Otman Sarrhini

Abnormal in vivo myocardial energy substrate uptake in diet-induced type 2 diabetic cardiomyopathy in rats

The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET (microPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [(18)F]fluorodeoxyglucose ([(18)F]FDG) was reduced by approximately 81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [(18)F]fluorothia-6-heptadecanoic acid ([(18)F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [(11)C]acetate and myocardial perfusion index as assessed by [(13)N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by microPET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was approximately 40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [(18)F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA.

Simultaneous attenuation and scatter corrections in small animal PET imaging

The aim of this work is to simultaneously correct for attenuation and scatter in positron emission tomography (PET) by analytically assessing the distribution of the scattered photons using the emission images, the probability of scatter interactions and the detection efficiency. Above the usual lower energy threshold of 300 keV, the attenuated photons are dominantly those which have undergone a Compton scattering. A simple equation is established by considering that each voxel in the image is the measurement of the transmitted photons through the subject, added to the contribution from the other sources by means of their scatter. The solution of this equation allows to correct from scatter and attenuation simultaneously. This new method was applied for data measured with the Sherbrooke small animal PET scanner in line sources, hot spot phantoms, and in rat hearts and tumors.

Angiotensin II Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling and Myocardial Energetics in Experimental Aortic Regurgitation

Background—Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation. Methods and Results—Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use. Conclusions—In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial.

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

BackgroundPatients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR.MethodsLV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months.ResultsMicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them.ConclusionThis study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.

Assessment of inflammation in large arteries with 18F-FDG-PET in elderly.

This paper presents repeated measurements of atherosclerosis using bimodality positron emission tomography and computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) to assess its uptake in aorta, iliac and femoral arteries in three groups of elderly subjects classified as normals (N), hypercholesterolemics (H) and with stable angina (A) in a 12 months follow-up (T0 to T12). The subjects in group H were taking rosuvastatin (20mg/d) for 12 months before the second scan. The calcifications in the arteries were determined by CT imaging and the artery PET images were analyzed slice by slice. The standard uptake values (SUVs) for 18F-FDG uptake were classified in two main groups: calcified and non-calcified arteries and each main group comprises six sub-groups for the three subject groups N, H and A, and for the two measurements 12 months apart. Although the calcifications were present at some portions of the arteries in all subjects (23%, 36% and 44% of calcified sites to total sites analyzed, respectively, in groups N, H and A), the results show the most noticeable SUV changes after 12 months was in group N of non-calcified arteries. In the three groups, the calcified arteries showed no significant differences between T0 and T12 while significant differences were observed for the non-calcified arteries. However, there were no significant changes at T12 between groups N and H following rosuvastatin intake in group H. In conclusion, the quantitative analysis with 18F-FDG-PET/CT could be efficient in the localization of the inflammation and evaluation of its progression in atherosclerosis instead of global evaluations with systemic inflammation biomarkers.

Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

Left ventricular hypertrophy (LVH) is often associated with a change in myocardial energy substrate preference from fatty acids to glucose. A possible anti hypertrophic treatment strategy could aim at stimulating or restoring normal myocardial energy metabolism. Metformin, an adenosine monophosphate-activated protein kinase (AMPK) activator used in the management of glucose metabolism in diabetes, is also a fatty acid oxidation stimulator. The effect of metformin on the development of eccentric LVH and ventricular function in chronic left ventricular (LV) volume overload (VO) is unknown. This study was designed to study this question in a VO rat model caused by severe aortic valve regurgitation (AR). Male Wistar rats were divided in four groups (13-15 animals / group): Shams (S) treated or not (C) with metformin (M; 100 mg/kg/d PO) and severe ARreceiving or not metformin. Treatment was started one week before surgery and the animals were sacrificed 9 weeks later. As expected AR rats developed severe eccentric LVH during the course of the protocol. Metformin treatment did not influence the total heart weight. However, LV remodeling associated with the severe VO was severe in ARM than in ARC. Fractional shortening, a marker of systolic function, was significantly higher in ARM compared to ARC group. Metformin also increased the activity of enzymes associated with fatty acid oxidation while inhibiting phosphofructokinase, a glycolytic enzyme. A 2 month treatment with metformin reduced LV eccentric remodeling associated with severe VO and helped maintain a better systolic function.

Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism

Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA β-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling.

A real-time follow-up of photodynamic therapy during PET imaging

PURPOSE To monitor a real-time follow-up of tumor response to photodynamic therapy (PDT) by dynamic 2-deoxy-2-[(18)F]fluoro-d-glucose ((18)FDG) and positron emission tomography (PET) using two photosensitizing drugs in vivo, and to assess their mechanisms of action. METHODS Two types of photosensitizers with different action mechanisms were used in rats implanted with two tumors: AlPcS4 mainly affecting the tumor vascular system, and ZnPcS2 largely inducing direct cell kill. Twenty-four hours after administration of either photosensitizer, one tumor served as control while the other was treated with red light during 30min within the 2h PET imaging by infusion of (18)FDG. The usual two-tissue compartment kinetic model was modified to take into account the perturbation of the treatment during imaging. RESULTS The illumination of the tumors during PET imaging provoked a net decrease of (18)FDG uptake in tumors treated with AlPcS4 and a near total absence of (18)FDG uptake in tumors treated with ZnPcS2. After the end of illumination, the tumors regained (18)FDG uptake with a more pronounced uptake in the tumors treated with ZnPcS2. The rate constant values of the new (18)FDG kinetic model reflected the response of the tumors to the treatment in both photosensitizers. CONCLUSIONS Dynamic PET imaging can be used to quantitatively assess in vivo and in real-time the response of tumors to treatments. It is demonstrated that the 30min of treatment was not sufficient to reduce the activity of the tumors. The technique could be extended to directly monitor the effects of drugs in vivo.

Arterial input function sampling without surgery in rats for positron emission tomography molecular imaging.

AimThe purpose of this study was to develop a minimally invasive procedure to derive an arterial input function (AIF) in rats through tail artery blood sampling for pharmacokinetic modeling in preclinical PET molecular imaging studies. The procedure involved a microvolumetric blood counter (&mgr;BC) and a correction to compensate for delay and dispersion of the automatic blood sampling. Materials and methodsAIFs were simultaneously obtained from femoral and tail arteries in rats, manually and using a &mgr;BC, after 18F-FDG injection (n=6) in order to compare the shape of the AIFs and the kinetic analysis results at equilibrium and after implementation of a dispersion correction method. These AIFs were used to estimate the myocardial metabolic rate of glucose (MMRG). AIFs were also obtained from a single withdrawal site by three methods to confirm accurate MMRG values: manual tail artery (n=5), &mgr;BC tail artery (n=5), and &mgr;BC femoral artery (n=3). ResultsSimultaneous withdrawal at equilibrium results in similar AIF shapes and influx rate constants (Ki) from Patlak analysis (P>0.05). Manually withdrawn and dispersion-corrected &mgr;BC AIFs in the simultaneous experiment did not reveal statistically different shapes and constants (K1, Ki) from a three-compartment kinetic analysis, regardless of the withdrawal methods or sites (P>0.05). Kinetic analysis of the three single-site blood sampling methods yielded similar MMRG (one-way ANOVA; Patlak, P=0.52; three-compartment, P=0.10). ConclusionBoth minimally invasive manual withdrawal and dispersion-corrected &mgr;BC-based blood sampling in the tail artery are reliable methods for deriving AIFs for pharmacokinetic follow-up studies in the same animal.

A comparison of a Monte Carlo-based detection probability matrix with analytical probability matrix for small animal PET scanners

Positron Emission Tomography (PET) offers the possibility to quantitatively measure the radiotracer distribution in tissues. In order to obtain images of these tissues, the detection probability matrix (DPM) must be accurately determined. Usually, DPM is analytically calculated. However, this approach does not take into account the whole probabilistic interactions of the photons. On the other hand, Monte Carlo simulations (MC) are more accurate to calculate the DPM as they selectively consider diverse photon interactions. In this work, MC DPM (MCDPM) and analytically calculated DPM (ACDPM) were compared in terms of image quality. The results showed that the images obtained from the MCDPM were qualitatively better resolved and provided a significant improvement of the signal-to-noise ratio (SNR). The MCDPM yielded to an increase of up to 40% in SNR and up to 25% in contrast in comparison with ACDPM. On the other hands, MCDPM enhanced the counts distribution by more than 12% with respect to ACDPM.