Angiotensin-converting Enzyme Values Research Articles

ACE values in the diagnosis of sarcoidosis

Abstract Background In clinical practice, we often encounter the patients with sarcoidosis showing relatively high in the normal range of serum angiotensin-converting enzyme (ACE) value. Purpose We aimed to examine the serum ACE value of the patients with sarcoidosis and determine the new cut-off value for detecting the patients with sarcoidosis. Methods and results We retrospectively examined all 3781 subjects (51.1% men, 60.1±17.0 y.o.) in whom ACE was measured for any reasons including suspected sarcoidosis between 2009 and 2020 in our hospital. Of 293 patients with sarcoidosis, 101, 212, 84, and 88 were diagnosed as sarcoidosis in heart, lung, skin, and eyes, respectively. After excluding 477 patients taking ACE inhibitor and/or immunosuppression agent or those with any diseases affecting serum ACE levels, we analyzed 3304 subjects including 215 with sarcoidosis. Serum ACEs were 19.6 IU/L [IQR, 15.1–31.5] in the subjects with sarcoidosis and 10.7 [8.4–16.5] in those without (P<0.01). In ROC curve analysis of ACE for diagnosis of sarcoidosis, the cut-off point was 14.7 IU/L and the AUC was 0.865. When we used the current cut-off of 21.4 or new cut-off value of 14.7, sensitivity, specificity, PPV, NPV, and accuracy were shown in Table. Finally, they were divided into four groups based on the presence of cardiac and/or extra cardiac sarcoidosis, ACE values in Group A, B, C, and D were 17.9, 20.9, 18.6, and 10.7, respectively (Figure 1). Conclusion(s) In the current cut-off value of serum ACE, sensitivity for detecting sarcoidosis was comparatively low, though positive predictive value was low when the new-cut-off value was used in our study. Further examinations may be needed for the patients suspected sarcoidosis with relatively high ACE in the normal range. Funding Acknowledgement Type of funding sources: None.

Structure\u2013function engineering of novel fish gelatin-derived multifunctional peptides using high-resolution peptidomics and bioinformatics

The multifunctional properties of fish gelatin hydrolysates have not been completely elucidated. Here, the biological characterization of these peptides was performed to engineer multifunctional peptides. Bioactive peptides were produced from mackerel byproducts via successive enzymatic hydrolysis reactions using subtilisin A and actinidin as microbial and herbal proteases. The antibacterial activity against both gram-negative and -positive food-borne pathogens, including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae, as well as the inhibitory potential of angiotensin-converting enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV), was accessed in vitro. The synthesized peptides demonstrated multifunctional properties, which were further confirmed by in silico protocols. The ACE and DPP-IV inhibitory (IC50) values of P1, P2, and P3 were 0.92 and 0.87, 0.51 and 0.93, 0.78 and 1.16 mg mL−1, respectively. Moreover, the binding energy was sufficient for all three peptides to inhibit both ACE and DPP-IV enzymes with excellent three-dimensional conformation (RMSD = 0.000) for all six docking mechanisms.

High sensitivity cardiac troponin T is a useful biomarker for predicting prognosis of the patients with sarcoidosis

Abstract Background Cardiac involvement is one of the most significant prognostic factors for the patients with sarcoidosis. In spite of the advancement of diagnostic tools, such as cardiac magnetic resonance imaging or 18F-fluoro-2-deoxyglucose positron emission tomography, there is still significant room for improvement in cardiac screening and prognostic prediction. Purpose To evaluate the prognostic factors for the patients with sarcoidosis. Methods and results We prospectively studied 133 patients with sarcoidosis and evaluated clinical data including biomarkers. The mean age at diagnosis was 62.1±12.8 years. During a mean follow up period of 5.6±4.1 years, nine patients died and 27 patients suffered from cardiac events (cardiac death, heart failure admission, arrhythmic event). We divided patients into two groups according to cardiac events, event group had high serum high-sensitivity cardiac troponin T (hs-cTnT) (0.028±0.017 vs. 0.015±0.011 ng/ml, p<0.001), high BNP (409.2±634.0 vs. 122.4±195.8 pg/ml, p<0.001), low EF (43.1±16.4 vs. 59.2±15.5%, p<0.001). This was observed even if those patients were not diagnosed with cardiac involvement at the enrollment. On the other hand, there were no significant differences in the values of angiotensin-converting enzyme, lysozyme, soluble interleukin-2 receptor, or calcium in both groups. Multivariate analysis revealed that hs-cTnT was an independent biomarker to predict cardiac events (hs-cTnT >0.014 ng/ml: HR 3.2, 95% CI 1.02 to 10.19, p=0.046). Conclusion Hs-cTnT was a useful biomarker for predicting cardiac events for the patients with sarcoidosis even if cardiac involvement was not detected at initial evaluation. Figure 1 Funding Acknowledgement Type of funding source: None

Understanding COVID-19: A hypothesis regarding digit ratio (2D:4D), ACE I/D polymorphism, oxygen metabolism and national case fatality rates

ObjectiveMale digit ratio (2D:4D) correlates positively with the national case fatality rate (CFR) for COVID-19. The severity of COVID-19 may be influenced by a counterbalance between the angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). SARS-CoV2 cleaves with ACE2 and enters cells leaving an unopposed effect of ACE in the lungs. Both 2D:4D and the ACE I/D polymorphism are covariates of oxygen metabolism. COVID-19 leads to lung damage and a reduction in oxygen saturation of the blood. Here, we examine the interrelationships between 2D:4D, ACE polymorphism, and COVID-19 CFR. MethodsNational frequencies/rates were obtained for 2D:4D from the BBC Internet study (n = 41), published values of ACE I/II (n = 39), and COVID-19 CFR from three World Health Organization situation reports (n = 41). Results2D:4D was negatively associated with national ACE I/II frequencies. However, there was a positive relationship between male 2D:4D and CFR (right and left 2D:4D, two, and three situation reports respectively). The relationships between ACE I/II and CFR were non-significant. Relationships between male 2D:4D and CFR's were independent of female 2D:4D and ACE I/II. ConclusionsThe ACE I/D polymorphism may influence 2D:4D such that ACE II individuals have lower 2D:4D than ACE DD individuals. Low 2D:4D and ACE II individuals show efficient oxygen metabolism. Therefore, low 2D:4D and ACE II together may protect against COVID-19 severity. The sex-dependent positive correlation between male 2D:4D and CFR is independent of ACE I/II, suggesting that the sex-dependent variation in the ACE2 gene may also influence the 2D:4D phenotype.

Measurement of angiotensin-I-converting enzyme in the blood: help for method validation

Blood angiotensin-converting enzyme (ACE) assay is now realized by the determination of enzyme activity on synthetic substrate, mostly furylacryloyl-phenylalanyl-L-glycyl-L-glycine (FAPGG). The matrix can be serum or heparin-plasma, with or without a separator; the assay developed on serum or plasma is not adapted to other matrix such as cerebrospinal fluid where the ACE activity is much lower. This assay has been adapted on a number of automated biochemistry analyzers with the specifications of the supplier of reagents, sometimes with modification of volumes or times for analysis. Samples can be stored at +4̊C for at least for one week, freezing at -20̊C is possible but refreezing is not advised. The assay is linear from 10 to 200 UI/L. Fidelity is excellent after calibration of the assay. Accuracy can be calculated from IQA and EQA results, and the analytical uncertainty is between 2% and 5% in function of the serum ACE value. Usual values will be soon available from studies on age brackets and sex, because ACE activity seems to be more elevated in boys during adolescence. At signature, it is interesting to have medical information on the diagnosis of sarcoidosis or its treatment including ACE inhibitors as a proof of intake; we can give a commentary on elevation of serum ACE activity from other causes than sarcoidosis and the causes for low activities.

Reconsideration of the cut-off value of angiotensin-converting enzyme for screening of sarcoidosis in Japanese patients

BackgroundIn clinical practice, we frequently experience patients with sarcoidosis who show relatively high but normal values of angiotensin-converting enzyme (ACE). The objective of this study was to reconsider the cut-off value of ACE. MethodsWe studied 79 Japanese patients who were diagnosed as having sarcoidosis at our hospital. We excluded patients who had taken steroids or ACE inhibitors and patients with renal impairment. We respectively evaluated ACE values and performed receiver operating characteristic (ROC) analysis from a comparison with data for 299 normal Japanese subjects who showed ACE values in the current Japanese standard normal range (7.0–25.0IU/L). ResultsPatients with sarcoidosis had higher ACE values than those in normal subjects (ACE: 20.3IU/L [IQR, 16.0–24.4] vs. 15.4IU/L [IQR, 12.8–18.5]; p<0.001). However, 62 patients (78.5%) had normal ACE levels (cut-off value <25.0IU/L), and the sensitivity of ACE level for detecting sarcoidosis was only 21.5%. From ROC analysis, a cut-off value of 17.7IU/L (AUC: 0.727, 95% CI: 0.660–0.794, p<0.001) was the best cut-off value for detecting sarcoidosis and sensitivity increased to 67.0%. ConclusionsThe possibility of sarcoidosis cannot be ruled out by using the current Japanese standard value even in patients who have normal ACE levels. Careful interpretation of this biomarker is needed.

Serum Angiotensin-Converting Enzyme Has a High Negative Predictive Value in the Investigation for Systemic Sarcoidosis

To examine whether measurement of serum angiotensin-converting enzyme (ACE) is useful in diagnosing sarcoidosis in undifferentiated uveitis. Evaluation of a diagnostic test. Data collection was performed from 1035 consecutive subjects presenting with uveitis to Moorfields Eye Hospital undergoing measurement of serum ACE as part of baseline investigations for underlying systemic disease. The main outcome measures were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of elevated serum ACE. Mean age of the sample was 41.7 years and 56.1% of subjects were female. Sarcoidosis was the underlying cause for the uveitis in 110 subjects (10.6%) and was more common in adults, female subjects, black subjects, and subjects with intermediate uveitis or panuveitis. ACE was elevated in 196 subjects (18.9%) and elevated levels were observed in 85 subjects eventually diagnosed with underlying sarcoidosis (true positive 77.3%) and in 111 subjects with an alternate diagnosis (false positive 12.0%). In adult subjects, sensitivity of serum ACE was 78.1%, specificity 90.0%, and PPV 43.6%, but the NPV was 97.0%. The test performed well, with area under curve (AUC) 0.897 (95% confidence interval [CI] 0.854-0.941). Serum ACE performed less well in distinguishing sarcoid uveitis in pediatric subjects, with sensitivity 60.0%, specificity 78.5%, and PPV 10.0%, but again NPV was high at 96.9% and AUC was 0.828 (95% CI 0.571-1.000). Serum ACE had a very high negative predictive value for sarcoid uveitis, eliminating the need for further screening tests in subjects with normal serum ACE, unless clinical suspicion was high.

Analysis of Age Distribution and Disease Presentation of 1269 Patients with Sarcoidosis.

While the incidence of sarcoidosis peaks between 20 and 39 years, it is comparatively low in elderly subjects. We sought to determine whether there are age-dependent differences in the demographic and laboratory characteristics of patients with sarcoidosis. We retrospectively collected information from our database using the International Classification of Disease (ICD) diagnostic code D86 between 2008 and 2014. Patients were divided into three groups: 20-39 years old (Group 1), 40-59 years old (Group 2), and 60-80 years old (Group 3). A total of 3988 patients with code of D86 were included in the study. After the exclusion of non-eligible patients, the number of cases in Groups 1, 2, and 3 were 276, 641, and 352, respectively. The groups were compared according to demographic characteristics, ICD diagnostic codes, and laboratory parameters. The ratio of female patients was significantly higher in Group 3 than in Groups 1 and 2 (p=0.000). There was no difference in diagnostic codes of the ICD subgroups between groups (p=0.19). While the level of blood-urea nitrogen was significantly higher in Group 3 patients than in other groups (p=0.000), serum angiotensin-converting enzyme (ACE) values were found to be significantly low in Group 3 (p=0.010). The mean ACE values did not differ between females and males (50.8±39.3 and 59.1±45.5 mg/dL, respectively) (p=0.18). The majority of patients with sarcoidosis were female in all age groups and pulmonary sarcoidosis was the most common presentation of the disease. Elderly patients (≥60 years) with sarcoidosis had lower serum ACE levels than younger patients.

Utility of angiotensin-converting enzyme activity in aqueous humor in the diagnosis of ocular sarcoidosis.

Purpose:Many studies include elevated activity of angiotensin-converting enzyme (ACE) in serum in sarcoidosis and in ocular sarcoidosis as well, but there are only a few analyzing ACE activities in aqueous humor. The aim of this study is to illuminate the diagnostic value of ACE in aqueous humor in patients with ocular sarcoidosis.Methods:We analyzed twenty patients with ocular sarcoidosis and 18 patients with nonocular involvement. All patients have biopsy-positive sarcoidosis of the lungs and/or mediastinal lymph nodes. Blood samples for ACE serum levels were obtained from all patients. Aqueous humor samples were taken by paracentesis with a 25-gauge needle in local anesthesia. With appropriate statistical tests, we compared ACE activity in serum and aqueous humor in patients with and without ocular sarcoidosis.Results:The majority of our patients with ocular sarcoidosis were female (12/20), also in the group with systemic sarcoidosis and without ocular involvement (12/6). Mean age of the whole analyzed group of sarcoidosis patients was 45 ± 6 years. There is no statistically significant difference in ACE activity in serum between two groups of patients (with and without ocular sarcoidosis). There is statistically significant difference in ACE activity in aqueous humor among patients with ocular and nonocular sarcoidosis. ACE activity in aqueous humor is significantly higher in patients with ocular sarcoidosis.Conclusion:Increased ACE activity in aqueous humor can point to a diagnosis of ocular sarcoidosis, without the need for ocular biopsy.

Angiotensin Converting Enzyme and Dipeptidyl Peptidase-IV Inhibitory, and Antioxidant Activities of a Blue Mussel (Mytilus edulis) Meat Protein Extract and Its Hydrolysates

ABSTRACTProtein extracted from mussel processing coproducts was hydrolyzed with four different food-grade enzyme preparations and assessed for angiotensin converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) inhibitory and oxygen radical antioxidant capacity (ORAC) activities. All hydrolysates tested showed higher activity than the intact protein. ACE and DPP-IV IC50 values in the range 1.13–3.34 and 0.33–2.43 mg mL−1, respectively, and ORAC values in the range 66.26–121.56 µmol trolox equivalents g–1 were obtained. These results suggest that some of the mussel meat protein hydrolysates may have potential as functional food ingredients for the management of diseases such as type II diabetes and hypertension.

Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis.

PurposeTo study the impact of soluble IL2 receptor (sIL2R), chest x-ray (CxR), and angiotensin-converting enzyme (ACE) as markers for sarcoidosis in uveitis patients.DesignRetrospective study.MethodsSerum concentrations of sIL2R and ACE were measured in patients with active uveitis. Those with elevated sIL2R and /or ACE values were examined for suspected systemic sarcoidosis.Main Outcome MeasureOur main outcome parameters were the specificity and sensitivity of sIL2R, CxR and ACE in screening for ocular sarcoidosis.ResultsWe measured 261 patients with uveitis for sarcoidosis using sIL2R and ACE between January 2008 and November 2011; sarcoidosis was been diagnosed using other tests (e.g. computer tomography, brochoalveolar lavage, biopsy) in 41 of 53 patients with elevated sIL2R values (>639 U/ml) and in one patient with normal sIL2R (582 U/ml). Their mean sIL2R value was 1310 U/ml, extending from 582 to 8659 U/ml. Only 9 patients, however, presented elevated ACE (>82 U/l). Their mean ACE value was 116.4 U/l, ranging from 84.1 to 175.5 U/l. IL2R specificity was 94% with 98% sensitivity. In contrast, ACE had a specificity of 99.5%, but a sensitivity of only 22%; the chest x-ray had a specificity of 100% with 50% sensitivity in detecting sarcoidosis. We observed the entire spectrum of uveitis: sixteen patients suffered from anterior, 8 from intermediate, 16 from posterior, and 2 from panuveitis.ConclusionsAn elevated level of soluble IL2R suggests sarcoidosis with uveitis more convincingly than ACE, making sIL2R a more effective marker parameter for sarcoidosis than ACE or chest x-ray in uveitis patients.

Angiotensin-converting enzyme for noninvasive assessment of liver fibrosis in autoimmune hepatitis.

There are no validated noninvasive markers of liver fibrosis in autoimmune hepatitis (AIH). An activated renin-angiotensin system (RAS) and its key element angiotensin-converting enzyme (ACE) have been implicated in the pathogenesis of hepatic fibrogenesis. We aimed to study the assumed role of activated RAS in the fibrogenic process and whether the serum concentration of ACE can predict different fibrosis stages in AIH. Serum samples of 73 consecutive patients who were diagnosed with AIH were analysed for ACE concentration. All patients underwent a liver biopsy. Serum ACE levels increased significantly for each fibrosis score. The median ACE was 45 U/l in patients with fibrosis score I, 54 U/l in patients with fibrosis score II, 68 U/l in patients with fibrosis score III and 87 U/l in patients with fibrosis score IV. For significant fibrosis (≤F2), a 56 U/l cut-off value of ACE had 95.5% sensitivity and 74.5% specificity, and receiver-operating characteristic curves showed an area under the curve (AUC) of 0.89. For advanced fibrosis (≤F3), a 64 U/l cut-off level of ACE had 85.2% sensitivity and 94.8% specificity, and AUC was 0.91. For cirrhosis, a 68 U/l cut-off level of ACE had 100% sensitivity and 84.4% specificity, and AUC was 0.95. Our results suggest that activated RAS may sustain hepatic fibrogenesis in AIH. Measurement of serum ACE offers an easy, accurate and inexpensive noninvasive method that differentiates significant from nonsignificant liver fibrosis in AIH. Blockade of RAS may exert beneficial effects on fibrosis progression in AIH.

The effects of ethylene treatment on the bioactivity of conventional and organic growing ‘Hayward’ kiwi fruit

Conventional (CG) and organically grown (OG) ‘Hayward’ kiwi fruits were submitted to ethylene treatment for 24h, followed by storage at 20°C for 10 days. Radical scavenging assays, UV spectrometry, fluorometry and chemometrical processing were used to determine the main kiwi fruits’ compounds. Firmness gradually decreased the longer they were stored, regardless of cultivation type. The rate of softening was slightly higher in OG than in CG fruits. The sensory value of kiwi fruit increased with reduced firmness and did not vary among cultivation types. Soluble solids content increased with the storage time, while acidity decreased in all fruits. Significant differences were found in polyphenols (189.98±12.75 and 219.43±15.73mg gallic acid equivalents (GAE)/100g fresh weight, FW) in the last day of treatment between treated conventional and organic kiwi fruits. The values of angiotensin-converting enzyme (ACE, %) – inhibiting activity (85.35±5.97 and 92.33±6.46) and electron donating abilities (EDA, %), using 1-diphenyl-2-picrylhydrazyl (56.80±5.87 and 70.63±6.67) showed significant differences between treated conventional and organic kiwi fruit. The antioxidant capacities by 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)diammonium salt (ABTS+μM TE/g DW) for conventional and organic kiwi fruits were 24.1±3.18 and 27.6±3.85 and by nitrite oxide scavenging assay (NSE, %) as 56.35±3.94 and 59.87±4.19 for conventional and organic kiwi fruits, respectively, but not always significant. The observed peaks by 3-D fluorescence showed differences in the position of the main peaks and their fluorescence intensity for conventional and organic kiwi fruits in comparison with non-ethylene-treated samples. In conclusion, ethylene treatment increased the bioactivity of organic and conventional kiwi fruits. The antioxidant values for organic fruits were significantly higher than for conventional and higher than in those not treated with ethylene. All fruits showed a high level of correlation between the contents of phenolic compounds and their antioxidant values. According to the bioactivity of kiwi fruits from two cultivation systems, a combination of these fruits has to be included in the diet.

Abstract TP115: The Increase In Plasma Angiotensinogen Is Associated With The Reduction Of Neurological Severity In Ischemic Stroke

Background and Purpose: Activation of the renin-angiotensin system (RAS) is a crucial factor leading to the development of hypertension and atherosclerosis, thereby causing brain infarction. However, the significance of RAS in the acute phase of brain infarction has not been fully understood. Our goal was to elucidate the significance of RAS in the acute phase of ischemic stroke. Methods: We measured plasma angiotensinogen (AGTN), angiotensin-converting enzyme (ACE) and some associated biomarkers, and examined clinical information in 171 ischemic stroke patients at 5 time points (days 0, 3, 7, 14 and 90) after the onset and 171 age- and gender-matched healthy subjects. Results: plasma AGTN values were increased in all stroke subtypes with different profiles in the acute phase of brain infarction: they were continuously elevated in atherothrombotic brain infarction, while they fluctuated in cardioembolic and lacunar infarction. On the other hand, plasma ACE values remained decreased from the onset to the 90 day in all subtypes, suggesting that the final product Angiotensin II (Ang II) was increased in the plasma and suppressed the production of ACE in a feedback mechanism during the period. AGTN values were not significantly associated with blood pressure. Among the biomarkers we tested, AGTN was highly associated with adrenocorticotropic hormone (ACTH) (r = 0.62, p &lt; 0.0001), but not with other pituitary hormones and inflammatory cytokines (IL-1b, IL-6 and TNFa). Neurological severity assessed by NIH Stroke Scale at day 0 was associated negatively with the AGTN values, while positively with ACE. Conclusions: Ang II production may be increased in the acute phase of brain infarction with decreased plasma ACE in all subtypes and different profiles of AGTN according to stroke subtypes. Increased production of AGTN leading to the increase in Ang II appears to be associated with the reduction of neurological severity in ischemic stroke.

Aliskiren, ALTITUDE, and the implications for ATMOSPHERE

Blockade of the renin–angiotensin system (RAS) is a core therapeutic strategy in systolic heart failure.1 The value of angiotensin-converting enzyme (ACE) inhibitors was proven in two pivotal trials conducted >20 years ago. More recently, angiotensin receptor blockers (ARBs) have also been shown to be beneficial in systolic heart failure both as an alternative to and when added to an ACE inhibitor. Separately, mineralocorticoid receptor antagonists (MRAs) reduce mortality and morbidity when added to an ACE inhibitor or ARB (MRAs are not considered further here). The latest approach to RAS blockade to be tested in clinical practice is renin inhibition. Currently the efficacy and safety of the renin inhibitor aliskiren is being tested in two clinical trials in heart failure, the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE) and the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT), described previously in this journal.2,3 However, on 20 December 2011, treatment in another study, the Aliskiren Trial In Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE), was stopped on the recommendation of its Data Monitoring Committee (DMC).2,3 ALTITUDE was comparing placebo or aliskiren 300 mg once daily, added to background ACE inhibitor or ARB therapy in patients with diabetes and either (i) increased urinary albumin excretion or (ii) both a reduced estimated glomerular filtration rate (eGFR 30–60 mL/min/1.73 m2) and established cardiovascular disease. The primary outcome in ALTITUDE is a composite of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, end-stage renal disease, renal death, or doubling of baseline serum creatinine concentration, sustained for at least a month. As a result of the DMC recommendation, ALTITUDE is currently being closed out in an orderly fashion. The basis of the DMC recommendation was futility (i.e. no prospect of demonstrating the treatment benefit anticipated in the protocol) as well as safety concerns. These concerns included renal dysfunction, hyperkalaemia, and hypotension (which are unsurprising) as well as an excess of strokes. In the publically released information, the number of patients experiencing a non-fatal stroke in the placebo group was 85 (2.0%) and 112 (2.6%) in the aliskiren group (nominal, unadjusted, P-value 0.04).6 Although this unexpected finding has provoked concern and discussion, the reported numbers do not represent the final number of events in ALTITUDE (at the time of the DMC's recommendation it was estimated that approximately a third of events remained to be collected and adjudicated). Consequently, while the apparent imbalance in strokes may persist or increase, it may also attenuate. Furthermore, given all prior data relating use of antihypertensive therapy to a reduced incidence of stroke in patients with diabetes, it is also possible that the imbalance in strokes represents a chance finding.7–9 In response to these findings it has been recommended that dual aliskiren and ACE inhibitor/ARB therapy not be used in patients with both hypertension (the current indication for aliskiren) and diabetes or moderate to severe renal dysfunction (eGFR <60 mL/min/1.73 m2).10 This recommendation has led to questions about the use of dual aliskiren therapy in patients with diabetes in the ongoing ATMOSPHERE trial (and, to a lesser extent, also the ASTRONAUT trial which has almost finished recruitment and will complete follow-up this year). In ATMOSPHERE, patients with systolic heart failure and an elevated B-type natriuretic peptide (BNP) or N-terminal pro BNP ( NT-proBNP) concentration are randomized in equal proportions to receive either enalapril 10 mg twice daily, aliskiren 300 mg once daily, or the combination of both drugs.3 ATMOSPHERE is an event-driven trial with a primary composite outcome of cardiovascular death or heart failure hospitalization. We believe that the preliminary results of ALTITUDE should not lead to any alteration in the conduct of ATMOSPHERE. The reasons for taking this view are discussed in detail below.

Clinical evaluation of enalapril maleate and furosemide usage in dogs with degenerative myxomatous mitral valve, CHF functional class Ib

Degenerative myxomatous mitral valve (DMMV) is a heart disease of high incidence in small animal clinical medicine, affecting mainly older dogs and small breeds. Thus, a scientific investigation was performed in order to evaluate the clinical use of the medicines furosemide and enalapril maleate in dogs with this disease in CHF functional class Ib before and after the treatment was established. For this purpose 16 dogs with the given valve disease were used, separated into two groups: the first received furosemide (n=8) and the second received enalapril maleate (n=8) throughout 56 days. The dogs were evaluated in four stages (T0, T14, T28 and T56 day) in relation to clinical signs, hematological, biochemical and serum assessment, which included serum angiotensin converting enzyme (ACE) and aldosterone, as well as radiography, electrocardiography, Doppler-echocardiography and blood pressure. The results regarding the clinical, hematological and serum chemistry evaluations revealed no significant changes in both groups, but significant reductions in the values of ACE and aldosterone in the group receiving enalapril maleate were verified. The radiographic examination revealed reductions of VHS values and variable Pms wave of the electrocardiogram in both groups, but no changes in blood pressure values were identified. The echocardiogram showed a significant decrease of the variables LVDd/s in the studied groups and the FS% in animals that received only enalapril. Therefore, analysis of results showed that monotherapy based on enalapril maleate showed better efficiency of symptoms control in patients with CHF functional class Ib.

Biomarkers in Serbian patients with Gaucher disease

Objectives The aim of the study was to evaluate the efficiency of the biomarkers chitotriosidase (Chito), total acid phosphatase (TACP), angiotensin converting enzyme (ACE) and ferritin in the diagnosis of Gaucher disease (GD) and to assess the utility of biomarkers for monitoring the effects of enzyme replacement therapy (ERT). Design and methods Forty treatment-naive Gaucher patients were studied. 27/40 GP were put on ERT and monitored every 6 months. Results The baseline median values of Chito, TACP, ACE and ferritin were highly elevated in GP: 10216 nmol/mL/h, 26.1 U/L, 253 U/L, 515 μg/L, and 555 μg/L, respectively. The only significant difference between mild and moderate GP subgroups is observed for Chito activity (p = 0.0116). During ERT, Chito showed the steepest decrease in regard to TACP and ACE, mainly within the first year (71.4%). Conclusions Among these biomarkers, Chito proved to be the most useful biomarker for diagnosing GD and monitoring the ERT.

The Relationship Between Angiotensin Converting Enzyme Insertion/deletion Polymorphism and Age-related Macular Degeneration

Background: To assess the role of serum angiotensin converting enzyme (ACE) levels and ACE insertion /deletion (I/D) genetic polymorphism in Turkish age-related macular degeneration (AMD) patients and control subjects.Methods: This prospective study consisted of 78 patients with AMD and 68 control subjects. The I/D polymorphism of the ACE was carried out by polymerase chain reaction. Serum ACE levels were determined by using the ELISA method.Results: There was no significant difference in the mean serum values of ACE between the control and patient groups (p = 0.107). The genotypic frequencies of ACE polymorphism in the control and patient groups were not significantly different either (p = 0.218).Conclusion: We could not show a significant role of serum ACE levels and ACE I/D genetic polymorphism in the etiopathogenesis of AMD in the Turkish population, and our findings did not support the idea that serum ACE levels and ACE DD genotype were risk factors for AMD.

Bone events and evolution of biologic markers in Gaucher disease before and during treatment

IntroductionKnown biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date.MethodsBE of 62 treated patients, among the 73-patient cohort followed at Beaujon Hospital, Clichy, France, were described with Kaplan-Meier curves, and linear-mixed models were used to analyze their biomarker changes and the influence of several covariates (splenectomy, diagnosis year, genotype, age at diagnosis and sex).ResultsBE occurred before (54 events in 21 patients), but also during, ERT (12 events in 10 patients), with respective frequencies (95% confidence interval) at 10 years of 22.4% (13.3 to 36.3) and 20.0% (10.2 to 36.9). Biomarker slope changes before and during ERT differed significantly for platelets (+190/mm3/year and 7,035/mm3/year, respectively; P < 0.0001) and ferritin (+4% and -14%; P < 0.0001). High ferritin levels and low platelet counts at ERT onset were significantly associated with BE during ERT (P = 0.019 and 0.039, respectively). Covariates significantly influenced biomarker changes (baseline and/or slope): splenectomy affected platelets (baseline and changes), TRAP changes and chitotriosidase changes; diagnosis date influenced ACE and TRAP baseline values; and genotype influenced chitotriosidase baseline and changes.ConclusionsPlatelet counts and ferritin levels and their slope changes at ERT onset seem to predict BE during treatment. Biomarker baseline values and changes are dependent on several covariables.

Integrating Serum Biomarkers and Dose–volume Metrics to Predict Radiation Pneumonitis

Published reports have correlated the development of radiation pneumonitis (RP) among NSCLC patients to various biomarkers, dose–volume (D-V) metrics, and anatomic factors. This study aims to improve predictive models for the development of RP by integrating multiple serum biomarkers and D-V metrics in patients receiving radiotherapy for NSCLC. In the present study, we examine the role serum biomarkers play in predicting pneumonitis and the potential for combining these markers with anatomic information gathered from dose–volume assessment. We analyzed a cohort of 19 inoperable Stage III NSCLC patients accrued prospectively, who received radiotherapy treatment with a mean follow-up of 1 year. Three events were identified as RP (RTOG Grade ≥3). Serum was collected from the patients immediately prior to RT, during (at 3 weeks), at the conclusion of RT, as well as at 3-months post-RT. Concentrations of three potential radiation pneumonitis biomarkers, namely angiotensin converting enzyme (ACE), transforming growth factor-β (TGF-β), and interleukin-6 (IL-6), were determined using enzyme-linked immunoassays. Previously reported D-V metrics, including mean dose to both lungs minus the GTV and GTV location in the superior-inferior direction, were also extracted from the patients' radiation therapy planning CT scans. Models based on logistic regression, combining the candidate biomarkers and a previous dose–volume model based on the mean dose and GTV position (Bradley et al., IJROBP 2007), were evaluated. Statistic association was measured using Spearman's rank correlation (Rs). None of the markers (biologic or dosimetric) was individually significant on univariate analysis. With multivariate logistic regression model building, however, models based on adding either normalized midtherapy ACE (Rs = 0.560; p = 0.008) or IL-6 levels (Rs = 0.730; p = 0.013) to the previously reported mean lung dose and GTV position metrics (the Bradley model) were significant. A model based on the midtherapy TGF-β concentration, added to the Bradley model, but was less predictive (Rs = 0.346; p = 0.067). Improved significance was achieved by including both midtherapy ACE and IL-6 values with the Bradley model (Rs = 0.845; p = 0.004). On leave-one-out cross validation, the predictive Rs improved from 0.18 to 0.34 by adding ACE and IL-6 to the Bradley model. In our preliminary analysis, we show that physical and biologic markers can be combined to improve the prediction of RP, with an 89% improvement in prediction ability when multiple biomarkers (IL-6 and ACE) are combined with dose–volume information. However, analysis on larger datasets will be required to elucidate and verify these observations.