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Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function.
Laurila, S, Rebelos, E, Lahesmaa, M, Sun, L, Schnabl, K, Peltomaa, TM, Klén, R, U-Din, M, Honka, MJ, Eskola, O, et al
American journal of physiology. Endocrinology and metabolism. 2022;(1):E54-E62
Abstract
The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG) positron emission tomography. Kidney function was measured with [18F]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means ± SD, 15.5 ± 7.4 vs. 9.7 ± 4.9 μmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [18F]FDG renal clearance (44.5 ± 5.4 vs. 39.5 ± 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 ± 9.8 vs. 6.0 ± 5.2 ΔmL/min/1.73 m2, 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure.NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.
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Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients-a description of the DAPACARD study.
Åkerblom, A, Oldgren, J, Latva-Rasku, A, Johansson, L, Lisovskaja, V, Karlsson, C, Oscarsson, J, Nuutila, P
Upsala journal of medical sciences. 2019;(1):59-64
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BACKGROUND Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels. METHODS DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET). CONCLUSION The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.
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Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study.
Shroff, R, Bayazit, A, Stefanidis, CJ, Askiti, V, Azukaitis, K, Canpolat, N, Agbas, A, Anarat, A, Aoun, B, Bakkaloglu, S, et al
BMC nephrology. 2018;(1):199
Abstract
BACKGROUND Cardiovascular disease is prevalent in children on dialysis and accounts for almost 30% of all deaths. Randomised trials in adults suggest that haemodiafiltration (HDF) with high convection volumes is associated with reduced cardiovascular mortality compared to high-flux haemodialysis (HD); however paediatric data are scarce. We designed the haemodiafiltration, heart and height (3H) study to test the hypothesis that children on HDF have an improved cardiovascular risk profile, growth and nutritional status and quality of life, compared to those on conventional HD. We performed a non-randomised parallel-arm intervention study within the International Paediatric Haemodialysis Network Registry comparing children on HDF and conventional HD to determine annualised change in cardiovascular end-points and growth. Here we present the 3H study design and baseline characteristics of the study population. METHODS 190 children were screened and 177 (106 on HD and 71 on HDF) recruited from 28 centres in 10 countries. There was no difference in age, underlying diagnosis, comorbidities, previous dialysis therapy, dialysis vintage, residual renal function, type of vascular access or blood flow between HD and HDF groups. High flux dialysers were used in 63% of HD patients and ultra-pure water was available in 52%. HDF patients achieved a median convection volume of 13.3 L/m2; this was associated with the blood flow rate only ((p = 0.0004, r = 0.42) and independent of access type (p = 0.38). DISCUSSION This is the largest study on dialysis outcomes in children that involves deep phenotyping across a wide range of cardiovascular, anthropometric, nutritional and health-related quality of life measures, to test the hypothesis that HDF leads to improved cardiovascular and growth outcomes compared to conventional HD. TRIAL REGISTRATION ClinicalTrials.gov: NCT02063776 . The trial was prospectively registered on the 14 Feb 2014.
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Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block.
Vicente, J, Johannesen, L, Hosseini, M, Mason, JW, Sager, PT, Pueyo, E, Strauss, DG
PloS one. 2016;(12):e0163619
Abstract
BACKGROUND Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. METHODS AND RESULTS In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). CONCLUSIONS Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block. TRIAL REGISTRATION NCT02308748 and NCT01873950.
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Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.
Iqbal, J, Andrew, R, Cruden, NL, Kenyon, CJ, Hughes, KA, Newby, DE, Hadoke, PW, Walker, BR
The Journal of clinical endocrinology and metabolism. 2014;(3):915-22
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CONTEXT Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. OBJECTIVE This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. PARTICIPANTS AND INTERVENTIONS Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. RESULTS There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. CONCLUSIONS Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart.
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Efficacy of thyroid blockade on thyroid radioiodine uptake in 123I-mIBG imaging.
Friedman, NC, Hassan, A, Grady, E, Matsuoka, DT, Jacobson, AF
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2014;(2):211-5
Abstract
UNLABELLED Although iodinated radiopharmaceuticals usually contain a small quantity of unbound iodine, it is difficult to establish the degree to which thyroid activity on scintigraphic images reflects uptake of free radioiodine. The objective of the present study was to examine the effectiveness of thyroid blockade in subjects undergoing (123)I-meta-iodobenzylguanidine (mIBG) imaging and to estimate the relative contribution of bound and unbound radioiodine to imaging findings. METHODS All subjects were participants in prospective trials of (123)I-mIBG cardiac imaging in which pretreatment with thyroid blockade was optional unless locally required. In a pilot project, 15 subjects (6 blocked) had thyroid uptake measured at 4 h using a probe system. Fifteen-minute (early) and 4-h (late) anterior planar chest images that included the thyroid region were visually scored for thyroid uptake (scale of 0-4) in another group of 152 subjects (98 blocked). Quantitative analysis based on thyroid regions of interest was performed on anterior planar images from a further sample of 669 subjects (442 blocked). For all 3 investigations, quantitative comparisons of thyroid uptake were made between the blocked and nonblocked subjects. RESULTS There was no statistical difference between probe uptake of the 6 blocked and 9 nonblocked subjects. However, in the second series, mean visual score on the late images was significantly lower for blocked than nonblocked subjects (P < 0.001). In the region-of-interest analyses, net thyroid counts were significantly higher on the late images of nonblocked subjects (P < 0.0001), and compared with early images, 87% of subjects who received blockade showed decreased or unchanged counts whereas 75% of nonblocked subjects had increased net thyroid activity. In nonblocked subjects, an estimated 79% of thyroid counts on late images could be attributed to unbound (123)I. CONCLUSION On the basis of 3 different methods for assessing thyroid uptake of (123)I, use of thyroid blockade pretreatment in (123)I-mIBG imaging prevents increase of thyroid activity over time because of uptake of unbound (123)I. In most subjects, there is a low level of (123)I-mIBG thyroid activity that probably represents specific uptake in sympathetic nerve terminals.
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Enhancing of women functional status with metabolic syndrome by cardioprotective and anti-inflammatory effects of combined aerobic and resistance training.
Tibana, RA, Nascimento, Dda C, de Sousa, NM, de Souza, VC, Durigan, J, Vieira, A, Bottaro, M, Nóbrega, Ode T, de Almeida, JA, Navalta, JW, et al
PloS one. 2014;(11):e110160
Abstract
These data describe the effects of combined aerobic plus resistance training (CT) with regards to risk factors of metabolic syndrome (MetS), quality of life, functional capacity, and pro- and anti-inflammatory cytokines in women with MetS. In this context, thirteen women (35.4 ± 6.2 yr) completed 10 weeks of CT consisting of three weekly sessions of ~60 min aerobic training (treadmill at 65-70% of reserve heart rate, 30 min) and resistance training (3 sets of 8-12 repetitions maximum for main muscle groups). Dependent variables were maximum chest press strength; isometric hand-grip strength; 30 s chair stand test; six minute walk test; body mass; body mass index; body adiposity index; waist circumference; systolic (SBP), diastolic and mean blood pressure (MBP); blood glucose; HDL-C; triglycerides; interleukins (IL) 6, 10 and 12, osteoprotegerin (OPG) and serum nitric oxide metabolite (NOx); quality of life (SF-36) and Z-Score of MetS. There was an improvement in muscle strength on chest press (p = 0.009), isometric hand-grip strength (p = 0.03) and 30 s chair stand (p = 0.007). There was a decrease in SBP (p = 0.049), MBP (p = 0.041), Z-Score of MetS (p = 0.046), OPG (0.42 ± 0.26 to 0.38 ± 0.19 ng/mL, p<0.05) and NOx (13.3 ± 2.3 µmol/L to 9.1 ± 2.3 µmol/L; p<0.0005). IL-10 displayed an increase (13.6 ± 7.5 to 17.2 ± 12.3 pg/mL, p < 0.05) after 10 weeks of training. Combined training also increased the perception of physical capacity (p = 0.011). This study endorses CT as an efficient tool to improve blood pressure, functional capacity, quality of life and reduce blood markers of inflammation, which has a clinical relevance in the prevention and treatment of MetS.
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Prospective evaluation of corrected QT intervals and arrhythmias after exposure to epirubicin, cyclophosphamide, and 5-fluorouracil in women with breast cancer.
Kitagawa, K, Kawada, K, Morita, S, Inada, M, Mitsuma, A, Sawaki, M, Iino, S, Inden, Y, Murohara, T, Imai, T, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(3):743-747
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BACKGROUND Corrected QT (QTc) interval prolongation can induce fatal arrhythmias such as torsade de pointes. PATIENTS AND METHODS To assess the characteristics of QTc intervals and arrhythmias in women with early breast cancer who received FEC100 adjuvant chemotherapy, electrocardiograms (ECGs) were recorded before and after each chemotherapy. Associations between QTc interval prolongation and single nucleotide polymorphisms (SNPs) of potassium channel genes were also investigated. RESULTS A total of 131 ECG records were obtained in 34 patients who received 153 cycles of FEC100. QTc intervals could be measured in 127 records. There was a significant trend toward QTc interval prolongation after each treatment, persisting through four cycles of chemotherapy (P < 0.001). Median QTc interval prolongations were 13, 11, 18, and 14 ms in the first through fourth cycles of chemotherapy, respectively. QTc intervals differed significantly between cycles 1 and 4 before treatment as well as after treatment (P < 0.05). A single supraventricular premature contraction was noted in 3 (2.3%) of the 131 cycles in 2 (5.9%) of the 34 patients. There was no significant association between QTc interval prolongation and SNPs of potassium channel genes. CONCLUSION This prospective study confirmed that FEC100 is associated with significant QTc interval prolongation in women with early breast cancer.
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Relationship between labile plasma iron, liver iron concentration and cardiac response in a deferasirox monotherapy trial.
Wood, JC, Glynos, T, Thompson, A, Giardina, P, Harmatz, P, Kang, BP, Paley, C, Coates, TD
Haematologica. 2011;(7):1055-8
Abstract
The US04 trial was a multicenter, open-label, single arm trial of deferasirox monotherapy (30-40 mg/kg/day) for 18 months. Cardiac iron response was bimodal with improvements observed in patients with mild to moderate initial somatic iron stores; relationship of cardiac response to labile plasma iron is now presented. Labile plasma iron was measured at baseline, six months, and 12 months. In patients having a favorable cardiac response at 18 months, initial labile plasma iron was elevated in only 31% of patients at baseline and no patient at six or 12 months. Cardiac non-responders had elevated labile plasma iron in 50% of patients at baseline, 50% patients at six months, and 38% of patients at 12 months. Risk of abnormal labile plasma iron and cardiac response increased with initial liver iron concentration. Persistently increased labile plasma iron predicts cardiac non-response to deferasirox but labile plasma iron suppression does not guarantee favorable cardiac outcome. Study registered at www.clinicaltrials.gov (NCT00447694).
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Phase I, first-in-human study of BMS747158, a novel 18F-labeled tracer for myocardial perfusion PET: dosimetry, biodistribution, safety, and imaging characteristics after a single injection at rest.
Maddahi, J, Czernin, J, Lazewatsky, J, Huang, SC, Dahlbom, M, Schelbert, H, Sparks, R, Ehlgen, A, Crane, P, Zhu, Q, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2011;(9):1490-8
Abstract
UNLABELLED (18)F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of (18)F activity in urine after injection of a single dose of the tracer at rest in healthy subjects. METHODS Thirteen healthy subjects were injected with 170-244 MBq (4.6-6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software. RESULTS The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64-12.41 percentage injected dose). CONCLUSION These preliminary data suggest that (18)F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.