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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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Prognostic usefulness of planar 123I-MIBG scintigraphic images of myocardial sympathetic innervation in congestive heart failure: Follow-Up data from ADMIRE-HF.
Agostini, D, Ananthasubramaniam, K, Chandna, H, Friberg, L, Hudnut, A, Koren, M, Miyamoto, MI, Senior, R, Shah, M, Travin, MI, et al
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2021;(4):1490-1503
Abstract
BACKGROUND To evaluate whether planar 123I-MIBG myocardial scintigraphy predicts risk of death in heart failure (HF) patients up to 5 years after imaging. METHODS AND RESULTS Subjects from ADMIRE-HF were followed for approximately 5 years after imaging (964 subjects, median follow-up 62.7 months). Subjects were stratified according to the heart/mediastinum (H/M) ratio (< 1.60 vs ≥ 1.60) on planar 123I-MIBG scintigraphic images obtained at baseline in ADMIRE-HF. Cox proportional hazards models and Kaplan-Meier analyses were used to evaluate time to death, cardiac death, or arrhythmic events for subjects stratified by H/M ratio, baseline left ventricular ejection fraction (LVEF: < 25% and 25 to ≤ 35%), and by H/M strata within LVEF strata. All-cause mortality was 38.4% vs 20.9% and cardiac mortality was 16.8% vs 4.5%, in subjects with H/M < 1.60 vs ≥ 1.60, respectively (P < 0.05 for both comparisons). Subjects with preserved sympathetic innervation of the myocardium (H/M ≥ 1.60) were at significantly lower risk of all-cause and cardiac death, arrhythmic events, sudden cardiac death, or potentially life-threatening arrhythmias. Within LVEF strata, a trend toward a higher mortality for subjects with H/M < 1.60 was observed reaching significance for LVEF 25 to ≤ 35% only. CONCLUSIONS During a median follow-up of 62.7 months, patients with H/M ≥ 1.60 were at significantly lower risk of death and arrhythmic events independently of LVEF values.
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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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Abstract
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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1-23I-MIBG thyroid uptake: Implications for MIBG imaging of the heart.
Giubbini, R, Milan, E, Marcassa, C, Paghera, B, Fracassi, F, Camoni, L, Rodella, C, Bertagna, F, Motta, F, Bertoli, M, et al
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2016;(6):1335-1339
Abstract
BACKGROUND 123I-MIBG has been widely used in patients with heart failure and neurological disorders. The patients are pre-treated with Lugol's oral solution or potassium perchlorate to prevent thyroid uptake of unlabeled 123I to limit the thyroid radiation exposure. However, despite the inhibition of the iodide pump, the thyroid is frequently visualized. The aim of this study was to study the pattern of thyroid uptake. METHODS We reviewed the 123I-MIBG images of 57 patients studied in three different centers in Italy for cardiac (n = 42) or neurological (n = 15) indications. They were imaged at 15 minutes and 4 hours after injection and in all patients, the thyroid was included in the imaging field of view. In 2 of the 3 centers, the patients were pre-treated with Lugol's oral solution and/or potassium perchlorate (group 1) but in the third center, they were not (group 2). The following imaging parameters were evaluated: heart-to-mediastinum ratio (H/M), thyroid-to-mediastinum ratio (T/M) at 4 hours, and tracer wash out from the heart (HWO) and from the thyroid (TWO). RESULTS In the cardiac patients, the HWO was 22.98 ± 7.16% and TWO was 11.4 ± 11.86% (P < .0001). The TWO was 12.2 ± 13.1% in group 1 and 10.05 ± 8.97% in group 2 (P = NS). In the neurological patients the HWO was 26 ± 8.1% and the TWO was 20.32 ± 6.41 (P < .05). The difference in TWO was statistically significant (P < .01) between cardiac and neurological patients, whereas the HWO was not. The 4-hour H/M was 1.49 ± 0.23 in cardiac patients vs 1.4 ± 0.39 in neurological patients (P = NS). The 4-hour T/M was 1.33 ± 0.3 in cardiac patients vs 1.15 ± 0.13 in neurological patients (P < 0.05). CONCLUSION The thyroid visualization in MIBG imaging is likely an expression of thyroid sympathetic innervation. The differences in TWO and T/M ratio in cardiac and neurological patients probably express differences in thyroid dopaminergic receptors. Thus, pre-treatment with potassium perchlorate or Lugol's solution may not be justified in patients undergoing 123I-MIBG imaging in whom the risk of side effects due to pre-treatment could be higher than the risk due to thyroid radiation exposure.
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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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Improvement of myocardial fatty acid metabolism by oral nicorandil in hemodialysis patients without coronary artery disease.
Nishimura, M, Okamoto, Y, Takatani, T, Sato, N, Nishida, M, Hashimoto, T, Yamazaki, S, Kobayashi, H, Ono, T
Journal of nephrology. 2015;(2):227-34
Abstract
BACKGROUND We investigated the potential of oral nicorandil to improve myocardial fatty acid metabolism assessed by single-photon emission computed tomography (SPECT) using (123)I-β-methyliodophenyl pentadecanoic acid (BMIPP) in hemodialysis patients without obstructive coronary artery disease (CAD). METHODS This study was based on a cohort study of 155 hemodialysis patients with angiographic absence of obstructive CAD, with analysis performed in 100 propensity-matched patients (54 men and 46 women, 64 ± 10 years); 50 with oral administration of nicorandil (15 mg/d, nicorandil group) and 50 without (control). BMIPP SPECT was performed every year after angiography. Uptake on SPECT was graded in 17 segments on a five-point scale (0 normal, 4 absent) and assessed as BMIPP summed scores (SS). RESULTS Over a mean follow-up period of 5.3 ± 1.9 years, we observed 25 cardiac deaths among 100 propensity-matched patients. Myocardial uptake of BMIPP in SPECT improved in the nicorandil group compared with the control group from 2 years of administration. In Kaplan-Meier survival analyses, free survival rate from cardiac death was higher in patients with a BMIPP SS improvement rate of ≥20% compared to those with ≥0% <20% or with <0% BMIPP SS improvement rate. At multiple logistic analysis, a ≥20% BMIPP SS improvement rate was positively associated with serum albumin concentration and oral nicorandil. CONCLUSIONS Long-term oral nicorandil may inhibit cardiac death by improving myocardial fatty acid metabolism in hemodialysis patients without obstructive CAD.
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Single therapeutic and supratherapeutic doses of anacetrapib, a cholesteryl ester transfer protein inhibitor, do not prolong the QTcF interval in healthy volunteers.
Lauring, B, Liu, Y, Li, XS, Larson, P, Moreau, A, Farmer, HF, Johnson-Levonas, AO, Wagner, JA, Lai, E
Journal of clinical pharmacology. 2014;(7):765-75
Abstract
Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.
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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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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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Abstract
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.