We studied the metabolic effects of 48-h GLP-1 treatment in insulin resistant heart failure patients. In a randomized placebo-controlled double-blinded cross-over study, 11 non-diabetic HF patients with IHD received 48-h GLP-1 and placebo-infusion. We applied OGTT, hyperinsulinemic clamp, indirect calorimetry, forearm, and tracer methods. 7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body protein turnover (p=0.08) but did not cause muscle wasting. No significant changes in circulating levels of insulin, glucagon, free fatty acids or insulin sensitivity were detected. GLP-1 treatment decreased glucose levels and increased glucose tolerance in insulin resistant HF patients with IHD. Hypoglycemia was common and may limit the use of GLP-1 in these patients. Insulin sensitivity, lipid-, and protein metabolism remained unchanged. Data were collected at the examinational laboratories of Department of Endocrinology and Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

The incretin hormone glucagon-like peptide-1 (GLP-1) and its analogs are currently emerging as antidiabetic medications. GLP-1 improves left ventricular ejection fraction (LVEF) in dogs with heart failure (HF) and in patients with acute myocardial infarction. We studied metabolic and cardiovascular effects of 48-h GLP-1 infusions in patients with congestive HF. In a randomized, double-blind crossover design, 20 patients without diabetes and with HF with ischemic heart disease, EF of 30 +/- 2%, New York Heart Association II and III (n = 14 and 6) received 48-h GLP-1 (0.7 pmol.kg(-1).min(-1)) and placebo infusion. At 0 and 48 h, LVEF, diastolic function, tissue Doppler regional myocardial function, exercise testing, noninvasive cardiac output, and brain natriuretic peptide (BNP) were measured. Blood pressure, heart rate, and metabolic parameters were recorded. Fifteen patients completed the protocol. GLP-1 increased insulin (90 +/- 17 pmol/l vs. 69 +/- 12 pmol/l; P = 0.025) and lowered glucose levels (5.2 +/- 0.1 mmol/l vs. 5.6 +/- 0.1 mmol/l; P < 0.01). Heart rate (67 +/- 2 beats/min vs. 65 +/- 2 beats/min; P = 0.016) and diastolic blood pressure (71 +/- 2 mmHg vs. 68 +/- 2 mmHg; P = 0.008) increased during GLP-1 treatment. Cardiac index (1.5 +/- 0.1 l.min(-1).m(-2) vs. 1.7 +/- 0.2 l.min(-1).m(-2); P = 0.54) and LVEF (30 +/- 2% vs. 30 +/- 2%; P = 0.93), tissue Doppler indexes, body weight, and BNP remained unchanged. Hypoglycemic events related to GLP-1 treatment were observed in eight patients. GLP-1 infusion increased circulating insulin levels and reduced plasma glucose concentration but had no major cardiovascular effects in patients without diabetes but with compensated HF. The impact of minor increases in heart rate and diastolic blood pressure during GLP-1 infusion requires further studies. Hypoglycemia was frequent and calls for caution in patients without diabetes but with HF.

Circulating free fatty acids (FFAs) may worsen heart failure (HF) due to myocardial lipotoxicity and impaired energy generation. We studied cardiac and whole body effects of 28 days of suppression of circulating FFAs with acipimox in patients with chronic HF. In a randomized double-blind crossover design, 24 HF patients with ischemic heart disease [left ventricular ejection fraction: 26 ± 2%; New York Heart Association classes II (n = 13) and III (n = 5)] received 28 days of acipimox treatment (250 mg, 4 times/day) and placebo. Left ventricular ejection fraction, diastolic function, tissue-Doppler regional myocardial function, exercise capacity, noninvasive cardiac index, NH(2)-terminal pro-brain natriuretic peptide (NT-pro-BNP), and whole body metabolic parameters were measured. Eighteen patients were included for analysis. FFAs were reduced by 27% in the acipimox-treated group [acipimox vs. placebo (day 28-day 0): -0.10 ± 0.03 vs. +0.01 ± 0.03 mmol/l, P < 0.01]. Glucose and insulin levels did not change. Acipimox tended to increase glucose and decrease lipid utilization rates at the whole body level and significantly changed the effect of insulin on substrate utilization. The hyperinsulinemic euglycemic clamp M value did not differ. Global and regional myocardial function did not differ. Exercise capacity, cardiac index, systemic vascular resistance, and NT-pro-BNP were not affected by treatment. In conclusion, acipimox caused minor changes in whole body metabolism and decreased the FFA supply, but a long-term reduction in circulating FFAs with acipimox did not change systolic or diastolic cardiac function or exercise capacity in patients with HF.

BackgroundDiscriminatory values have been defined for both N-terminal-pro Brain Natriuretic Peptide (Nt-pro-BNP) and BNP but the general values established so far are controversial in insulin resistant patients due to their lower levels of natriuretic peptides. The aim of the present study was to address whether short-term modulation of insulin and FFA affects Nt-pro-BNP and BNP levels in heart failure patients.MethodsIn a crossover design eight male non-diabetic patients with chronic heart failure and ischemic heart disease were studied during an euglycemic insulin clamp and during a heparin/somatostatin infusion.ResultsThe influence of insulin and heparin infusions on absolute and relative Nt-pro-BNP levels differed at steady state. During the euglycemic insulin clamp Nt-pro-BNP levels decreased when compared to heparin/somatostatin infusion [change in Nt-pro-BNP (pg ml−1): −21 pg/ml±9 (insulin) vs. −4 pg/ml±8 (heparin), P=0.038]. Neither urinary Nt-pro-BNP excretion nor hemodynamics differed.ConclusionShort term modulation of circulating insulin and FFA concentrations by glucose-insulin and heparin-somatostatin infusions affects circulating Nt-pro-BNP concentrations. These findings indicate that factors other than cardiac status impact on BNP and NT-pro-BNP concentrations and support the proposal that discriminatory Nt-pro-BNP values should be decreased in insulin resistant individuals.

HomeCirculationVol. 115, No. 21Response to Letters Regarding Article, "Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letters Regarding Article, "Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure" Helena Tuunanen, MD, Alexandru Naum, MD, Kjell Någren, PhD, Pirjo Nuutila, MD, PhD, Patricia Iozzo, MD, PhD, Heikki Ukkonen, MD, PhD and Juhani Knuuti, MD, PhD Erik Engblom, MD, PhD and K.E. Juhani Airaksinen, MD, PhD Birger Hesse, MD, PhD Lionel H. Opie, MD, PhD Helena TuunanenHelena Tuunanen Turku PET Centre, Turku, Finland , Alexandru NaumAlexandru Naum Turku PET Centre, Turku, Finland , Kjell NågrenKjell Någren Turku PET Centre, Turku, Finland , Pirjo NuutilaPirjo Nuutila Turku PET Centre, Turku, Finland , Patricia IozzoPatricia Iozzo Turku PET Centre, Turku, Finland , Heikki UkkonenHeikki Ukkonen Turku PET Centre, Turku, Finland and Juhani KnuutiJuhani Knuuti Turku PET Centre, Turku, Finland Erik EngblomErik Engblom Department of Medicine, Turku University Central Hospital, Turku, Finland and K.E. Juhani AiraksinenK.E. Juhani Airaksinen Department of Medicine, Turku University Central Hospital, Turku, Finland Birger HesseBirger Hesse Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Lionel H. OpieLionel H. Opie Hatter Heart Research Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa Originally published29 May 2007https://doi.org/10.1161/CIRCULATIONAHA.107.691329Circulation. 2007;115:e547We appreciate the opportunity of answering the points raised in the Letters to the Editor by Fragasso et al and Wiggers et al. Unfortunately, our results have been misinterpreted.The main purpose of our study was not to study the effect of acipimox on cardiac contractile function but to compare the responses in patients with heart failure with those in healthy volunteers.1 Therefore, a placebo group was not necessary. Our initial hypothesis was "that acute FFA depletion would result in an increased myocardial efficiency of forward work in patients with heart failure." Although in both groups cardiac function was slightly depressed by acipimox, only in the healthy volunteers did changes in oxidative metabolism parallel the changes in cardiac function. In contrast, in patients with heart failure, oxidative metabolism was not downregulated so that myocardial efficiency deteriorated further. Therefore, we considered our results unexpected and contrary to our hypothesis.We do not understand the comment by Wiggers et al that our results were not in agreement with our previous study by Mäki et al2 because we do not see any link between the 2 studies. In the study by Mäki et al,2 the effect of insulin on the glucose uptake in hibernating myocardium was investigated.Furthermore, we do not agree with Fragasso et al that a metabolic situation similar to our study could be mimicked by administration of food that increases insulin (not so with acipimox). Neither do we know of any evidence that reduced insulin and glucose concentrations after acipimox prevent an increase in cardiac glucose uptake. In contrast, in our previous studies,3–5 after administration of acipimox, serum insulin and glucose concentrations remain at the fasting levels, whereas myocardial glucose uptake increases 6-fold in fasting volunteers.However, we do agree with Fragasso et al that just reducing free fatty acid availability by acipimox may not be sufficient to optimize cardiac metabolism. Actually, that was also our conclusion.1 In regard to the effects of direct cellular free fatty acid oxidation inhibitors such as trimetazidine, further studies are needed to understand their effects on myocardial metabolism in heart failure.In summary, our study clearly documents that switching substrate metabolism acutely by nicotinic acid derivatives does not improve myocardial efficiency and is not an option for the treatment of patients with dilated cardiomyopathy. Further studies are needed to fully understand the potential of metabolic modulation in the treatment of heart failure.DisclosuresNone.1 Tuunanen H, Engblom E, Naum A, Nagren K, Hesse B, Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006; 114: 2130–2137.LinkGoogle Scholar2 Mäki M, Luotolahti M, Nuutila P, Iida H, Voipio-Pulkki L-M, Ruotsalainen U, Haaparanta M, Solin O, Hartiala J, Härkönen R, Knuuti J. Glucose uptake in the chronically dysfunctioning but viable myocardium. Circulation. 1996; 93: 1658–1666.CrossrefMedlineGoogle Scholar3 Knuuti MJ, Maki M, Yki-Jarvinen H, Voipio-Pulkki LM, Harkonen R, Haaparanta M, Nuutila P. The effect of insulin and FFA on myocardial glucose uptake. J Mol Cell Cardiol. 1995; 27: 1359–1367.CrossrefMedlineGoogle Scholar4 Knuuti MJ, Yki-Järvinen H, Voipio-Pulkki L-M, Mäki M, MD, Ruotsalainen U, Härkönen R, Teräs M, Haaparanta M, Bergman J, Hartiala J, Wegelius U, Nuutila P. Enhancement of myocardial 18-FDG uptake by nicotinic acid derivative. J Nucl Med. 1994; 35: 989–98.MedlineGoogle Scholar5 Nuutila P, Knuuti MJ, Ruotsalainen U, Teräs M, Voipio-Pulkki L-M, Haaparanta M, Solin O, Wegelius U, Yki-Järvinen H. Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol. 1994; 267: E941–E946.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails May 29, 2007Vol 115, Issue 21 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.691329 Originally publishedMay 29, 2007 PDF download Advertisement SubjectsCongenital Heart DiseaseMetabolismNuclear Cardiology and PETPharmacology

N-terminal pro-brain natriuretic peptide (NT-proBNP), osteoprotegerin (OPG), and adiponectin (ADI) are risk markers in cardiovascular disease. Metabolic modulation with insulin and glucose exerts beneficial effects on myocardial function, whereas free fatty acids (FFA) may compromise contractile function. It is unknown whether short-term modulation of myocardial substrate supply affects risk markers of HF severity.

Objective.  It is well known that chronic heart failure (CHF) is associated with insulin resistance and cachexia, but little is known about the underlying substrate metabolism. The present study was undertaken to identify disturbances of basal glucose, lipid and protein metabolism.

It is unknown whether human chronically ischemic dysfunctional myocardium degenerates over time or adapts to, chronic ischemia. We studied whether perfusion, metabolism, and contractile function and reserve can be preserved in nonrevascularized human chronically stunned and hibernating myocardium. We studied 16 event-free, medically treated patients with ejection fractions of 31 +/- 2% and chronically stunned or hibernating myocardium. in 56 +/- 5% of the left ventricle on technetium-99m sestamibi single-photon emission computed tomography/fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography. Patients underwent repeat single-photon emission computed tomography, positron emission tomography, and tissue Doppler echocardiography at rest and during stress at follow-up after 25 4 months, and we investigated whether measurements of myocardial viability remained stable over time. Patients were stable with respect to New York Heart Association class and global left ventricular function (30 +/- 2%, p = 0.81). Wall motion score was unaltered in hibernating myocardium, and chronically stunned regions, and a contractile reserve by tissue Doppler stress echocardiography was preserved. Overall, 74% of hibernating myocardium and chronically stunned regions retained their initial perfusion/metabolism pattern at follow-up. In hibernating myocardium, initial and follow-up sestamibi uptakes (53 +/- 1% and 53 +/- 2%, p = 0.85) and FDG uptakes (76 +/- 1% and 74 1%, p = 0.21) did not differ. In chronically stunned regions, sestamibi uptake displayed a minor decrease at follow-up (70 +/- 1% vs 67 +/- 1%, p < 0.01) and FDG uptake remained constant (68 +/- 2% and 67 +/- 1%, p 0.21). In conclusion, myocardial perfusion, FDG uptake, and contractile function in nonrevascularized chronically stunned and hibernating myocardium adapt to chronic ischemia in patients who are free of events. In chronically stunned regions, adaptation may be less complete than in hibernating myocardium. (c) 2006 Elsevier Inc. All rights reserved.