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Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial).
Trippel, TD, Van Linthout, S, Westermann, D, Lindhorst, R, Sandek, A, Ernst, S, Bobenko, A, Kasner, M, Spillmann, F, González, A, et al
European journal of heart failure. 2018;(3):460-470
Abstract
AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C-terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels. METHODS AND RESULTS We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel-group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (≥110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) >29 mL/m2 and abnormal PIP levels (≥70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m2 , 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of >60%, a left ventricular mass index >120 g/m2 , an E/e' ratio of 14, and a LAVI of 40 mL/m2 with a NT-proBNP of 174 ng/L and a 6-minute walk distance of 421 m. Mean per cent change in PIP was 2.63 ± 5.68% (±SEM) in torasemide vs. 2.74 ± 6.49% in furosemide (P = 0.9898) treated patients. Torasemide was not superior to furosemide in improving functional capacity, diastolic function, quality of life, or neuroendocrine activation. CONCLUSION In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted.
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The Use of Glycomacropeptide in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis.
Pena, MJ, Pinto, A, Daly, A, MacDonald, A, Azevedo, L, Rocha, JC, Borges, N
Nutrients. 2018;(11)
Abstract
In phenylketonuria (PKU), synthetic protein derived from L-amino acids (AAs) is essential in a low-phenylalanine (Phe) diet. Glycomacropeptide (GMP), an intact protein, is very low in Phe in its native form. It has been modified and adapted for PKU to provide an alternative protein source through supplementation with rate-limiting amino acids (GMP-AAs), although it still contains residual Phe. This review aims to systematically evaluate published intervention studies on the use of GMP-AAs in PKU by considering its impact on blood Phe control (primary aim) and changes in tyrosine control, nutritional biomarkers, and patient acceptability or palatability (secondary aims). Four electronic databases were searched for articles published from 2007 to June 2018. Of the 274 studies identified, only eight were included. Bias risk was assessed and a quality appraisal of the body of evidence was completed. A meta-analysis was performed with two studies with adequate comparable methodology which showed no differences between GMP-AAs and AAs for any of the interventions analysed. This work underlines the scarcity and nature of studies with GMP-AAs interventions. All were short-term with small sample sizes. There is a need for better-designed studies to provide the best evidence-based recommendations.
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Eccentric Overload Muscle Damage is Attenuated By a Novel Angiotensin- (1-7) Treatment.
Becker, LK, Totou, N, Moura, S, Kangussu, L, Millán, RDS, Campagnole-Santos, MJ, Coelho, D, Motta-Santos, D, Santos, RAS
International journal of sports medicine. 2018;(10):743-748
Abstract
The development of new strategies to attenuate exercise-induced muscle damage may be helpful for training regimens. The aim of this study was to determine whether a oral formulation of angiotensin Ang-(1-7)[HPβCD/Ang-(1-7)] is effective to reduce pain, and muscle damage markers after eccentric-overload exercise. HPβCD (Placebo) and HPβCD/Ang-(1-7) (Ang-(1-7) group were treated for 7 days (one capsule/day). The pain was measured by visual analogue scale, maximal strength (MS) using force platform. Blood samples were collected for cytokines and creatine kinase (CK) analysis. The Ang-(1-7)-treated group reported less pain immediately (3.46±0.64 vs. placebo 3.80±0.77 cm) and 24 h after exercise (3.07±0.71 vs. 3.73±0.58 cm placebo) and higher MS at 24 h (24±12 N) and 48 h (30±15 N) vs. placebo (-8±9 N and -10±9 N). The CK for Ang-(1-7) (0.5±0.1 and 0.9±0.2 U/L) were lower at 48 and 72 h vs. placebo (fold changes of 1.7±0.5 and 1.5±0.3 U/L). The TNF-α level was lower in the treated group post-exercise (38±2.5 pg/ml) vs. placebo (45±2.9 pg/ml) but no significant changes were observed for IL-6 and IL-10. Our data indicate that treatment with Ang-(1-7) may attenuate pain, some of the muscle damage markers and improves performance following eccentric exercise.
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N-Terminal Pro-Brain Natriuretic Peptide Concentrations After Hypertensive Intracerebral Hemorrhage: Relationship With Hematoma Size, Hyponatremia, and Intracranial Pressure.
Li, F, Chen, QX, Xiang, SG, Yuan, SZ, Xu, XZ
Journal of intensive care medicine. 2018;(12):663-670
Abstract
INTRODUCTION The role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with hypertensive intracerebral hemorrhage (HICH) is poorly understood. This study aimed to investigate the secretion pattern of NT-proBNP in patients with HICH and to assess its relationship with hematoma size, hyponatremia, and intracranial pressure (ICP). METHODS This prospective study enrolled 147 isolated patients with HICH. Blood samples were obtained from each patient, and values of serum NT-proBNP, hematoma size, blood sodium, and ICP were collected for each patient. RESULTS The peak-to-mean concentration of NT-proBNP was 666.8 ± 355.1 pg/mL observed on day 4. The NT-proBNP levels in patients with hematoma volume >30 mL were significantly higher than those in patients with hematoma volume <30 mL ( P < .05). In patients with severe HICH, the mean concentration of NT-proBNP was statistically higher than that in patients with mild-moderate HICH ( P < .05), and the mean level of NT-proBNP in hyponatremia group was significantly higher than that in normonatremic group ( P < .05). In addition, the linear regression analysis indicated that serum NT-proBNP concentrations were positively correlated with ICP ( r = .703, P < .05) but negatively with blood sodium levels only in patients with severe HICH ( r = -.704, P < .05). The serum NT-proBNP levels on day 4 after admission were positively correlated with hematoma size ( r = .702, P < .05). CONCLUSION The NT-proBNP concentrations were elevated progressively and markedly at least in the first 4 days after HICH and reached a peak level on the fourth day. The NT-proBNP levels on day 4 were positively correlated with hematoma size. There was a notable positive correlation between plasma NT-proBNP levels and ICP in patients with severe HICH. Furthermore, only in patients with severe HICH, the plasma NT-proBNP levels presented a significant correlation with hyponatremia, which did not occur in patients with mild-moderate HICH.
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Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study.
Timmers, M, Streffer, JR, Russu, A, Tominaga, Y, Shimizu, H, Shiraishi, A, Tatikola, K, Smekens, P, Börjesson-Hanson, A, Andreasen, N, et al
Alzheimer's research & therapy. 2018;(1):85
Abstract
BACKGROUND β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aβ1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. RESULTS In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aβ1-40 reductions, respectively. The trend of the reduction was similar across the Aβ1-37, Aβ1-38, and Aβ1-42 fragments in both atabecestat dose groups, consistent with Aβ1-40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. CONCLUSIONS JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. TRIAL REGISTRATION ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.
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N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts the cardio-renal response to aliskiren in patients with type 2 diabetes at high renal and cardiovascular risk.
Idzerda, NMA, Persson, F, Pena, MJ, Brenner, BM, Brunel, P, Chaturvedi, N, McMurray, JJ, Parving, HH, de Zeeuw, D, Heerspink, HJL
Diabetes, obesity & metabolism. 2018;(12):2899-2904
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Abstract
Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.
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Amyloid-β/Drug Interactions from Computer Simulations and Cell-Based Assays.
Nguyen, PH, Del Castillo-Frias, MP, Berthoumieux, O, Faller, P, Doig, AJ, Derreumaux, P
Journal of Alzheimer's disease : JAD. 2018;(s1):S659-S672
Abstract
Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer's disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40/Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.
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Favorable Vascular Actions of Angiotensin-(1-7) in Human Obesity.
Schinzari, F, Tesauro, M, Veneziani, A, Mores, N, Di Daniele, N, Cardillo, C
Hypertension (Dallas, Tex. : 1979). 2018;(1):185-191
Abstract
Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1-mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1-7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1-7) on vasodilator tone and endothelin-1-dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1-7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow (P=0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; P>0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1-7) administration compared with saline (both P>0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1-7) (P=0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified (P=0.91). Finally, Ang-(1-7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; P<0.001); nitric oxide inhibition by l-N-monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1-7 Ang-(1-7) (P=0.69). Our findings indicate that in obese patients Ang-(1-7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1-dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1-7) to counteract the hemodynamic abnormalities of human obesity.
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Metabolomic profiling implicates adiponectin as mediator of a favorable lipoprotein profile associated with NT-proBNP.
Masuch, A, Pietzner, M, Bahls, M, Budde, K, Kastenmüller, G, Zylla, S, Artati, A, Adamski, J, Völzke, H, Dörr, M, et al
Cardiovascular diabetology. 2018;(1):120
Abstract
BACKGROUND The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an important biomarker for the diagnosis of heart failure. Apart from this and only recently recognized, NT-proBNP levels associate with higher HDL- and lower LDL-cholesterol levels comprising a favorable blood lipid profile. To further examine this observation, the lipoprotein profile in relation to NT-proBNP was examined in-depth by proton nuclear magnetic resonance spectroscopy (1H-NMR). We complemented this investigation with a state-of-the-art untargeted metabolomics approach. METHODS Lipoprotein particles were determined by 1H-NMR spectroscopy in 872 subjects without self-reported diabetes from the population-based Study of Health in Pomerania (SHIP)-TREND with available NT-proBNP measurements. Comprehensive metabolomics data for plasma and urine samples were obtained. Linear regression models were performed to assess the associations between serum concentrations of NT-proBNP and the metabolites/lipoprotein particles measured in plasma or urine. RESULTS An increase in serum NT-proBNP was associated with a benefical lipoprotein profile, including a decrease in VLDL, IDL and LDL-particles along with an increase in large HDL particles. These findings were replicated in a second independent cohort. Serum concentrations of NT-proBNP showed significant inverse associations with seven plasma metabolites while associations with 39 urinary metabolites, mostly comprising amino acids and related intermediates, were identified. Mediation analyses revealed adiponection as mediating factor for the associations observed with lipoproteins particles. CONCLUSIONS Most of the metabolic changes associated with NT-proBNP implicate significant influence on the blood lipid profile besides vasodilatory and the diuretic action of BNP signaling. Our data suggest that the more favorable lipoprotein profile as associated with elevated NT-proBNP concentrations in mainly cardiac healthy individuals might relate to adiponectin signaling indicating even indirect cardio-protective effects for NT-proBNP.
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Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF).
Januzzi, JL, Butler, J, Fombu, E, Maisel, A, McCague, K, Piña, IL, Prescott, MF, Riebman, JB, Solomon, S
American heart journal. 2018;:130-136
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Abstract
BACKGROUND Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. METHODS This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. CONCLUSIONS Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183).