Alexandru Naum

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

Background— The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy. Methods and Results— Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [15O]H2O, [11C]acetate, and [11C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9±8.5% to 34.8±12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and &bgr;-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9±0.7 versus 5.5±0.6 mmol/L, P=0.047; insulin: 10±6.9 versus 7.6±3.6 mU/L, P=0.031; homeostasis model assessment index: 2.75±2.28 versus 1.89±1.06, P=0.027). The degree of &bgr;-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001). Conclusions— In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater &bgr;1-adrenoceptor occupancy, suggesting a synergistic mechanism.

Free Fatty Acid Depletion Acutely Decreases Cardiac Work and Efficiency in Cardiomyopathic Heart Failure

Background— Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM). Methods and Results— Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8±8.0 years, ejection fraction 33±8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate–pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071±0.019 to 0.055±0.016 min−1, P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4±12.6 to 31.6±13.3 mm Hg · L · g−1, P<0.05). Conclusions— Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.

Myocardial perfusion quantitation with 15O-labelled water PET: high reproducibility of the new cardiac analysis software (Carimas™)

PurposeCarimas™ (Cardiac Image Analysis System) is a new software package developed at the Turku PET Centre for the quantitation of PET studies of the heart with a broad range of tracers. The goal of this study was to assess the reproducibility of results the package provides for myocardial perfusion (MP) quantitation using 15O-labelled water.MethodsFour observers with various levels of experience in nuclear medicine independently analysed 20 MP studies (10 rest flow: “rest”, 10 adenosine-induced hyperaemia: “stress”). Each study was analysed twice. The linear mixed model for repeated measures was fitted to the data to calculate intraclass correlation coefficients (ICC), differences between the repeats (the intraobserver differences) and differences between the observers (the interobserver differences). Also, Pearson correlation coefficients (r) were calculated and Bland-Altman plots were drawn. The reproducibility of MP was assessed on global, regional and segmental levels. Thereafter, this analysis was applied in 48 consecutive clinical patients with suspected coronary heart disease (CHD).ResultsFor the experienced observer the Pearson r for all segments was 0.974 at rest and 0.978 at stress (pu2009<u20090.0001), and the repeatability coefficients were 0.145xa0ml/g per min (15.5% of the average) and 0.389xa0ml/g per min (14.9%), correspondingly. The ICC reflected very good overall reproducibility. The intraobserver and interobserver differences were small, and the difference between the most and the least experienced observers at stress was 8.5% for the global MP. The clinical accuracy of the perfusion in the detection of CHD was excellent (positive predictive value 91% and negative predictive value 88%) against invasive angiography.ConclusionThe results demonstrate high reproducibility of myocardial perfusion quantitation with 15O-labelled water PET using Carimas™. The results support the feasibility of robust analysis and good clinical accuracy.

Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals

BACKGROUND & AIMSnHepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings.nnnMETHODSnAnesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis.nnnRESULTSnIn pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 micromol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003).nnnCONCLUSIONSnPET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.

The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation.

Assessment of right ventricular oxidative metabolism by PET in patients with idiopathic dilated cardiomyopathy undergoing cardiac resynchronisation therapy

PurposeRight ventricular (RV) performance is known to have prognostic value in patients with congestive heart failure (CHF). Cardiac resynchronisation therapy (CRT) has been found to enhance left ventricular (LV) energetics and metabolic reserve in patients with heart failure. The interplay between the LV and RV may play an important role in CRT response. The purpose of the study was to investigate RV oxidative metabolism, metabolic reserve and the effects of CRT in patients with CHF and left bundle brach block. In addition, the role of the RV in the response to CRT was evaluated.MethodsTen patients with idiopathic dilated cardiomyopathy who had undergone implantation of a biventricular pacemaker 8±5 months earlier were studied under two conditions: CRT ON and after CRT had been switched OFF for 24xa0h. Oxidative metabolism was measured using [11C]acetate positron emission tomography (Kmono). The measurements were performed at rest and during dobutamine-induced stress (5xa0μg/kg per minute). LV performance and interventricular mechanical delay (interventricular asynchrony) were measured using echocardiography.ResultsCRT had no effect on RV Kmono at rest (ON: 0.052±0.014, OFF: 0.047±0.018, NS). Dobutamine-induced stress increased RV Kmono significantly under both conditions but oxidative metabolism was more enhanced when CRT was ON (0.076±0.026 vs 0.065±0.027, p=0.003). CRT shortened interventricular delay significantly (45±33 vs 19±35xa0ms, p=0.05). In five patients the response to CRT was striking (32% increase in mean LV stroke volume, range 18–36%), while in the other five patients no response was observed (mean change +2%, range −6% to +4%). RV Kmono and LV stroke volume response to CRT correlated inversely (r=−0.66, p=0.034). None of the other measured parameters, including all LV parameters and electromechanical parameters, were associated with the response to CRT. In responders, RV Kmono with CRT OFF was significantly lower than in non-responders (0.036±0.01 vs 0.058±0.02, p=0.047).ConclusionCRT appears to enhance RV oxidative metabolism and metabolic reserve during stress. Patients responding to CRT appear to have lower RV oxidative metabolism at rest, suggesting that the RV plays a significant role in the response to CRT.

Motion detection and correction for dynamic 15O-water myocardial perfusion PET studies

PurposePatient motion during dynamic PET studies is a well-documented source of errors. The purpose of this study was to investigate the incidence of frame-to-frame motion in dynamic 15O-water myocardial perfusion PET studies, to test the efficacy of motion correction methods and to study whether implementation of motion correction would have an impact on the perfusion results.MethodsWe developed a motion detection procedure using external radioactive skin markers and frame-to-frame alignment. To evaluate motion, marker coordinates inside the field of view were determined in each frame for each study. The highest number of frames with identical spatial coordinates during the study were defined as “non-moved”. Movement was considered present if even one marker changed position, by one pixel/frame compared with reference, in one axis, and such frames were defined as “moved”. We tested manual, in-house-developed motion correction software and an automatic motion correction using a rigid body point model implemented in MIPAV (Medical Image Processing, Analysis and Visualisation) software. After motion correction, remaining motion was re-analysed. Myocardial blood flow (MBF) values were calculated for both non-corrected and motion-corrected datasets.ResultsAt rest, patient motion was found in 18% of the frames, but during pharmacological stress the fraction increased to 45% and during physical exercise it rose to 80%. Both motion correction algorithms significantly decreased (p<0.006) the number of moved frames and the amplitude of motion (p<0.04). Motion correction significantly increased MBF results during bicycle exercise (p<0.02). At rest or during adenosine infusion, the motion correction had no significant effects on MBF values.ConclusionSignificant motion is a common phenomenon in dynamic cardiac studies during adenosine infusion but especially during exercise. Applying motion correction for the data acquired during exercise clearly changed the MBF results, indicating that motion correction is required for these studies.

Quantification of liver perfusion with [15O]H2O-PET and its relationship with glucose metabolism and substrate levels

BACKGROUND/AIMSnHepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism.nnnMETHODSnLiver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods.nnnRESULTSnHepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009).nnnCONCLUSIONSnEstimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.

Coronary Artery Flow Velocity Profile Measured by Transthoracic Doppler Echocardiography Predicts Myocardial Viability After Acute Myocardial Infarction

Objective: To study whether flow velocity profile in the left anterior descending coronary artery (LAD) measured by transthoracic Doppler echocardiography (TTDE) predicts myocardial viability after reperfused anterior acute myocardial infarction (AMI). Patients and methods: 15 patients who had their first anterior ST elevation AMI and were successfully reperfused by coronary angioplasty and five controls without coronary artery disease were selected. Blood flow velocity spectrum was measured from the mid-LAD by TTDE 3 days after coronary angioplasty. Myocardial viability in the LAD region was quantified 3 months after AMI by relative uptake of 18F-fluorodeoxyglucose (FDG) imaged with positron emission tomography. Myocardium was graded as viable, partially viable or non-viable (relative FDG uptake >85%, 67–85% and <67%, respectively). Main outcome measures were diastolic deceleration time (DDT) of LAD flow velocity 3 days after AMI and myocardial viability 3 months after AMI. Results: DDT of LAD flow velocity correlated with myocardial FDG uptake in the LAD region (ru200a=u200a0.91, p<0.01). DDT was markedly longer in patients with viable myocardium (876±76 ms, nu200a=u200a3) than partially viable (356±89 ms, nu200a=u200a6, p<0.01), or non-viable myocardium (128±13 ms, nu200a=u200a6, p<0.01). In controls, DDT was comparable (909±76 ms, nu200a=u200a5) to patients with viable myocardium. DDT <190 ms was always associated with non-viable myocardium. Conclusions: DDT of LAD flow velocity is strongly associated with myocardial viability after reperfused anterior AMI. Non-invasive TTDE of the LAD may be used in the acute phase to predict long-term viability of the jeopardised myocardium.

Novel electrophilic synthesis of 6-[18F]fluorodopamine and comprehensive biological evaluation

Purpose6-[18F]Fluorodopamine (4-(2-aminoethyl)-5-[18F]fluorobenzene-1,2-diol, 6-[18F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[18F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15xa0GBq/μmol. We also sought to determine an extensive biodistribution pattern for 6-[18F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[18F]FDA. In addition, to investigate the safety profile of 6-[18F]FDA in larger animals, we performed in vivo studies in pigs.Methods6-[18F]FDA was synthesised using high SA electrophilic [18F]F2 as the labelling reagent. Biodistribution and metabolism of 6-[18F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs.Results6-[18F]FDA was synthesised with 2.6u2009±u20091.1% radiochemical yield. The total amount of purified 6-[18F]FDA was 663u2009±u2009291xa0MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2u2009±u20092.7xa0GBq/μmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[18F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[18F]FDA in rat plasma declined rapidly, with a half-life of 2xa0min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects.Conclusion6-[18F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[18F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[18F]FDA was specific in various peripheral organs, indicating that 6-[18F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.