Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS.

BACKGROUND AND AIMS: Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS). METHODS: We analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2 weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated. RESULTS: Circulating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients. CONCLUSION: This study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.

Disease course and treatment outcomes of Crohn's disease patients with early or late surgery - A Danish nationwide cohort study from 1997 to 2015.

BACKGROUND: Studies on early surgery among Crohn's disease patients are few and focus on ileocolonic resections. AIM: The aim of this nationwide cohort study was to investigate the disease course in all Crohn's disease patients who underwent early and late major abdominal surgery. METHODS: In a Danish nationwide cohort of Crohn's disease patients from 1997 to 2015 we included 493 patients (group 1) resected within 29 days, 472 patients (group 2) resected between 30 and 180 days, and 1,518 patients (group 3) resected after 180 days of diagnosis. Re-operation, hospitalisations and medications were analysed. RESULTS: The cumulative risk of re-operation was lower among patients from group 1 (five-year risk: 16.5% vs. group 2: 18.2% and group 3: 21.2%, p = 0.004). Fewer patients from group 2 and 3 required hospitalisations (269 (56.5%) and 803 (52.8%) vs. group 1: 329 (66.8%) p<0.001). Patients from group 3 had a higher cumulative use of immunomodulators in the first three years after initial surgery (one-year risk: 24.6% vs. group 1: 19.4% and group 2: 17.0%, p<0.001). CONCLUSION: Crohn's disease patients resected within 29 days of diagnosis had a lower cumulative risk of re-operation and a lower cumulative exposure to immunomodulators in the initial years after surgery.

Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.

OBJECTIVES: Recent studies suggest that cardiac dysfunction precedes development of the hepatorenal syndrome. In this follow-up study, we aimed to investigate the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival. PATIENTS AND DESIGN: Twenty-four patients with cirrhosis and ascites were included. Cardiac function was investigated by gated myocardial perfusion imaging (MPI) for assessment of cardiac index (CI) and cardiac volumes. The renal function was assessed by determination of glomerular filtration rate (GFR) and renal blood flow (RBF) and the patients were followed up for 12 months. RESULTS: In patients with a CI below 1.5 l/min/m(2) on MPI, GFR was lower (39 (SD 24) vs 63 (SD 23) ml/min, p = 0.03), RBF was lower (352 (SD 232) vs 561 (SD 229) ml/min, p = 0.06), and serum creatinine was higher (130 (SD 46) vs 78 (SD 29) mumol/l, p<0.01). The number of patients who developed hepatorenal syndrome type 1 within 3 months was higher in the group with low CI than in the high CI group (43% vs 5%, p = 0.04). Patients with the lowest CI (N = 8) had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (N = 16), p<0.05. In contrast, the Model for End-stage Liver Disease (MELD) score failed to predict mortality in these patients. CONCLUSIONS: The development of renal failure and poor outcome in patients with advanced cirrhosis and ascites seem to be related to a cardiac systolic dysfunction. Other parameters may be more important than MELD score to predict prognosis.

Diagnostic performance of Baveno IV criteria in cirrhotic patients with upper gastrointestinal bleeding: analysis of the F7 liver-1288 study population.

BACKGROUND & AIMS: The definition of failure to control bleeding agreed upon at the Baveno IV consensus meeting, included the Adjusted Blood Requirement Index [ABRI: number of blood units/(final-initial hematocrit+0.01)]. ABRI ≥0.75 denotes failure. However, timing for hematocrit measurements was not defined. The aims of this study were: (1) to assess the Baveno IV criteria performance to classify treatment success or failure to control bleeding at 5 days, (2) to determine the appropriate timing for hematocrit. METHODS: Two hundred and forty-two cirrhotic patients with gastrointestinal bleeding were independently classified by three clinical experts according to the Baveno IV criteria, by analysis of the database of a randomized trial. ABRI was calculated by using the closest hematocrit to the 5 day time point from the first trial product administration (ABRI-1) or after the latest transfusion within the 5-day period (ABRI-2). The gold standard for success/failure for 5-day control of bleeding was the clinical judgment of the three independent observers based on all the clinical and follow-up data. RESULTS: Inter-observer agreement for the final outcome assessment was 0.82 and a final consensus was obtained in 236/242 patients. Inter-observer agreement on patient classification with Baveno IV criteria was 0.70 with ABRI-1 and 0.84 with ABRI-2. c-statistics for correct patients classification were 0.86 for ABRI-1, 0.84 for ABRI-2, and 0.88 for Baveno IV criteria without ABRI. ABRI-1 caused misclassification of 27 patients and ABRI-2 of 39. CONCLUSIONS: Baveno IV criteria are accurate to assess outcome of patients with variceal bleeding. There is a substantial observer variability linked to timing of hematocrits for ABRI calculation. With the current definition ABRI does not add to the performance of the other criteria.

Increased abundance of proteobacteria in aggressive Crohn's disease seven years after diagnosis.

Intestinal dysbiosis in inflammatory bowel disease (IBD) patients depend on disease activity. We aimed to characterize the microbiota after 7 years of follow-up in an unselected cohort of IBD patients according to disease activity and disease severity. Fifty eight Crohn's disease (CD) and 82 ulcerative colitis (UC) patients were included. Disease activity was assessed by the Harvey-Bradshaw Index for CD and Simple Clinical Colitis Activity Index for UC. Microbiota diversity was assessed by 16S rDNA MiSeq sequencing. In UC patients with active disease and in CD patients with aggressive disease the richness (number of OTUs, p = 0.018 and p = 0.013, respectively) and diversity (Shannons index, p = 0.017 and p = 0.023, respectively) were significantly decreased. In the active UC group there was a significant decrease in abundance of the phylum Firmicutes (p = 0.018). The same was found in CD patients with aggressive disease (p = 0.05) while the abundance of Proteobacteria phylum showed a significant increase (p = 0.03) in CD patients. We found a change in the microbial abundance in UC patients with active disease and in CD patients with aggressive disease. These results suggest that dysbiosis of the gut in IBD patients is not only related to current activity but also to the course of the disease.

Changes in Disease Behaviour and Location in Patients With Crohn's Disease After Seven Years of Follow-Up: A Danish Population-based Inception Cohort.

BACKGROUND AND AIM: Crohn's disease [CD] is a progressive inflammatory bowel disease that can lead to complications such as strictures or penetrating disease, and ultimately surgery. Few population-based studies have investigated the predictors for disease progression and surgery in CD according to the Montreal classification. We aimed to identify clinical predictors associated with complicated CD in a Danish population-based inception cohort during the biologic era. METHODS: All incident patients with CD in a well-defined Copenhagen area, between 2003 and 2004, were followed prospectively until 2011. Disease progression was defined as the development of bowel stricture [B2] or penetrating disease [B3] in patients initially diagnosed with non-stricturing/non-penetrating disease [B1]. Associations between disease progression and/or resection, and multiple covariates, were investigated by Cox regression analyses. RESULTS: In total, 213 CD patients were followed. A total of 177 [83%] patients had B1 at diagnosis. Patients who changed location had increased risk of disease progression (hazard ratio [HR] = 3.1, 95% CI: 1.12,8.52). Biologic treatment was associated with lower risk of change in location [HR = 0.3, 95% CI: 0.1-0.7]. Colonic involvement [L2 or L3 vs L1] was associated with a lower risk of surgery (HR = 0.34/0.22, 95% CI: [0.13,0.86]/[0.08,0.60]). All CD patients who progressed in behaviour or changed location had an increased risk of surgery [p < 0.05]. CONCLUSIONS: This population-based inception cohort study demonstrates that changes in disease location or behaviour in patients with CD increase their risk of resection. Our findings highlight the protective effect of biologic treatment with regard to change in disease location, which might ultimately improve the disease course for CD patients.

Reduced risk of decompensation and death associated with use of statins in patients with alcoholic cirrhosis. A nationwide case-cohort study.

BACKGROUND: Reports have indicated that the use of statins may ameliorate the course of cirrhosis. AIM: To determine the relationship between use of statins and mortality rate in patients with cirrhosis. METHODS: We did a retrospective case-cohort analysis based on data from the Danish registers from the period 1995 through 2014. Index date was time of diagnosis of cirrhosis (ICD-10: K703) and cohort entry depended on whether the patient was statin user or not. We used propensity score matching with a statin:non-statin ratio of 1:2. We included the exposure to statins (ATC classification C10AA) from the index date until death or end of follow-up based on prescription claims. Use of statins based on at least two statin claims as well as the longitudinal pattern over time of statin claims was tested against mortality. The main outcome was mortality rate. RESULTS: A total of 24 748 patients with alcoholic cirrhosis were identified and 5417 were eligible for matching. The mean age was 56 (SD 10) years and 36% were females. The prevalence of use of statins was 15%. We included 744 in the matched cohort. Mortality rates were 88 (95% CI 73-105) per 1000 years for patients using statin and 127 (95% CI 114-141) for non-statin patients with a HR of 0.57 (95% CI 0.45-0.71). A more regular pattern of statin claims was related to a lower risk of death. CONCLUSIONS: Our results showed an association between regular use of statins and reduced mortality in patients with alcoholic cirrhosis.

Advances in the treatment of portal hypertension in cirrhosis.

Non-selective beta-blockers and handling of esophageal varices has been key elements in the treatment of portal hypertension in recent decades. Liver vein catheterization has been essential in diagnosis and monitoring of portal hypertension, but ongoing needs for noninvasive tools has led to research in areas of both biomarkers, and transient elastography, which displays promising results in discerning clinically significant portal hypertension. Novel research into the areas of hepatic stellate cell function and the dynamic components of portal hypertension has revealed promising areas of treatment modalities, targeting intestinal decontamination, angiogenesis, inflammation and oxidative stress. Future studies may reveal if these initiatives lead to developments of new drugs for treatment of portal hypertension.

The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis.

BACKGROUND: Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM: To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis. METHODS: We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase-1 and procollagen-III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163-fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant. RESULTS: Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child-Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC's of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS: The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.

Review article: volume expansion in patients with cirrhosis.

Adequate size and distribution of the circulating medium are important for cardiovascular function, tissue oxygenation, and fluid homoeostasis. Patients with cirrhosis have cardiovascular dysfunction with a hyperkinetic systemic circulation, abnormal distribution of the blood volume, vasodilation with low systemic vascular resistance, increased whole-body vascular compliance, and increased arterial compliance. The effectiveness and temporal relations of plasma/blood volume expansion depend highly on the type of load (water, saline, oncotic material, red blood cells). Patients with cirrhosis respond in some aspects differently from healthy subjects, owing to their disturbed circulatory function and neurohormonal activation. Thus the increase in cardiac output and suppression of the renin-angiotensin-aldosterone system and sympathetic nervous system during volume expansion may be somewhat blunted, and in advanced cirrhosis, especially the non-central parts of the circulation, including the splanchnic blood volume, are expanded by a volume load. Infusion of oncotic material (preferably albumin) is important in the prevention of post-paracentesis circulatory dysfunction. In conclusion, volume expansion in advanced cirrhosis is qualitatively and quantitatively different from that of healthy subjects, and in those with early cirrhosis. Timely handling is essential, but difficult as it is a balance between the risks of excess extravascular volume loading and further circulatory dysfunction in these patients with a hyperdynamic, but hyporeactive, circulation.

Effect of omeprazole on intragastric and duodenal bulb acidity in duodenal ulcer patients.

Intraluminal pH was measured simultaneously in the stomach and duodenal bulb with six small, glass electrodes tied together at 1.5-cm intervals. Ten patients with duodenal ulcer disease were studied under fasting conditions and for 3 h after a standard liquid meal on three occasions: day 1, before treatment; day 8, when the proton pump blocker omeprazole had been taken in a daily dose of 30 mg for 7 days consecutively, including the day of the pH study; day 9, 24 h after the last dose of omeprazole. Mean hydrogen ion activity and the percentage of time with pH below 3 was calculated from the digital pH data sampled at a frequency of 1 per second from each electrode. On day 8, five of the patients were permanently anacidic (pH greater than 4) in the stomach and duodenum, while the food-stimulation broke off anacidity for shorter periods in the other five patients. The pH pattern in the duodenal bulb was markedly altered in all patients with disappearance of the typical pH fluctuations, and a decrease in the time that the pH was below 3 from a median value of 30% before treatment to 0% in seven patients and close to 0% in three patients. On day 9, a large patient-to-patient variation was observed in gastric pH: three patients were still anacidic, four were markedly suppressed, but three patients reached near pre-treatment acidity. Duodenal bulb acidity was still decreased significantly on day 9 in all patients, with post-prandial pH below 3 for less than 5% of the time, compared with 30% before treatment.

The organ extraction and splanchnic haemodynamic effects of octreotide in cirrhotic patients.

BACKGROUND: Intravenous octreotide is an established treatment of oesophageal variceal haemorrhage in the cirrhotic patient. AIM: To examine the organ extraction and splanchnic haemodynamic effects of octreotide in cirrhotic patients with portal hypertension. METHODS: Thirteen patients with cirrhosis had hepatic venous catheterization performed. Hepatic venous pressure gradient (HVPG), indocyanine green (ICG) clearance and hepatic blood flow (HBF) were determined in the basal state and during 60 min of octreotide infusion by bolus injection (0.75 microg/kg) followed by continuous infusion of 0.75 microg/kg x h. Blood samples were simultaneously drawn from the femoral artery and the hepatic and renal veins. RESULTS: The extraction fraction of octreotide in the liver was 0.05 (-0.01 - 0.14) (median (interquartile range)) and in the kidneys 0.16 (-0.06 - 0.35). The extraction fraction ratio (E(liver)/E(kidney)) was 0.69 (-0.20 - 1.06). Hepatic clearance was 47 mL/min (3-88) (n = 11). No correlations were found between liver biochemistry or galactose elimination capacity (GEC; a metabolic measure of liver function) and renal extraction fraction or liver clearance. Octreotide had no effect on HVPG or wedged hepatic venous pressure although free hepatic venous pressure increased during octreotide infusion: 6 mmHg (5-9) vs. 7 mmHg (6-10) (P = 0.02). No effect on HBF was observed while ICG clearance decreased significantly. CONCLUSIONS: Octreotide is extracted in cirrhotic patients by both the liver and the kidney, the latter being the most important organ of elimination. Octreotide decreases liver metabolic activity determined by the ICG clearance technique, but no significant effects of octreotide on HVPG or HBF could be demonstrated.

Duodenal ulcer healing on 2 g of sucralfate daily at bedtime compared to 1 g four times daily.

Seventy-seven patients with endoscopically verified duodenal ulcers were randomized to treatment with either 2 g sucralfate daily at bedtime or 1 g sucralfate q.d.s. in a controlled double-blind comparative study. After a 4-week treatment period, the healing rate was 68% for the former and 69% for the latter treatment.

Splanchnic removal of human alpha-atrial natriuretic peptide in humans: enhancement after food intake.

In order to assess the effect of food ingestion on splanchnic disposal of human alpha-atrial natriuretic peptide (ANF), hepatic-intestinal removal of ANF was determined before and after a test meal. Hepatic venous and arterial plasma samples were obtained from six subjects, most of whom had only disorders of minor degree. Hepatic blood flow (HBF) increased significantly after meal ingestion (1.10 +/- 0.17 [SEM] to 1.51 +/- 0.26 L/min, P less than .01). Baseline arterial ANF (10.9 +/- 3.1 pmol/L) did not change significantly. In contrast, hepatic venous ANF increased after meal intake (5.7 +/- 2.0 to 8.4 +/- 1.9 pmol/L, P less than .05), and accordingly the splanchnic fractional extraction decreased (0.53 +/- 0.09 to 0.35 +/- 0.08), although this was not statistically significant. Splanchnic clearance of ANF increased from 347 +/- 90 mL/min to a maximal value of 615 +/- 158 mL/min (P less than .05). Splanchnic removal of ANF was 3.0 +/- 0.5 pmol/min before and increased to a maximum value (7.1 +/- 2.2 pmol/min, P less than .05) 35 minutes after ingestion of the meal. Our results showed enhanced splanchnic removal of ANF after food intake. This is due to increased hepatic-intestinal clearance of the peptide consequent on increased splanchnic blood flow, rather than altered fractional extraction of ANF.

Increased circulating calcitonin in cirrhosis. Relation to severity of disease and calcitonin gene-related peptide.

Increased circulating levels of the neuropeptide calcitonin gene-related peptide (CGRP) have recently been described in cirrhosis. CGRP is formed by alternative transcription of the calcitonin/alpha-CGRP gene, which also gives rise to calcitonin (CT). This study was undertaken to determine circulating plasma concentrations of CT in patients with cirrhosis in relation to the severity of disease and the plasma level of CGRP. Moreover, the kinetics of CT was evaluated for different organ systems by determination of arteriovenous extraction. Thirty-nine patients with cirrhosis (Child-Turcotte classes A/B/C, n = 10/22/7) were studied under a hemodynamic investigation and compared with 13 control subjects without liver disease. CT and CGRP in arterial and organ venous plasma were determined by radioimmunoassays. In patients with cirrhosis, circulating CT was significantly increased versus control (12.1 v 6.9 pmol/L, P < .001) and a direct relation to the Child-Turcotte score was found (P < .005). The increased circulating CT was directly correlated with increased CGRP (r = .29, P < .05). No significant arteriovenous extraction of circulating CT was observed in the kidneys, hepatosplanchnic system, lower extremities, or peripheral circulation, but there was a substantial rate of pulmonary disposal and clearance (P < .005). It is concluded that in addition to thyroid production, increased circulating CT in cirrhosis is most likely due to overexpression of the calcitonin/alpha-CGRP gene, with relation to the severity of disease and possibly to an accompanying pulmonary dysfunction.

Oesophageal pressure-cross-sectional area distributions and secondary peristalsis in relation to subclassification of systemic sclerosis.

The aim of the present study was to correlate the severity of oesophageal motor dysfunction with the severity of cutaneous disease in systemic sclerosis (SS). Patients were divided into three groups based on the degree of skin involvement: type I, acrosclerosis distal to the wrist; type II, scleroderma extending above the wrist in proximal direction; type III, diffuse cutaneous systemic sclerosis. Impedance planimetry employing distensions with pressures up to 5 kPa with the concomitant measurement of oesophageal cross-sectional area (CSA) was used in combination with standard oesophageal manometry. Measurements were made at 7 and 15 cm above the lower oesophageal sphincter (LOS). Thirty patients (16 type I, six type II and eight type III patients) and 23 normal controls were included. LOS pressure was lower in SS patients than in normal patients, with the lowest values in type III. The CSAs were higher in SS patients than in controls at both sites (P < 0.001). The CSAs at the distal site were highest in type III, as compared to type I and II (P < 0.03). The CSA at the highest induced pressure (5.0 kPa) was 613 +/- 45, 719 +/- 79, and 808 +/- 115 mm2 in types I, II and III, respectively. No differences in CSA were found at the proximal site between the three types of SS. The distensibility did not differ between SS and normal patients at the distal site. The distensibility was lowest in SS patients (P < 0.001) at the proximal distension site. The distensibility did not vary with the type of SS at either site. Significant differences in contraction frequency of the secondary peristalsis as function of wall tension were demonstrated between the SS patients and controls at the distal site (P < 0.05). No differences were found at the proximal site. The contraction frequency and amplitude at the distal and proximal sites did not differ among the three types. In conclusion for most parameters studied, SS patients differed from normal patients. Among SS types, the most pronounced changes were found in type III.

A phylogenetic analysis elucidating a case of patient-to-patient transmission of hepatitis C virus during surgery.

A phylogenetic hepatitis C virus (HCV) assay based on the core-Envelope 1 (C-E1) region was developed and used to elucidate a case of a patient-to-patient transmission. The index patient showed clinical symptoms of hepatitis seven weeks after surgery for hallux valgus under general anaesthesia. She progressed to a chronic persistent infection as indicated by positive HCV PCR results two years after surgery. Before her operation, a patient with HCV antibodies and positive HCV PCR had undergone surgery in the same room. There were two possibilities whereby the index patient could have been infected with hepatitis C, either through her work as a nurse or by transmission during surgery. By sequencing the 5' non-coding region PCR product, we found that both patients were infected with genotype 1a. Phylogenetic analysis with the variable C-E1 region suggested that the two patients clustered together with a bootstrap 100% in a tree with 75 sequence references. We further performed a phylogenetic analysis in this region with the genotype 1a reference sequences and an additional 25 genotype 1a sequences consecutively collected from Danish patients with HCV. The two patients still clustered together, supported by a high bootstrap 1000 value of 999. Homology analyses combined with the epidemiological findings indicate that the patient operated on in the same room before the index case was the most likely source of transmission. The mode of transmission could not be conclusively established, but a reusable part of the anaesthetic respiratory circuit is a possibility and a well known risk.

Comparative pharmacokinetics and pharmacodynamics of lisinopril and enalapril, alone and in combination with propranolol.

In an open, crossover study, the pharmacokinetic and pharmacodynamic profiles of lisinopril and enalapril, administered alone and in combination with propranolol, were evaluated in 12 volunteers. The maximum serum concentration (Cmax) of lisinopril and time to reach maximum concentration (Tmax) were 64 +/- 16 ng/ml and 7.5 +/- 1.5 h, respectively. The area under the serum curve (AUC) was 916 +/- 239 h. ng/ml. The Cmax of enalaprilat (89 +/- 34 ng/ml) was greater than that of lisinopril whilst Tmax was shorter (4.3 +/- 1.7 h) and AUC smaller (718 +/- 17 h.ng/ml) (P less than 0.01). Renal clearance of drug 48 h post-dosing showed that enalaprilat (164 +/- 38 ml/min) was cleared from plasma significantly more rapidly than lisinopril (82 +/- 16 ml/min) (P less than 0.001). Mean supine blood pressure decreased significantly with all treatments, as did heart rate. No significant changes were observed in either the serum concentrations or the urinary outputs of these ACE inhibitors following combination with propranolol, apart from a greater variability of Cmax after addition of propranolol to enalapril compared with lisinopril in combination.