathectomy surgeries.However,these approaches had an unacceptably high rates of periprocedural complications and disabling adverse events.Recently,an innovative non-pharmacological therapy that modulates sympathetic activation has been successfully developed.Renal sympathetic percutaneous denervation is an endovascular procedure that uses radiofrequency energy to destroy the autonomic renal nerves running inside the adventitia of renal arteries.This method represents a promising new approach to the strategy of inhibiting the sympathetic nervous system.The aim of this review is to examine the background knowledge that resulted in the development of this hypertension treatment and to critically appraise the available clinical evidence.

Exercise training in the management of patients with resistant hypertension

Hypertension is a very prevalent risk factor for cardiovascular disease. The prevalence of resistant hypertension, i.e., uncontrolled hypertension with 3 or more antihypertensive agents including 1 diuretic, is between 5% and 30% in the hypertensive population. The causes of resistant hypertension are multifactorial and include behavioral and biological factors, such as nonadherence to pharmacological treatment. All current treatment guidelines highlight the positive role of physical exercise as a non-pharmacological tool in the treatment of hypertension. This paper draws attention to the possible role of physical exercise as an adjunct non-pharmacological tool in the management of resistant hypertension. A few studies have investigated it, employing different methodologies, and taken together they have shown promising results. In summary, the available evidence suggests that aerobic physical exercise could be a valuable addition to the optimal pharmacological treatment of patients with resistant hypertension.

Effect of Prepared Rhubarb on Insulin Resistance in Patients With Pregnancy Induced Hypertension

Objective: To investigate the effect of prepared rhubarb on insulin resistance in patients with pregnancy induced hypertension (PIH) and its mechanism. Methods: All the 92 patients accepted 75 g oral glucose tolerance test (OGTT) and insulin release test before and after treatment. These patients were divided into two groups (treated group and control group). Prepared rhubarb and nifedipine were given to the treated group, while nifedipine was given to the control group alone. Circulating endothelial cell (CEC), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were measured and glucose area under curve (GAUC), insulin area under curve (IAUC), insulin sensitivity index (ISI) were calculated. And 30 normal pregnant women were selected as the healthy group. Results: CEC, TNF-a, IL-6, GAUC and IAUC of PIH patients were significantly higher than those of the normal healthy group; while ISI of PIH patients was significantly lower than that of the healthy group. ISI was significantly negatively correlated to CEC, TNF-a and IL-6. After treatment, CEC, TNF-α, IL-6, GAUC decreased and ISI increased significantly in the treated group; while in the control group, all above-mentioned parameters showed no change. Conclusion: Prepared rhubarb can improve insulin resistance of PIH by reducing vascular endothelial cell's damage.

Transcatheter therapies for resistant hypertension: Clinical review

Resistant hypertension(RHTN) is a commonly encountered clinical problem and its management remains a challenging task for healthcare providers. The prevalence of true RHTN has been difficult to assess due to pseudoresistance and secondary hypertension. Atherosclerotic renal artery stenosis(RAS) has been associated as a secondary cause of RHTN. Initial studies had shown that angioplasty and stenting for RAS were a promising therapeutic option when added to optimal medical management. However, recent randomized controlled trials in larger populations have failed to show any such benefit. Sympathetic autonomic nervous system dysfunction is commonly noted in individuals with resistant hypertension. Surgical sympathectomy was the treatment of choice for malignant hypertension and it significantly improved mortality. However, postsurgical complications and the advent of antihypertensive drugs made this approach less desirable and it was eventually abandoned. Increasing prevalence of RHTN in recent decades has led to the emergence of minimally invasive interventions such as transcatheter renal denervation for better control of blood pressure. It is a minimally invasive procedure which uses radiofrequency energy for selective ablation of renal sympathetic nerves located in the adventitia of the renal artery. It is a quick procedure and has a short recovery time. Early studies in small population showed significant reduction in blood pressure. The most recent Symplicity HTN-3 study, which is the largest randomized control trial and the only one to use a sham procedure in controls, failed to show significant BP reduction at 6 mo.

Computed tomography-guided chemical renal sympathetic nerve modulation in the treatment of resistant hypertension: A case report

BACKGROUND Resistant hypertension(RH)has always been a difficult problem in clinical diagnosis and treatment.At present,there is no recognized safe and effective minimally invasive treatment.CASE SUMMARY An 80-year-old woman was admitted to hospital due to trigeminal neuralgia(TN).The patient had a history of RH for more than 10 years and her blood pressure(BP)was not well-controlled.Before the treatment for TN,we decided to perform chemical renal sympathetic denervation with ethanol in the Pain Department of our hospital.One year after the operation,she stopped taking antihypertensive drugs,and her BP was satisfactorily controlled within 4 years after surgery.CONCLUSION Computed tomography-guided chemical renal sympathetic modulation may be a feasible method for the treatment of RH.

A Very Severe Obstructive Sleep Apnea Syndrome: In a Cause of Resistant Hypertension with One Sample Case

When blood pressure values remain above the target in a hypertensive patient treated concomitantly with three anti-hypertensive drugs including a diuretic, maximum well-tolerated doses, this is a resistant arterial hypertension. In this case, it is advisable to look for a secondary cause such as a drug intake that influencing the blood pressure or the presence of obstructive sleeping syndrome (OSAS). We report a clinical case of a patient with a high cardiovascular risk at the age of 50, hypertensive and diabetic, with dyslipidemia and obesity. He was on anti-hypertensive triple therapy at an optimal dose. Her diabetes was balanced with 6.4% glycated hemoglobin. Dyslipidemia has being treated. Despite healthy diet including a low sodium diet and weight loss, blood pres- sure target was not reached. With self-measurement, the mean arterial pressure was 180/110 mmHg and on ABPM it was 167/113 mmHg. The ventilatory polygraphy finds a severe OSA with an IAH = 56.6. Treatment with PCP (Con- tinuous positive pressure) allowed this patient to control blood pressure. The search for OSA should be systematic in face of resistant hypertension, in par- ticular in overweight or obese patients.

Clinical characteristics, target organ damage and associate risk factors ofresistant hypertension determined by ambulatory blood pressure monitoringin patients aged ≥80 years

Objectives To investigate clinical characteristics, target organ damage, and the associated risk factors of the patients aged ≥ 80 yearswith true resistant hypertension （RH）. Methods Patients aged ≥ 80 years with hypertension （n = 1163） were included in this study. Theincluded participants attended a structured clinical examination and an evaluation of RH was carried out. The prevalence, clinical characteristicsand target organ damage of patients with RH were assessed. The associated clinical risk factors were analyzed by using logistic regression.Results The prevalence of RH diagnosis by 24-h ambulatory blood pressure monitoring assessment was 21.15%. End-diastolic left ven-tricular internal dimension, left ventricular mass index as well as prevalence of left ventricular hypertrophy were significantly greater in pa-tients with RH than in control group. The common carotid artery intimal media thickness, carotid walls thickness, common carotid arterydiameter and relative wall thickness were significant greater in RH group than in control. A relatively higher level of creatinine, estimatedglomerular filtration rate, microalbuminuria and retinal changes was found in RIt group than in control. A multivariate analysis showed thatpatients with a history of diabetes, higher body mass index （BMI） and lipid profiles were independent risk factors of RH. Conclusions Theprevalence of RH in patients aged ≥ 80 years was within the range of reported rates of the general population. Subjects with RH diagnosisshowed a higher occurrence of target organ damage than patients with well controlled blood pressure. Patients with diabetes, higher BMI andserum lipid profiles were independent risk factors for RH in patients aged ≥ 80 years.

Overview of resistant hypertension:A glimpse of the cardiologist's current standpoint

Hypertension is a major risk factor for cardiovascular disease,resulting in increased incidence of cerebrovascular events,ischaemic heart disease,heart failure,and renal impairment.Thus,it is one of the most important preventable causes of premature morbidity and mortality.Despite current knowledge on the management of hypertension and the availability of several effective antihypertensive medications,uncontrolled hypertension remains a common and challenging clinical problem.Resistant hypertension is a complex condition with multiple contributing factors and overlapping comorbidities.Although there is limited hard evidence regarding resistant hypertension,our understanding of this condition has improved recently.This article will present an overview of resistant hypertension and highlight recent publications about this topic.

Place of baroreceptor activation therapy in the treatment of resistant hypertension

This mini review describes the development of the therapeutic concept of baroreceptor stimulation over the last fifty years alongside the more recent introduction of it for the treatment of drug- resistant hypertension. The pros and cons of this strategy of treatment over renal sympathetic denervation are also discussed in the light of the results of the studies done in the last decade.

Achieving control of resistant hypertension:Not just the number of blood pressure medications

Resistant hypertension(RH) has a prevalence of around 12% and is associated with an increased risk of cardiovascular disease, progression to end-stage renal disease, and even mortality. In 2017, the American College of Cardiology and American Heart Association released updated guidelines that detail steps to ensure proper diagnosis of RH, including the exclusion of pseudoresistance.Lifestyle modifications, such as low salt diet and physical exercise, remain at the forefront of optimizing blood pressure control. Secondary causes of RH also need to be investigated, including screening for obstructive sleep apnea. Notably, the guidelines demonstrate a major change in medication management recommendations to include mineralocorticoid receptor antagonists. In addition to advances in medication optimization, there are several device-based therapies that have been showing efficacy in the treatment of RH. Renal denervation therapy has struggled to show efficacy for blood pressure control, but with a redesigned catheter device, it is once again being tested in clinical trials. Carotid baroreceptor activation therapy(BAT) via an implantable pulse generator has been shown to be effective in lowering blood pressure both acutely and in longterm follow up data, but there is some concern about the safety profile. Both a second-generation pulse generator and an endovascular implant are being tested in new clinical trials with hopes for improved safety profiles while maintaining therapeutic efficacy. Both renal denervation and carotid BAT need continued study before widespread clinical implementation. Central arteriovenous anastomosis has emerged as another possible therapy and is being actively explored. The ongoing pursuit of blood pressure control is a vital part of minimizing adverse patient outcomes. The future landscape appears hopeful for helping patients achieve blood pressure goals not only through the optimization of antihypertensive medications but also through device-based therapies in select individuals.

Comparison of a 5 F Microtube-Irrigated Ablation Catheter and a General Ablation Catheter in the Treatment of Resistant Hypertension with Renal Denervation

Objective:To assess the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with resistant hypertension using a 5 F microtube-irrigated ablation catheter.Methods:Sixty patients with resistant hypertension were divided into two groups:a microtube-irrigated ablation catheter group and a general ablation catheter group.We conducted 12-month follow-up of all patients and recorded clinical blood pressure,ambulatory blood pressure,medication use,and biochemistry test results in both groups at the baseline and at the 12-month follow-up.Results:All patients underwent renal denervation.At the 6-month follow-up,ambulatory blood pressure in the mi-crotube-irrigated ablation catheter group was signifi cantly lower than in the general ablation catheter group(systolic blood pressure 142.0±14.4 mmHg vs.150.8±17.9 mmHg,P=0.04;diastolic blood pressure 81.2±7.0 mmHg vs.87.6±8.0 mmHg,P=0.002).At the 12-month follow-up,the between-group difference in ambulatory blood pressure was not statistically signifi cant.At the 12-month follow-up,the number of antihypertensive drugs and diuretics used in the microtube-irrigated ablation catheter group was less than in the general ablation catheter group(P=0.043).There was no statistical difference between the two groups in the results of biochemistry tests and echocardiography.Conclusion:The microtube-irrigated ablation catheter is more effective in treating hypertension than the general ablation catheter at the 6-month follow up and thus fewer antihypertensive drugs were used in the microtube-irrigated ablation catheter group than in the general ablation catheter group.

Main Renal Artery Plus Branch Ablation in the Treatment of Resistant Hypertension with Renal Denervation

Objective:To study the safety and effi cacy of denervation of renal artery branches in the treatment of resistant hy-pertension.Methods:Sixty patients with resistant hypertension were enrolled.The patients were randomly assigned to the main renal artery plus branch ablation group or the main renal artery ablation group.The clinical data and operation-related parameters,including number of ablation points,temperature,and average energy,were recorded.Ambulatory blood pressure was taken for all patients at the baseline and at 6 months after treatment.Offi ce blood pressure was recorded before treatment and after treatment every 3 months for 2 years.Results:Sixty patients with resistant hypertension were enrolled in this study.There were 30 patients in each group.Angiography was performed after ablation.No renal artery complications,such as stenosis and dissection,occurred in the two groups.There was no signifi cant difference in age,sex,BMI,comorbid disease,and medication between the two groups(P>0.05).The number of ablation points for the main renal artery plus branch ablation group was greater than that for the main renal artery ablation group.The offi ce blood pressure and 24-hour blood pressure were signifi cantly lower 6 months after treatment than before treatment in both groups(P<0.05).Offi ce blood pressure in the main renal artery plus branch ablation group was lower than that in the main renal artery ablation group during the 3-12-month follow-up period,with a statistical difference.However,as the follow-up time increased,the difference disappeared.Conclusion:The results of this study show that main renal artery plus branch ablation is a safe interventional method,but there was no obvious advantage on long-term follow-up compared with only main renal artery ablation.

True Resistant Hypertension among Treated Hypertensive Black Patients.A Clinical-Based Cross-Sectional Study

Background and Objective: 24-h ambulatory blood pressure monitoring (ABPM) aids to precisely identify patients with true resistant hypertension (tRH). The present study was aimed to assess the frequency and correlates of tRH among patients with clinically suspected RH. Methods: Medical records of treated hypertensive patients referred in four healthcare centers for BP control evaluation by 24-h ABPM were reviewed to assess the prevalence of tRH. Inclusion criteria were age ≥ 18 years, clinical diagnosis of RH. Data on demographic, clinical, laboratory, 2D-echocardiography and 24-h ABPM parameters were retrieved from patient’s medical records. True RH (tRH) was defined as office blood pressure (BP) ≥ 140/90 mmHg and 24-h ambulatory BP ≥ 130/80 mmHg. Simple and multiple linear regression analyses were used to assess factors associated with systolic BP (SBP) as a proxy of RH among patients with tRH. P 0.05 defined the level of statistical significance. Results: Of 636 patients referred for BP control evaluation by 24-h ABPM, 75 (11.7%) had suspected RH by office BP measurements. After 24-h ABPM, pseudo or apparent RH (aRH) and tRH were observed in 15 (2.3%) and 60 (9.4%) patients, respectively. BMI (p = 0.007) and blood glucose (p = 0.024) were positively associated with SBP whereas a negative association was observed with eGFR (p = 0.022) among tRH hypertensive patients in multiple regression analysis. Conclusion: True RH was a common finding among patients with clinical RH and associated with obesity and silent target organ, especially kidney dysfunction. The present study highlights the diagnostic and prognostic importance of 24-h ABPM among patients with clinical RH.

Prevalence and Characteristics of Treatment-Resistant Hypertension among Hypertensive Japanese Outpatients

Aims: To retrospectively investigate the prevalence and characteristics of treatment-resistant hypertension (R-HT) among consecutive hypertensive outpatients, since patients with R-HT are candidates for catheter-based renal sympathetic denervation (RD). Methods: Consecutive hypertensive outpatients (n = 999) were recruited in our hospital. R-HT patients who were candidates for RD had clinic systolic blood pressure > 160 mmHg despite taking three or more antihypertensive drugs including at least one diuretics at higher than standard doses. Results: Our survey indicated that only 26 patients (2.6%) were potential candidates for renal denervation. Candidates for RD showed a significantly higher age (P < 0.005), brain natriuretic peptide level (P = 0.0001), urinary albumin/creatinine excretion ratio in spot urine (P < 0.005), pulse wave velocity (P < 0.01), left ventricular end-diastolic diameter (P < 0.005), and interventricular septal thickness (P < 0.005) than the other 973 patients. Candidates for denervation had a significantly lower hemoglobin (P = 0.0001), serum albumin (P < 0.001), eGFR (P < 0.0005), plasma renin activity (P = 0.0001), and plasma aldosterone level (P < 0.005) than other patients, while their urinary sodium/creatinine ratio was higher, indicating that patients with R-HT appeared to have a high salt intake. Conclusion: Our retrospective clinical survey indicated that only 0.5% of Japanese hypertensive outpatients (5/999 patients) were candidates for RD. Therefore, establishment of hypertension cohort network will be essential to recruit R-HT patients for RD.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

The Influence of the Pro12Ala Mutation of PPARγ2 Receptor Gene on β-cells Restoration and Insulin Resistance in Type 2 Diabetes with Hypertension

The aim of this investigation was to determine whether a PPAR72 Prol2Ala polymorphism was associated with insulin resistance, β-cellfunction and hypertension in Chinese populations. 289 unrelated Chinese subjects first diagnosed Type 2 diabetes （HbAC1〈6.0） were investigated, including 132 hypertensive diabetic （HTD） subjects, 157 normotensive diabetic （NTD） subjects. Blood pressure and anthropometric measurements were collected from all participants, as well as several venous blood samples during oral glucose tolerance test （OGTT）. Biochemical measurements （high-density lipoprotein （HDL） and low-density lipoprotein-cholesterol （LDL）, triglycerides） and PPARγ2 Pro12Ala genotype were also determined. And insulin resistance and β-cells function was assessed by HOMA-IR and HOMA-β respectively. The frequency of subjects bearing the Pro12Ala was lower in the hypertension group （3. 03 %） than in the non-hypertension group （5.7 %） （P〈0.05） after adjusted for age, BMI and gender. Hypertensive diabetic Pro12Ala subjects had lower fasting plasma glucose level （P=0. 0127）, and better glucose tolerance 60 min after oral glucose （P=0. 0361）. Moreover, plasma insulin concentrations at 60 min was lower than those without A variant （P = 0. 0275）, and both hypertensive Ala/Pro in HOMA-β （P ： 0. 0455） and AUC for insulin （P=0. 0473） were higher, and HOMA-IR was lower （P=0. 0375） as compared with hypertensive Pro/Pro subjects. No association was observed between Prol2Ala genotype and BMI, total cholesterol, HDL- cholesterol or triglycerides in either group. Our findings suggested that the Ala 12 allele of the PPARγ2 gene may improve insulin resistance and ameliorate β-cell function reserves in T2DM with hypertension, and protect patients from hypertension in T2DM. As an important thrifty gene, environment factors may exerts an effect of PPARγ2 on glucose homeostasis and insulin resistance.