[Show abstract][Hide abstract] ABSTRACT: Introduction
Heart failure is one of the most common cardiovascular complications of diabetes and the most disabling and deadly complication too. Many antidiabetic agents have been associated with increased morbidity and mortality in a subset of patients with chronic heart failure (CHF); thus, new treatment modalities are warranted. Interestingly, a beneficial effect of the incretin hormone, GLP-1, on cardiac function has been suggested in patients with diabetes and patients without diabetes. Liraglutide (Victoza) is a GLP-1 analogue developed for the treatment of type 2 diabetes (T2D); however, its impact on cardiac function has not previously been investigated in patients with CHF. This prompted us to investigate whether liraglutide treatment for 24 weeks improves left ventricular ejection fraction (LVEF) in patients with CHF with and without T2D compared with placebo treatment.
Methods and analysis
An investigator-initiated, multicentre, randomised, double-blind, parallel, placebo-controlled intervention trial. In total, 240 patients with CHF (with and without T2D) with LVEF≤45% will be randomised to either subcutaneous injection of liraglutide 1.8 mg or matching placebo once daily for 24 weeks. The effect of liraglutide on left ventricular function will be evaluated by advanced echocardiography, including three-dimensional contrast echocardiography.
Ethics and dissemination
The study will be performed and monitored according to the Good Clinical Practice-International Conference on Harmonisation (GCP-ICH) regulations and conducted according to the principles of the Helsinki Declaration. The Danish Medicines Agency, the local Research Ethics Committee and the Danish Data Protection Agency have approved the study.
Trial registration number
ClinicalTrials.gov Identifier: NCT01472640.
BMJ Open 05/2014; 4(5):e004885. DOI:10.1136/bmjopen-2014-004885 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Circulating lipid levels and myocardial lipid content (MyLC) is increased in type 2 diabetes mellitus. This may cause a state of lipotoxicity that compromises left ventricular function and aggravate heart failure. We investigated the relationship among circulating lipid levels, MyLC, and cardiac function together with the acute cardiac effects of high as opposed to low circulating free fatty acid (FFA) and triglyceride levels in patients with type 2 diabetes mellitus and heart failure.
Methods and results:
Eighteen patients underwent 8-hour intralipid/heparin-infusion (high FFA) and hyperinsulinemic-euglycemic clamping (low FFA) in a randomized crossover-designed study. We applied magnetic resonance proton spectroscopy to measure MyLC. Cardiac function was assessed by advanced echocardiography, cardiopulmonary exercise, and MRI. MyLC correlated positively with circulating triglyceride (r=0.47; r(2)=0.22; P=0.003) and FFA (r=0.45; r(2)=0.20; P=0.001) levels and inversely with left ventricular ejection fraction (r=-0.54; r(2)=0.29; P=0.004). Circulating FFA concentrations differed between study arms (0.05 ± 0.04 mmol/L [low FFA] versus 1.04 ± 0.27 mmol/L [high FFA]; P<0.001) and MyLC increased from 0.78 ± 0.59% (low FFA) to 1.16 ± 0.73% (high FFA; P<0.01). Resting left ventricular ejection fraction and global strain did not differ between high and low FFA, whereas resting systolic mitral plane velocity (S'max) was highest during high FFA (3.6±0.8 cm/s [low FFA] versus 3.8±0.7 cm/s [high FFA]; P=0.02). Peak exercise capacity and oxygen consumption did not differ between the study arms, and neither did postexercise measurements of left ventricular ejection fraction, global strain, and S'max.
Our findings indicate that the failing heart of patients with type 2 diabetes mellitus can adapt to short-term extreme changes in circulating substrates and does not display features of acute myocardial lipotoxicity. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192373.
[Show abstract][Hide abstract] ABSTRACT: AimsUndertreatment with evidence-based pharmacotherapy for heart failure (HF) is an important problem, and it has been suggested that specialized HF clinics (HFCs) can improve treatment initiation and correct dosing. The objective of this study was to examine long-term adherence to and dosages of evidence-based pharmacotherapy during and after participation in specialized HFCs.Methods and resultsInitiation, dosages, and adherence were studied in patients with systolic HF attending HFCs in Denmark from 2002 to 2009. Information was obtained from an electronic patient file and research database used in the HFCs combined with prescription data from the Danish Registry of Medicinal Product Statistics. A total of 8792 patients were included in the study. The mean age was 68 years; with a mean LVEF of 30%, and 72% were males. Long-term adherence to treatment was high for the patients who initiated renin-angiotensin system (RAS) inhibitors and beta-blockers. Adherence after 1 year was 93% for RAS inhibitors, 92% for beta-blockers, and 86% for spironolactone. After 3 years, it was 90% for RAS inhibitors, 88% for beta-blockers, and 74% for spironolactone. For patients referred back to their general practitioner (GP), adherence 1 year after they left the HFC was 89% for RAS inhibitors, 89% for beta-blockers, and 72% for spironolactone.Conclusion
In specialized outpatient HFCs, long-term adherence to RAS inhibitors and beta-blockers is close to optimal. Importantly, adherence was maintained after patients were referred back to their GP for continued management. This is likely to provide long-term benefits for the patients.
European Journal of Heart Failure 02/2013; 15(6). DOI:10.1093/eurjhf/hft011 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Guidelines for the treatment of left-sided infective endocarditis (IE) recommend 4 to 6 weeks of intravenous antibiotics. Conversion from intravenous to oral antibiotics in clinically stabilized patients could reduce the side effects associated with intravenous treatment and shorten the length of hospital stay. Evidence supporting partial oral therapy as an alternative to the routinely recommended continued parenteral therapy is scarce, although observational data suggest that this strategy may be safe and effective.
This is a noninferiority, multicenter, prospective, randomized, open-label study of partial oral treatment with antibiotics compared with full parenteral treatment in left-sided IE. Stable patients (n = 400) with streptococci, staphylococci, or enterococci infecting the mitral valve or the aortic valve will be included. After a minimum of 10 days of parenteral treatment, stable patients are randomized to oral therapy or unchanged parenteral therapy. Recommendations for oral treatment have been developed based on minimum inhibitory concentrations and pharmacokinetic calculations. Patients will be followed up for 6 months after completion of antibiotic therapy. The primary end point is a composition of all-cause mortality, unplanned cardiac surgery, embolic events, and relapse of positive blood cultures with the primary pathogen.
The Partial Oral Treatment of Endocarditis study tests the hypothesis that partial oral antibiotic treatment is as efficient and safe as parenteral therapy in left-sided IE. The trial is justified by a review of the literature, by pharmacokinetic calculations, and by our own experience.
American heart journal 02/2013; 165(2):116-22. DOI:10.1016/j.ahj.2012.11.006 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is unknown whether changes in circulating glucose levels due to short-term insulin discontinuation affect left ventricular contractile function in type 2 diabetic patients with (T2D-HF) and without (T2D-nonHF) heart failure.
In two randomized cross-over-designed trials, 18 insulin-treated type 2 diabetic patients with (Ejection Fraction (EF) 36±6%, n = 10) (trial 2) and without systolic heart failure (EF 60±3%, n = 8) (trial 1) were subjected to hyper- and normoglycemia for 9-12 hours on two different occasions. Advanced echocardiography, bicycle exercise tests and 6-minute hall walk distance were applied.
Plasma glucose levels differed between study arms (6.5±0.8 mM vs 14.1±2.6 mM (T2D-HF), 5.8±0.4 mM vs 9.9±2.1 mM (T2D-nonHF), p<0.001). Hyperglycemia was associated with an increase in several parameters: maximal global systolic tissue velocity (Vmax) (p<0.001), maximal mitral annulus velocity (S'max) (p<0.001), strain rate (p = 0.02) and strain (p = 0.05). Indices of increased myocardial systolic contractile function were significant in both T2D-HF (Vmax: 14%, p = 0.02; S'max: 10%, p = 0.04), T2D-nonHF (Vmax: 12%, p<0.01; S'max: 9%, p<0.001) and in post exercise S'max (7%, p = 0.049) during hyperglycemia as opposed to normoglycemia. LVEF did not differ between normo- and hyperglycemia (p = 0.17), and neither did peak exercise capacity nor catecholamine levels. Type 2 diabetic heart failure patients' 6-minute hall walk distance improved by 7% (p = 0.02) during hyperglycemia as compared with normoglycemia.
Short-term hyperglycemia by insulin discontinuation is associated with an increase in myocardial systolic contractile function in type 2 diabetic patients with and without heart failure and with a slightly prolonged walking distance in type 2 diabetic heart failure patients. (Clinicaltrials.gov identifier NCT00653510).
PLoS ONE 01/2013; 8(1):e53247. DOI:10.1371/journal.pone.0053247 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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
[Show abstract][Hide abstract] ABSTRACT: Hyponatraemia has been reported to be a potent predictor of poor outcome in patients hospitalized for heart failure (HF). The aim of the study was to determine the prevalence and prognostic significance of hyponatraemia in a large cohort of HF outpatients followed in clinics participating in the Danish Heart Failure Clinics Network.
The study population consisted of consecutive patients referred for HF management in 18 Danish heart failure clinics. Overall, 2863 patients (83%) had a normal plasma sodium (p-sodium) level and 602 patients (17%) had hyponatraemia with a p-sodium level <136 mmol/L. Outcome data were obtained from a validated, national registry. Patients were elderly with a mean age of 68 years. The mean P-[Na+] was 139.6 ± 2.4 mmol/L among patients with normonatraemia and 132.4 ± 3.2 mmol/L among patients with hyponatraemia. In multivariate Cox Proportional Hazard Models adjusted for confounders (age, gender, hospitalization within the last 90 days, loop diuretics, creatinine level, systolic blood pressure, New York Heart Association class III-IV, left ventricular ejection fraction <0.46, ischaemic heart disease and diabetes) hyponatraemic patients had increased risk of hospitalization or death [hazard ratio (HR) 1.2 (95% confidence interval (CI) 1.0-1.4, P = 0.011)]. Hyponatraemia was also an independent predictor of all-cause mortality [HR 1.5 (95% CI 1.2-1.9, P< 0.001)]. There was no interaction between hyponatraemia and the covariables on outcome in the multivariable models.
The presence of hyponatraemia in outpatients with HF is associated with increased risk of hospitalization or death.
European Journal of Heart Failure 09/2011; 13(9):968-73. DOI:10.1093/eurjhf/hfr086 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Our aim was to identify patterns in differentially regulated proteins associated with the progression of chronic heart failure. We specifically studied proteomics in chronic reversibly (RDM) and irreversibly dysfunctional myocardium (IRDM), as well as end-stage failing myocardium (ESFM).
We studied biopsies from 9 patients with stable chronic heart failure undergoing coronary artery bypass surgery (CABG) (EF 34% +/- 3%) and from 4 patients with ESFM undergoing heart transplantation (EF 17% +/- 5%). In CABG patients paired echocardiographic studies before and 6 months after revascularization classified dysfunctional myocardium as RDM or IRDM. Regions with preserved contractile function served as control. We used two-dimensional gel electrophoresis (2D-PAGE) and computerized image analysis to investigate myocardial protein expression. Proteins were identified by in-gel digestion and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Among 3 significantly altered protein spots in RDM we identified 2 up-regulated glycolytic enzymes. In IRDM 15 proteins were signficantly altered of which we identified 10, among these 6 were down-regulated mitochondrial enzymes. In ESFM 9 of 12 significantly altered protein spots were identified. Six were down-regulated mitochondrial enzymes.
Myocardial metabolism may be involved in the progression of heart failure to irreversible dysfunction and end-stage heart failure.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Discriminatory 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. METHODS: In 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. RESULTS: The 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. CONCLUSION: Short 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.
International journal of cardiology 02/2009; 144(1):140-2. DOI:10.1016/j.ijcard.2008.12.152 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with ischemic heart failure and reversible dysfunctional myocardium (Hibernating myocardium, HIB) can benefit from revascularization. These patients can be selected with nuclear methods. The purpose of this study was to describe the results of the imaging procedures in patients tested for HIB and relate the results to the choice of treatment and cause of death.
During a 2-year period 51 patients were referred to determine the amount of HIB. This can be determined with blood flow and metabolic imaging of the heart. Resting-myocardial perfusion imaging was performed with 99mTc-sestamibi and glucose metabolism was visualized with 18F-fluorodeoxyglucose (18F-FDG) gamma camera PET. Medical records and death certificate were reviewed retrospectively.
50 patients were included. We found an increased survival among patients with HIB who underwent revascularization (1 year mortality 6% vs. 33%, p = 0,004). Patients with HIB who did not undergo revascularization had an increased risk of sudden death. (5/15 patients vs. 0/35 patients, p = 0,003).
Despite a simplified method we find the same increased mortality among medically-treated patients with HIB as in earlier studies. This and earlier studies are all retrospective with the risk of selection bias. Prospective studies are underway. Nuclear imaging is useful in evaluating patients with heart failure before revascularization.
[Show abstract][Hide abstract] ABSTRACT: 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.
The American Journal of Cardiology 01/2007; 98(12):1574-80. DOI:10.1016/j.amjcard.2006.07.035 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
We studied eight nondiabetic patients with CHF (ejection fraction 30 +/- 4%) and eight healthy controls. Protein metabolism (whole body and regional muscle fluxes) and total glucose turnover were isotopically assayed. Substrate oxidation were obtained by indirect calorimetry. The metabolic response to exercise was studied by bicycle ergometry exercise.
Our data confirm that CHF patients have a decreased lean body mass. CHF patients are characterised by (i) decreased glucose oxidation [glucose oxidation (mg kg(-1) min(-1)): 1.25 +/- 0.09 (patients) vs. 1.55 +/- 0.09 (controls), P < 0.01] and muscle glucose uptake [a - v diff(glucose) (micromol L(-1)): -10 +/- 25 (patients) vs. 70 +/- 22 (controls), P < 0.01], (ii) elevated levels of free fatty acids (FFA) [FFA (mmol L(-1)): 0.72 +/- 0.05 (patients) vs. 0.48 +/- 0.03 (controls), P < 0.01] and 3-hydroxybutyrate and signs of elevated fat oxidation and muscle fat utilization [a - v diff(FFA) (mmol L(-1)): 0.12 +/- 0.02 (patients) vs. 0.05 +/- 0.01 (controls), P < 0.05] and (iii) elevated protein turnover and protein breakdown [phenylalanine flux (micromol kg(-1) h(-1)): 36.4 +/- 1.5 (patients) vs. 29.6 +/- 1.3 (controls), P < 0.01]. Patients had high circulating levels of noradrenaline, glucagon, and adiponectin, and low levels of ghrelin. We failed to observe any differences in metabolic responses between controls and patients during short-term exercise.
In the basal fasting state patients with CHF are characterized by several metabolic abnormalities which may contribute to CHF pathophysiology and may provide a basis for targeted intervention.
Journal of Internal Medicine 08/2006; 260(1):11-21. DOI:10.1111/j.1365-2796.2006.01663.x · 6.06 Impact Factor