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Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib.
Tardif, JC, Dubé, MP, Pfeffer, MA, Waters, DD, Koenig, W, Maggioni, AP, McMurray, JJV, Mooser, V, White, HD, Heinonen, T, et al
American heart journal. 2020;:157-165
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Abstract
The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.
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The Effect of Continuous Ventilation on Thiol-Disulphide Homeostasis and Albumin-Adjusted Ischemia-Modified Albumin During Cardiopulmonary Bypass.
Ozgunay, SE, Ozsin, KK, Ustundag, Y, Karasu, D, Ozyaprak, B, Balcı, B, Erel, O, Yavuz, S
Brazilian journal of cardiovascular surgery. 2019;(4):436-443
Abstract
OBJECTIVE To investigate the effect of continuous lung ventilation with low tidal volume on oxidation parameters, such as thiol/disulphide homeostasis and albumin-adjusted ischemia-modified albumin (AAIMA), during cardiopulmonary bypass (CBP) in coronary artery bypass grafting (CABG). METHODS Seventy-four patients who underwent elective CABG with CPB were included in the study. Blood samples were taken in the preoperative period, 10 minutes after CPB, and six and 24 hours postoperatively. Patients were assigned to the continuous ventilation group (Group 1, n=37) and the non-ventilated group (Group 2, n=37). The clinical characteristics, thiol/disulphide homeostasis, ischemia-modified albumin (IMA), and AAIMA levels of the patients were compared. RESULTS A significant difference was found between the groups regarding native thiol, total thiol, and IMA levels at the postoperative 24th hour (P=0.030, P=0.031, and P=0.004, respectively). There was no difference between the groups in terms of AAIMA. AAIMA levels returned to preoperative levels in Groups 1 and 2, at the 6th and 24th postoperative hours, respectively. Length of hospital stay was significantly shorter in Group 1 (P<0.001) than in Group 2. CONCLUSION Continuous ventilation during CPB caused an increase in native and total thiol levels, an earlier return of AAIMA levels, and shorter hospital stay. Continuous ventilation may reduce the negative effects of CPB on myocardium (Table 2, Figure 1, and Reference 31).
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The Effect of Different Intraabdominal Pressures on Thiol/Disulfide Homeostasis in Children Who Underwent Ambulatory Laparoscopic Surgery: A Prospective Randomized Study.
Ozgunay, SE, Ustundag, Y, Karasu, D, Uguz, I, Erel, O, Korfali, G, Kaya, M
Journal of laparoendoscopic & advanced surgical techniques. Part A. 2018;(9):1142-1147
Abstract
BACKGROUND Thiol/disulfide homeostasis is a significant parameter in determining the oxidative stress response after ischemia and reperfusion. We aimed to investigate the effects of applying different intraabdominal pressure (IAP) on thiol/disulfide homeostasis, ischemia-modified albumin (IMA) levels, and hemodynamics in pediatric laparoscopic surgery. MATERIALS AND METHODS Blood samples were collected from 36 pediatric patients who were planned to undergo laparoscopic surgery for nonpalpable testis or varicocele under general anesthesia, immediately after intubation as the baseline and 5 minutes after abdominal desufflation for determining the thiol/disulfide, and IMA levels. The patients were divided into two groups; group 1 received a pneumoperitoneum pressure of 8 mm Hg (n = 18), and group 2 received 12 mm Hg (n = 18). The clinical characteristics and thiol/disulfide homeostasis and IMA levels of the patients were compared. RESULTS No difference was detected regarding the clinical features between the groups. The comparison after intubation and after desufflation in group 1 demonstrated lower native thiol (453 ± 67 versus 422 ± 57 μmol/L, P = .059) and total thiol (497 ± 73 versus 466 ± 62 μmol/L, P = .061) levels, which was statistically insignificant. The serum native thiol level was found lower than baseline in group 2 where a 12 mm Hg IAP was applied, this difference was not statistically significant (429 ± 47 versus 412 ± 53 μmol/L, P = .078). The comparison of serum IMA levels after desufflation with the baseline (0.505 ± 0.018 versus 0.632 ± 0.022) in group 2 was found statistically significantly high (P = .031). The comparison of the perioperative heart rate and SpO2 levels with before induction was found statistically insignificant. CONCLUSIONS Neither of 8 nor 12 mm Hg IAPs in pediatric laparoscopic surgery caused any changes in novel indicators of thiol/disulfide homeostasis parameters; however, 12 mm Hg IAP increased the levels of IMA.
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Effect of Omega-3 and Vitamins E + C Supplements on the Concentration of Serum B-Vitamins and Plasma Redox Aminothiol Antioxidant Status in Elderly Men after Strength Training for Three Months.
Stea, TH, Stølevik, SB, Berntsen, S, Ezzathkah Bastani, N, Paulsen, G, Lohne Seiler, H, Hetlelid, KJ, Blomhoff, R, Mansoor, MA
Annals of nutrition & metabolism. 2016;(2):145-55
Abstract
BACKGROUND Data on redox plasma aminothiol status in individuals on strength training are very limited. Therefore, we studied the effect of omega-3 and vitamins E + C supplementation on the concentration of B-vitamins and redox aminothiol status in elderly men after strength training for 3 months. METHODS Healthy men, age 60 ± 6 (mean ± SD) were randomly divided into 3 groups: group I received placebo (n = 17), group II consumed omega-3 (700 mg, n = 17), and group III consumed vitamins E + C (235 mg +1 g, n = 16) daily for 3 months. All participants completed a strength training program for the same period. RESULTS The concentration of serum vitamin B12 decreased and the concentration of serum folate increased in group I after the intervention (p = 0.01, p = 0.009). The concentration of plasma 5-pyridoxal phosphate decreased in groups II and III (p = 0.03 and p = 0.01), whereas the concentration of serum uric acid decreased only in group II (p = 0.02). We detected an increase in the concentration of reduced form of aminothiols in all groups (p < 0.001). The red/ox plasma aminothiol status was significantly changed in all groups after the intervention (p < 0.05). CONCLUSION Omega-3 and vitamins E + C supplementation affect the concentrations of serum B-vitamins and redox plasma aminothiol status in healthy elderly men on strength training.
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Serum free thiols in chronic heart failure.
Koning, AM, Meijers, WC, Pasch, A, Leuvenink, HGD, Frenay, AS, Dekker, MM, Feelisch, M, de Boer, RA, van Goor, H
Pharmacological research. 2016;:452-458
Abstract
Oxidative stress is a key element of the pathophysiology of heart failure (HF). As free thiols are readily oxidized by reactive oxygen and sulfur species, their circulating level may directly reflect the systemic redox status. This study addresses the role of serum free thiols in chronic HF, which is of particular interest as free thiols are amenable to therapeutic modulation and thus are a potential target for therapy. Free thiols were measured in serum of 101 previously characterized stable chronic HF patients (93% male, age 63.7±10.0y, left ventricular ejection fraction 34.6±8.2%), adjusted for total serum protein, and subsequently analysed for associations with clinical and outcome parameters. The mean serum free thiol concentration was 3.6±0.5μM/g protein. Patients with above-average levels were younger, had better renal function, lower levels of NT-proBNP and PTH, and higher levels of cholesterol. Furthermore, above-average levels were associated with favourable disease outcome, i.e. a decreased rehospitalisation rate and increased patient survival (HR 0.27 (95% CI 0.11-0.62), P=0.002) independent of associated clinical parameters, age and PTH. After adjustment for cholesterol or established prognostic factors in HF, eGFR and NT-proBNP the association was no longer significant, suggesting involvement of these variables in a common pathophysiological pathway. This exploratory study demonstrates favourable associations of serum free thiols with markers of HF severity and prognosis as well as disease outcome, which should be further investigated in larger prospective studies. Restoring redox status by therapeutic modulation of free thiols may be a promising strategy to improve disease outcome in CHF.
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Treatment With Dalcetrapib Modifies the Relationship Between High-Density Lipoprotein Cholesterol and C-Reactive Protein.
Pitts, R, Gunzburger, E, Ballantyne, CM, Barter, PJ, Kallend, D, Leiter, LA, Leitersdorf, E, McMurray, JJ, Nicholls, SJ, Niesor, EJ, et al
Journal of the American College of Cardiology. 2016;(22):2488-2490
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Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib.
Tardif, JC, Rhéaume, E, Lemieux Perreault, LP, Grégoire, JC, Feroz Zada, Y, Asselin, G, Provost, S, Barhdadi, A, Rhainds, D, L'Allier, PL, et al
Circulation. Cardiovascular genetics. 2015;(2):372-82
Abstract
BACKGROUND Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile. METHODS AND RESULTS We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78). CONCLUSIONS The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene. CLINICAL TRIAL INFORMATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.
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Treatment of low HDL-C subjects with the CETP modulator dalcetrapib increases plasma campesterol only in those without ABCA1 and/or ApoA1 mutations.
Niesor, EJ, Kallend, D, Bentley, D, Kastelein, JJ, Kees Hovingh, G, Stroes, ES
Lipids. 2014;(12):1245-9
Abstract
We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with familial combined hyperlipidemia (FCH) or familial hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9%) and FCH (+18.4, +12.1%), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (-31.5, +120.9%) and FCH (-26.6, +111.9%), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0%), but only campesterol was markedly increased in FCH (+25.0%, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.
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The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial.
Ray, KK, Ditmarsch, M, Kallend, D, Niesor, EJ, Suchankova, G, Upmanyu, R, Anzures-Cabrera, J, Lehnert, V, Pauly-Evers, M, Holme, I, et al
European heart journal. 2014;(27):1792-800
Abstract
AIMS: The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. METHODS AND RESULTS The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. CONCLUSIONS High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.
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Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise.
Michailidis, Y, Karagounis, LG, Terzis, G, Jamurtas, AZ, Spengos, K, Tsoukas, D, Chatzinikolaou, A, Mandalidis, D, Stefanetti, RJ, Papassotiriou, I, et al
The American journal of clinical nutrition. 2013;(1):233-45
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Abstract
BACKGROUND The major thiol-disulfide couple of reduced glutathione (GSH) and oxidized glutathione is a key regulator of major transcriptional pathways regulating aseptic inflammation and recovery of skeletal muscle after aseptic injury. Antioxidant supplementation may hamper exercise-induced cellular adaptations. OBJECTIVE The objective was to examine how thiol-based antioxidant supplementation affects skeletal muscle's performance and redox-sensitive signaling during the inflammatory and repair phases associated with exercise-induced microtrauma. DESIGN In a double-blind, crossover design, 10 men received placebo or N-acetylcysteine (NAC; 20 mg · kg(-1) · d(-1)) after muscle-damaging exercise (300 eccentric contractions). In each trial, muscle performance was measured at baseline, after exercise, 2 h after exercise, and daily for 8 consecutive days. Muscle biopsy samples from vastus lateralis and blood samples were collected before exercise and 2 h, 2 d, and 8 d after exercise. RESULTS NAC attenuated the elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factor κB phosphorylation, and the decrease in strength during the first 2 d of recovery. NAC also blunted the increase in phosphorylation of protein kinase B, mammalian target of rapamycin, p70 ribosomal S6 kinase, ribosomal protein S6, and mitogen activated protein kinase p38 at 2 and 8 d after exercise. NAC also abolished the increase in myogenic determination factor and reduced tumor necrosis factor-α 8 d after exercise. Performance was completely recovered only in the placebo group. CONCLUSION Although thiol-based antioxidant supplementation enhances GSH availability in skeletal muscle, it disrupts the skeletal muscle inflammatory response and repair capability, potentially because of a blunted activation of redox-sensitive signaling pathways. This trial was registered at clinicaltrials.gov as NCT01778309.