Increased human urotensin II levels are correlated with carotid atherosclerosis in essential hypertension

BACKGROUND: Circulating blood levels of human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, are increased in patients with essential hypertension. Our previous studies showed that U-II accelerates human macrophage foam cell formation and vascular smooth muscle cell proliferation, suggesting development of atherosclerotic plaque. In this study, we demonstrated a correlation between plasma U-II level and progression of atherosclerosis in hypertensive patients. METHODS: The intima-media thickness (IMT) and plaque score in the carotid artery, blood pressure (BP), plasma levels of U-II, and atherosclerotic parameters were determined in 50 hypertensive patients and 31 normotensive controls. RESULTS: Plasma U-II level, maximum IMT, plaque score, systolic BP, and homeostasis model assessment for insulin resistance (HOMA-IR) were significantly greater in hypertensive patients than normotensive controls. Age, gender, body mass index, and serum levels of high-sensitive C-reactive protein (CRP), HDL and LDL cholesterols, small dense LDL, triglycerides, lipoprotein(a), insulin, and fasting plasma glucose level were not significantly different between the two groups. In all subjects, plasma U-II level showed significant positive correlations with systolic BP, maximum IMT, plaque score, and HOMA-IR. Multiple logistic regression analysis indicated that the contribution of plasma U-II levels to carotid plaque formation (plaque score >/=1.1) was significantly still greater with a 60% increase than those of established risk factors, such as age, systolic BP, high-sensitive CRP, small dense LDL, and HOMA-IR. CONCLUSIONS: Our results suggest that increased levels of U-II may play a crucial role in the development of carotid atherosclerosis in hypertensive patients.     

Prognosis in patients with cirrhosis and mild portal hypertension

OBJECTIVE: Sixty to 70% of upper gastrointestinal bleeding episodes in patients with cirrhosis are caused by oesophageal varices. Prophylaxis is indicated in patients with varices and a hepatic venous pressure gradient (HVPG) above 12 mmHg. The study of the natural history of patients with lower HVPG has been sparse. In this study, long-term survival and the risk of complications in mild portal hypertension were analysed. MATERIAL AND METHODS: Sixty-one patients with cirrhosis and HVPG below 10 mmHg were included in the study. Data were collected from medical files and National Patient Registries. Variceal bleeding, hepatic encephalopathy and death related to cirrhosis were registered. Thirty-nine patients were graded as Child class A, 19 as class B and 3 as class C. Median survival time was 11 years. RESULTS: Twenty-eight patients (46%) developed one or more complications: variceal bleeding in 10 (16%) and hepatic encephalopathy in 18 patients (30%). Twenty-three patients (38%) died from complications of cirrhosis. Two patients (3%) died from variceal bleeding, another two (3%) from gastrointestinal bleeding of unidentified source. Survival rate was significantly decreased compared with that in the background population. CONCLUSIONS: The frequency of complications in patients with mild portal hypertension is considerable, and guidelines for follow-up or medical prophylaxis are warranted. The risk of bleeding from oesophageal varices is low and bleeding-related deaths rare.     

Prognosis in patients with cirrhosis and mild portal hypertension

Objective. Sixty to 70% of upper gastrointestinal bleeding episodes in patients with cirrhosis are caused by oesophageal varices. Prophylaxis is indicated in patients with varices and a hepatic venous pressure gradient (HVPG) above 12 mmHg. The study of the natural history of patients with lower HVPG has been sparse. In this study, long-term survival and the risk of complications in mild portal hypertension were analysed. Material and methods. Sixty-one patients with cirrhosis and HVPG below 10 mmHg were included in the study. Data were collected from medical files and National Patient Registries. Variceal bleeding, hepatic encephalopathy and death related to cirrhosis were registered. Thirty-nine patients were graded as Child class A, 19 as class B and 3 as class C. Median survival time was 11 years. Results. Twenty-eight patients (46%) developed one or more complications: variceal bleeding in 10 (16%) and hepatic encephalopathy in 18 patients (30%). Twenty-three patients (38%) died from complications of cirrhosis. Two patients (3%) died from variceal bleeding, another two (3%) from gastrointestinal bleeding of unidentified source. Survival rate was significantly decreased compared with that in the background population. Conclusions. The frequency of complications in patients with mild portal hypertension is considerable, and guidelines for follow-up or medical prophylaxis are warranted. The risk of bleeding from oesophageal varices is low and bleeding-related deaths rare.     

Increased plasma levels of endothelin in diabetic patients with hypertension.

In order to gain insight into the potential role of endothelin, a 21 amino acid peptide produced by endothelial cells, in the development of complications of diabetes mellitus, basal plasma endothelin levels were measured in 152 patients with diabetes mellitus (83 patients with type 1 diabetes mellitus, 69 patients with type 2 diabetes mellitus) and compared to those in 50 healthy controls. Blood was drawn at 8:00 AM under resting conditions and endothelin was measured after prior extraction by a sensitive radioimmunoassay specific for both endothelin 1 and 2. Endothelin levels were increased in patients with diabetes mellitus in comparison to controls. In type 1 diabetes mellitus a positive correlation between endothelin levels and age was found. We found that 60% of patients with type 1 diabetes mellitus and elevated endothelin levels higher than 2.5 pg/mL (highest value in a control person) had had diabetes for more than 20 years (P less than .05 v patients with normal endothelin levels). In type 2 diabetes mellitus the relation between elevated endothelin levels and diabetes duration was reversed. Glycosylated hemoglobin (HbA1) concentrations above 10% of total hemoglobin were measured in 62% of the patients. Arterial hypertension was present in 60% of the patients with type 1 diabetes mellitus and increased endothelin levels greater than 2.5 pg/mL (both P less than .05 v patients with normal endothelin levels).(ABSTRACT TRUNCATED AT 250 WORDS)     

Irisin levels are associated with urotensin II levels in diabetic patients

Aims/Introduction

Irisin is a newly identified myokine that can promote energy expenditure. Previous studies showed that circulating urotensin II (UII) levels were increased in diabetes, and UII could inhibit the glucose transport in skeletal muscle in diabetic mice and aggravated insulin resistance. We presumed that irisin levels are associated with UII in diabetic patients.

Materials and Methods

A total of 71 patients with type 2 diabetes and 40 healthy subjects were recruited. Blood and urinary irisin concentrations were measured by using enzyme-linked immunosorbent assay, and UII concentrations were measured by bioelectrical impedance analysis. Every participant''s body composition was analyzed by bioelectrical impedance.

Results

The serum irisin levels were significantly lower in diabetic patients than that of controls, whereas serum UII levels were significantly higher in diabetic patients than that in that of controls. Serum irisin levels were negatively associated with circulating UII, hemoglobin A1c and the natural logarithm transformation of urinary albumin excretion, whereas serum irisin was positively associated with estimated glomerular filtration rate, and low-density lipoprotein cholesterol and urinary irisin were positively associated with urinary UII. Furthermore, circulating irisin is positively associated with muscle mass, whereas circulating UII is negatively associated with muscle mass in diabetic patients. Hemoglobin A1c and circulating UII are independent determinants of circulating irisin by multiple regression analysis.

Conclusions

The present results provide the clinical evidence of an association between irisin and UII in diabetic patients. Hemoglobin A1c and circulating UII are independent determinants of circulating irisin. Our results hint that UII and high glucose might inhibit the release of irisin from skeletal muscle in diabetic patients.     

Noninvasive assessment of portal hypertension in patients with cirrhosis

Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field.     

Natural history of portal hypertension in patients with cirrhosis

All patients with cirrhosis will eventually develop portal hypertension and esophagogastric varices. Bleeding from ruptured esophagogastric varices is the most severe complication of cirrhosis and is the cause of death in about one third of patients. The rate of development and growth of esophageal varices is poorly defined but in general seem to be related to the degree of liver dysfunction. Once varices have formed, they tend to increase in size and eventually to bleed. In unselected patients, the incidence of variceal bleeding is about 20% to 30% at 2 years. Variceal size is the single most important predictor of a first variceal bleeding episode. Several prognostic indexes based on endoscopic and clinical parameters have been developed to predict the risk of bleeding; however, their degree of accuracy is unsatisfactory. Death caused by uncontrolled bleeding occurs in about 6% to 8% of patients; the 6-week mortality rate after a variceal hemorrhage is 25% to 30%. There are no good prognostic indicators of death caused by uncontrolled bleeding or death within 6 weeks. Untreated patients surviving a variceal hemorrhage have a 1- to 2-year risk of rebleeding of about 60% and a risk of death of about 40% to 50%. The risk of bleeding is greatest in the first days after a bleeding episode and slowly declines thereafter. All patients surviving a variceal hemorrhage must be treated to prevent rebleeding. Varices can also be found in the stomach of cirrhotic patients, alone or in association with esophageal varices. Gastric varices bleed less frequently but more severely than esophageal varices. Portal hypertensive gastropathy is a common feature of cirrhosis, and its prevalence parallels the severity of portal hypertension and liver dysfunction. Portal hypertensive gastropathy can progress from mild to severe and vice-versa or even disappear completely. Acute bleeding from portal hypertensive gastropathy seems to be relatively uncommon, and less severe than bleeding from varices.     

Cardiac dysfunction in portal hypertension among patients with cirrhosis and non-cirrhotic portal fibrosis

BACKGROUND/AIMS: In cirrhosis, diastolic dysfunction of heart is well documented. Contribution of portal hypertension towards cardiac changes in cirrhosis is difficult to assess. We examined the patients of non-cirrhotic portal fibrosis who have portal hypertension without liver insufficiency to understand the contribution of portal hypertension in causing cardiac changes. METHODS: Cardiac function was studied in four groups of patients: normal controls, patients with non-cirrhotic portal fibrosis (having portal hypertension without liver dysfunction) and cirrhotics with and without ascites. Cardiac function was evaluated by echocardiography. Additional measurements of plasma renin activity and aldosterone levels were performed. RESULTS: Diastolic function as assessed by the ratio between E wave and A wave (E/A ratio), was significantly lower in patients with non-cirrhotic portal fibrosis (median 1.3) compared to normal controls (median 1.52). However, even lower values were observed in cirrhotics without ascites (median 1.05) and with ascites (median 0.94). There was a significant correlation (r=-0.75) between plasma aldosterone levels and the E/A ratio in cirrhotics. CONCLUSIONS: Diastolic dysfunction is not only present in cirrhosis but also in non-cirrhotic portal fibrosis. It indicates that portal hypertension is an important factor in the genesis of cardiac dysfunction.     

坎地沙坦对高血压合并2型糖尿病患者血浆尾加压素Ⅱ和脂联素的影响

目的：比较坎地沙坦和非洛地平对高血压合并2型糖尿病患者的降压作用及血浆尾加压素Ⅱ（UⅡ）、脂联素（ADI）水平的影响。方法纳入2011年5月~2012年6月湖北医药学院太和医院高血压合并2型糖尿病患者84例,随机分为坎地沙坦组（n=43）和非洛地平组（n=41）。前者予坎地沙坦（4mg, qd）,后者予非洛地平片（5mg,qd）,疗程均为16周。比较两种药物的降压效果,并分别采用酶联免疫吸附法（ELISA）及放射免疫法测定治疗前后患者静脉血中UⅡ、ADI和血管紧张素Ⅱ（AngⅡ）的水平,观察这两种不同的降压药物对上述血管活性物质的影响。结果两组患者血压均较治疗前下降,但两组间无统计学差异。治疗前两组血浆UⅡ、ADI、AngⅡ水平无统计学差异（P＞0.05）,治疗16周后,与非洛地平组比较,试验组患者血浆中UⅡ水平明显下降[（6.17±1.45）pmol/L vs.（8.92±1.21）pmol/L, P＜0.01],ADI水平明显升高[（6.13±1.45）mg/L vs.（4.12±1.46）mg/L,P＜0.01],AngⅡ水平两组间无统计学差异[（149.72±22.89）mg/L vs.（143.27±23.88）mg/L,P＞0.05]。结论坎地沙坦与非洛地平治疗合并2型糖尿病高血压疗效接近,同时可改善胰岛素抵抗,增加血管弹性。     

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis

BACKGROUND Clinically significant portal hypertension(CSPH) and severe portal hypertension(SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor(PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIM To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis,CSPH, SPH and potential to predict portal hypertension.METHODS A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient(HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffnessvalues were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age-and sex-matched individuals.RESULTS Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis(23.20 vs 9.85; P 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG(r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG(r =-0.267, P = 0.007). PlGF levels were higher in CSPH and SPH(P = 0.006; P 0.0001) whereas Nogo-A levels were lower(P = 0.01; P 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68(P = 0.003) and for Nogo-A-0.67(P = 0.01); for SPH 0.714(P 0.0001) and 0.65(P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices(P 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific(93.1%) for the diagnosis of CSPH.CONCLUSION Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.     

New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis

Aim: To evaluate the effect of the new oral angiotensin II type 1 receptor blocker olmesartan on portal hemodynamics in patients with cirrhosis. Methods: From January 2005 to March 2006, 18 cirrhosis patients treated with endoscopic band ligation for primary esophageal variceal bleeding were included in the present study. Hepatic venous pressure gradient (HVPG) of the patients was >/=12 mmHg at baseline measurement. The patients were given 10 mg olmesartan orally once daily for 2 weeks. Eighteen cirrhosis patients with esophageal variceal bleeding who did not receive any antihypertensive agents were included in the study as control. On day 14, HVPG, blood pressure, heart rate, and parameters of hepatic and renal function were examined after the treatment. Responders were defined as those with HVPG reduction of >20% versus baseline. Results: Olmesartan significantly reduced HVPG by -16.8 +/- 22.0% (P = 0.031) and mean arterial pressure by -13.1 +/- 10.8% (P = 0.0041). Six of 18 (33.3%) patients in the olmesartan group showed >20% reduction of HVPG from baseline values. None of the patients treated with olmesartan had any complications. Conclusion: Olmesartan reduces portal pressure and may be safe and highly effective in the treatment of portal hypertension.     

Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension

BACKGROUND & AIMS: Angiotensin II receptor antagonists have been proposed as new drugs for portal hypertension. This randomized, placebo-controlled, double-blind study aimed to assess the effect of the angiotensin II receptor antagonist irbesartan on portal and systemic hemodynamics and renal function in patients with cirrhosis. METHODS: Thirty-six patients with cirrhosis and portal hypertension received 150 mg/d irbesartan or placebo for 1 week. Systemic hemodynamics, kidney and liver function parameters were recorded regularly; hepatic venous pressure gradient and plasma renin were assessed on days 0 and 7. RESULTS: Irbesartan reduced the hepatic venous pressure gradient by 12.2% +/- 6.6% (P < 0.05) and mean arterial pressure by 5.3% +/- 4.0% in 13 of 18 verum patients. In 4 (22%) verum patients, arterial hypotension, accompanied by significant renal impairment, required withdrawal of irbesartan. In these patients, baseline plasma renin (P < 0.002) and cystatin C (P < 0.001) levels were higher, and creatinine clearance (P < 0.02), serum sodium (P < 0.01), and albumin (P < 0.05) were lower than in patients who tolerated irbesartan. Four of five patients with baseline renin >900 microU/mL developed treatment-limiting hypotension. CONCLUSIONS: The angiotensin II receptor antagonist irbesartan is not advisable in patients with advanced cirrhosis and high plasma renin because it may induce arterial hypotension and only moderately reduces portal pressure.     

Mineralocorticoid escape in patients with compensated cirrhosis and portal hypertension.

Failure to escape from mineralocorticoids in compensated cirrhosis is considered a major argument supporting the overflow theory of ascites. To assess the frequency and mechanism of mineralocorticoid escape in cirrhosis, 9-alpha-fluorohydrocortisone (0.6 mg/day) was administered to 19 patients with compensated cirrhosis, portal hypertension, and no history of ascites who were able to maintain sodium balance on a 250 mmol Na+ diet. Fifteen patients (78.9%) escaped from mineralocorticoids, while 4 patients (21.1%) did not escape and developed ascites. Patients who did not escape had significantly higher cardiac index (4.97 +/- 0.42 vs 3.46 +/- 0.21 L.min-1.m-2) and lower peripheral vascular resistance (485.9 +/- 37.5 vs. 665.8 +/- 32.9 dyne.s.cm-5/m2) than those who escaped. Hepatic venous pressure gradient was not significantly different. The escape phenomenon was associated with a significant increase in mean arterial pressure, creatinine clearance, and atrial natriuretic factor and suppression of plasma renin activity. All of these parameters showed minimal or no changes in patients who did not escape. These results indicate that failure to escape from mineralocorticoids is uncommon in patients with compensated cirrhosis, is related to an inadequate expansion of effective plasma volume due to the accumulation of ascites, and occurs in patients with marked peripheral arteriolar vasodilation.     

Colonic wall thickening in patients with cirrhosis and portal hypertension.

OBJECTIVE: To determine the prevalence of colonic wall thickening (CWT) and its relation with other clinical and radiological findings of portal hypertension. EXPERIMENTAL DESIGN: Retrospective observational study. The follow-up period was at least 1 year. The colon wall was considered to be thickened when it measured > 6 mm. SUBJECTS: The study included 63 patients, what were admitted in Liver Unit of University and General Hospital of Alicante with hepatic cirrhosis who had an abdominal CT scan performed between March 1996 and December 1998. RESULTS: 21 (33.3%) patients showed CWT. This finding was particularly associated with the presence of collateral circulation [ OR = 10.3(1.5-100.8)] and portal thrombosis [OR = 12.8(1.4-118.4)] p<0.05. Patients with CWT tended to develop spontaneous bacterial peritonitis (CWT 14.3% vs no CWT 4.8%) [RR = 3(0.5 -16.6)] but this did not reach statistical significance (p= 0.18). CONCLUSIONS: A third of the patients with cirrhosis and portal hypertension present colonic wall thickening. This finding is related to radiological features and clinical consequences of portal hypertension.     

Pharmacology of propranolol in patients with cirrhosis and portal hypertension.

Ten patients with cirrhosis and protal hypertension received an initial 20 mg oral test dose of propranolol and subsequently 160 mg of a slow release preparation, orally, each day for seven days. Protein binding, serial plasma propranolol concentrations and effects on heart rate were studied. Protein binding was slightly reduced (mean 85%, range 78.9-88.1%) compared with four normals (mean 87.9%). In patients with severe liver disease (serum albumin less than 30 g/l) propranolol remained detectable in plasma 24 hours after the single 20 mg dose and high steady state concentrations (mean 266.5 ng/ml, range 84-406) were observed during regular dosing. At steady state there was a significant correlation between log total plasma propranolol concentrations and the percentage fall in heart rate (r = 0.659, p less than 0.05). We suggest that in patients with severe liver chronic disease (serum albumin less than 30 g/l), propranolol therapy should be initiated in hospital. The starting dose should be low (20 mg of the conventional formulation tds or 80 mg of the slow release preparation daily) and that regular monitoring of the heart rate should be carried out.     

Surgical treatment of portal hypertension in patients with liver cirrhosis

Surgical options in the treatment of portal hypertension in cirrhotics are reviewed, regarding elective and emergency cases as well as the results in alcoholics and non-alcoholics. After literature review and personal experience analysis, it is concluded that endoscopic sclerotherapy should be the treatment of choice in cirrhotic patients with bleeding esophageal varices. When this fails, distal splenorenal shunt is indicated for compensated Child A and B. Regarding Child C and decompensated Child B, the choice should be a portocaval or meso caval shunts or esophageal transection with a stapler associated to splenectomy.     

Incidence of cholelithiasis among patients with cirrhosis and portal hypertension

One hundred and two patients with cirrhosis and portal hypertension were evaluated sonographically to determine the presence or absence of cholelithiasis. The gallbladder was visualized in 80 of 102 patients. Cholelithiasis was present in 43 of 80 cases (54%). All 22 patients in whom the gallbladder was not seen sonographically had had a previous cholecystectomy. Five of them were operated on prior to development of cirrhosis with portal hypertension, but 14 of the remaining 17 (82%) had evidence of cholelithiasis at pathology. Hence, there was an overall incidence of cholelithiasis of 59% among out 97 patients. This study as well as previous autopsy data indicate an increased incidence of cholelithiasis in patients with cirrhosis, irrespective of etiology or sex. The incidence of cholelithiasis in this study, however, was approximately twice that previously reported in cirrhotics at autopsy. Furthermore, patients with portosystemic shunts showed a significantly higher incidence of cholelithiasis compared to patients who were not shunted (68% vs 49%, p = 0.028). We believe the severity and duration of cirrhosis in our patient population, all with documented portal hypertension, may be the cause of this increased incidence.