Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.

Characterized by excessive myocardial glycogen deposition, cardiac hypertrophy, frequent cardiac arrhythmias and progressive conduction system disease, the PRKAG2 cardiac syndrome stems from a genetic mutation in the γ2-subunit of AMP-activated protein kinase (AMPK). Although functionally diverse, the main role of AMPK is to modulate cardiac metabolism in response to depleted ATP levels. A comprehensive study of the dysfunctional regulation of AMPK activity involved in the progression of the human PRKAG2 cardiac syndrome is hindered by the limitations of in vitro techniques. Positron emission tomography (PET) imaging with the glucose analogue, FDG, offers a quantitative assessment of myocardial glucose uptake non-invasively. The aim of this thesis was to determine the ability of FDG to detect changes in glucose uptake, storage and metabolism in the heart in relation to AMPK activity and provide insights into the mechanism of PRKAG2 cardiac hypertrophy. To achieve this aim, a transgenic AMPK γ2-subunit Arg302Gln mouse model was evaluated with small animal FDG PET with correlation to biochemical assays of cardiac AMPK activity and the glycogen metabolism pathway. Using the vena cava blood input function, FDG myocardial glucose uptake was reliably assessed in mice for the first time with Patlak modeling. Reduced FDG uptake in the Arg302Gln PRKAG2 mouse model suggested a feedback pathway reducing exogenous glucose uptake due to excessive intracellular glycogen stores. Despite an increase in FDG uptake in the skeletal muscle of the PRKAG2 mutant mice following insulin stimulation, there was no change in cardiac uptake, signifying myocardial insulin resistance. Increased reliance on glucose oxidation by TMZ inhibition of fatty acid oxidation reduced glycogen stores, restored cardiac function and eliminated ventricular preexcitation. The observed reduction in mouse myocardial FDG uptake mirrors the reduction previously observed in the human PRKAG2 patients. The potential now exists to evaluate both progression and therapeutic interventions for the PRKAG2 cardiac syndrome with the transgenic mouse model with translation to the affected patients using FDG cardiac imaging.

Trimetazidine, a clinically effective antianginal agent with no negative inotropic or vascular properties, acts by optimizing cardiac energy metabolism through inhibition of free faty acid oxidation, shifting substrate utilization from fatty acids to glucose. Up to now there has been no study associating trimetazidine's effect on metabolic processes with glucose utilization in the mammalian brain. The objective of the present study was to determine if trimetazidine altered [3H]glucose uptake in rat brain. Adult male Wistar rats were administered trimetazidine (Metazydyna, Polfa) either as a single dose (10.0 mg/kg po) or for 14 consecutive days (5.0 mg/kg po per day) or vehicle saline (2.0 ml/kg po). Sixty minutes after the single dose or 14th dose of trimetazidine, and 15 min before experiment termination and brain dissection, 6-[3H]D-glucose (500 Ci/kg ip; Amersham) was administered. Using liquid scintillation counting, trimetazidine, either in a single or multiple dose regimen, was found to increase [3H]glucose uptake (DPM/100 mg of wet tissue) in all dissected regions of the brain (i.e., striatum, hippocampus, frontal cortex, thalamus with hypothalamus, pons with medulla oblongata, and cerebellum). Therefore, central effects need to be taken into considereation as possibly adding to known beneficial cardiac effects of trimetazidine.

La mort subite d’origine cardiaque est fréquemment rencontrée chez les sportifs de haut niveau ayant recours à des produits illicites afin d’accroitre leur performances physiques. Parmi les substances consommées, les stéroïdes anabolisants occupent une place importante. L’objectif de notre travail était : 1) de préciser la nature exacte des lésions cardiaques consécutives à l’usage des stéroïdes anabolisants chez les sportifs décédés de morts subites et chez les lapins traités par la noréthandrolone (NED) et la testostérone (TST); 2) d’en élucider le(s) mécanisme(s) responsable(s) et enfin ; 3) de vérifier si des substances à effets antiischémiques (trimétazidine : TMZ) ou cardioprotecteurs (dexrazoxane : DEX) pouvaient protéger le cœur « agressé » par un stéroïde anabolisant et prévenir le développement de telles lésions / Sudden death of cardiac origin is frequently observed in athletes with a history of illicit products abuse to increase physical performance. Anabolic steroids play a significant role amongst these substances. The aim of this work was: 1) to precisely describe the nature of heart lesions resulting from anabolic steroid abuse in athletes who suddenly died, and in rabbits treated with norethandrolone (NED) or testosterone (TST); 2) to elucidate the underlying mechanism(s) and finally; 3) to test whether anti-ischemia (trimetazidine: TMZ) or cardioprotective (dexrazoxane: DEX) drugs could protect the heart from anabolic steroids and prevent the development of lesions

Objetivos: Avaliar a eficácia anti-isquêmica e efeito metabólico da trimetazidina em pacientes com angina refratária e diabete melito (DM) tipo 2, em uso de pelo menos duas medicações de efeito hemodinâmico, sem condições de revascularização. Métodos: Ensaio clínico randomizado, cruzado, duplo-cego, conduzido em 10 pacientes com DM tipo 2 e angina estável, em tratamento com pelo menos 2 anti-anginosos clássicos. Pacientes foram randomizados para receber trimetazidina (20 mg 3 vezes ao dia) ou placebo, por períodos de 6 semanas. Avaliação clínica, laboratorial, ergométrica e monitorização de pressão arterial (MAPA) e Holter de 24 horas foram realizadas no início do estudo e ao término de 6 semanas de cada intervenção. Resultados: Os pacientes em tratamento com trimetazidina apresentaram melhora significativa na classe funcional da angina (p<0,05), com diminuição significativa no número de episódios de crise anginosa por semana e na dose de nitrato sub-lingual utilizada (p<0,05). O tempo de início da isquemia no teste ergométrico foi maior após o uso da trimetazidina (229 ± 126 s no basal, 276 ± 101 s após o placebo e 348 ± 145 s após a trimetazidina; p<0,05). Não houve diferença nos níveis de pressão arterial, freqüência cardíaca e duplo-produto nas 24h, avaliadas concomitantemente com Holter e MAPA, ou no controle glicêmico e lipídico entre as intervenções. Conclusões: O uso da trimetazidina mostrou-se eficaz como tratamento coadjuvante da angina estável de difícil manejo em pacientes com DM tipo 2 em uso de múltiplos anti-anginosos, sem alteração de variáveis hemodinâmicas avaliadas nas 24 h. Estes dados ampliam o espectro de emprego da trimetazidina no manejo de pacientes sintomáticos e com limitadas opções de tratamento. / Aims: To evaluate the anti-ischemic and metabolic effect of trimetazidine in patients with refractory angina and type 2 diabetes (DM2) not eligible for revascularization and using at least two hemodynamic agents. Methods: Randomized, double-blind, crossover clinical trial conducted in 10 patients. Patients were randomized to receive trimetazidine (20 mg 3 times a day) or placebo for 6-week periods. Clinical and exercise evaluations, in addition to 24-h ambulatory blood pressure and Holter monitoring were carried out at baseline and at the end of each 6-week intervention period. Results: The patients receiving trimetazidine presented significant improvement in terms of angina functional class (p<0.05), with decrease in the number of weekly angina episodes at rest and in the sublingual nitrate dose (p<0.05). Time to 1 mm ST-segment depression was increased after trimetazidine use (229.2 ± 126.1 s at baseline, 276.3 ± 100.9 s after placebo and 347.5 ± 144.6 s after trimetazidine; p<0.001). No differences were observed between treatments group in terms of 24h-blood pressure, heart rate and ratepressure product as evaluated concomitantly with ambulatory blood pressure and Holter monitoring, or in terms of glycemic and lipid profile. Conclusions: The combined use of trimetazidine and haemodynamic agents was efficient to treat stable refractory angina in DM2 patients, significantly improving clinical and exercise parameters. The present data support the use of trimetazidine in the management of symptomatic patients with limited treatment options.

Objetivos: Avaliar a eficácia anti-isquêmica e efeito metabólico da trimetazidina em pacientes com angina refratária e diabete melito (DM) tipo 2, em uso de pelo menos duas medicações de efeito hemodinâmico, sem condições de revascularização. Métodos: Ensaio clínico randomizado, cruzado, duplo-cego, conduzido em 10 pacientes com DM tipo 2 e angina estável, em tratamento com pelo menos 2 anti-anginosos clássicos. Pacientes foram randomizados para receber trimetazidina (20 mg 3 vezes ao dia) ou placebo, por períodos de 6 semanas. Avaliação clínica, laboratorial, ergométrica e monitorização de pressão arterial (MAPA) e Holter de 24 horas foram realizadas no início do estudo e ao término de 6 semanas de cada intervenção. Resultados: Os pacientes em tratamento com trimetazidina apresentaram melhora significativa na classe funcional da angina (p<0,05), com diminuição significativa no número de episódios de crise anginosa por semana e na dose de nitrato sub-lingual utilizada (p<0,05). O tempo de início da isquemia no teste ergométrico foi maior após o uso da trimetazidina (229 ± 126 s no basal, 276 ± 101 s após o placebo e 348 ± 145 s após a trimetazidina; p<0,05). Não houve diferença nos níveis de pressão arterial, freqüência cardíaca e duplo-produto nas 24h, avaliadas concomitantemente com Holter e MAPA, ou no controle glicêmico e lipídico entre as intervenções. Conclusões: O uso da trimetazidina mostrou-se eficaz como tratamento coadjuvante da angina estável de difícil manejo em pacientes com DM tipo 2 em uso de múltiplos anti-anginosos, sem alteração de variáveis hemodinâmicas avaliadas nas 24 h. Estes dados ampliam o espectro de emprego da trimetazidina no manejo de pacientes sintomáticos e com limitadas opções de tratamento. / Aims: To evaluate the anti-ischemic and metabolic effect of trimetazidine in patients with refractory angina and type 2 diabetes (DM2) not eligible for revascularization and using at least two hemodynamic agents. Methods: Randomized, double-blind, crossover clinical trial conducted in 10 patients. Patients were randomized to receive trimetazidine (20 mg 3 times a day) or placebo for 6-week periods. Clinical and exercise evaluations, in addition to 24-h ambulatory blood pressure and Holter monitoring were carried out at baseline and at the end of each 6-week intervention period. Results: The patients receiving trimetazidine presented significant improvement in terms of angina functional class (p<0.05), with decrease in the number of weekly angina episodes at rest and in the sublingual nitrate dose (p<0.05). Time to 1 mm ST-segment depression was increased after trimetazidine use (229.2 ± 126.1 s at baseline, 276.3 ± 100.9 s after placebo and 347.5 ± 144.6 s after trimetazidine; p<0.001). No differences were observed between treatments group in terms of 24h-blood pressure, heart rate and ratepressure product as evaluated concomitantly with ambulatory blood pressure and Holter monitoring, or in terms of glycemic and lipid profile. Conclusions: The combined use of trimetazidine and haemodynamic agents was efficient to treat stable refractory angina in DM2 patients, significantly improving clinical and exercise parameters. The present data support the use of trimetazidine in the management of symptomatic patients with limited treatment options.

Objetivos: Avaliar a eficácia anti-isquêmica e efeito metabólico da trimetazidina em pacientes com angina refratária e diabete melito (DM) tipo 2, em uso de pelo menos duas medicações de efeito hemodinâmico, sem condições de revascularização. Métodos: Ensaio clínico randomizado, cruzado, duplo-cego, conduzido em 10 pacientes com DM tipo 2 e angina estável, em tratamento com pelo menos 2 anti-anginosos clássicos. Pacientes foram randomizados para receber trimetazidina (20 mg 3 vezes ao dia) ou placebo, por períodos de 6 semanas. Avaliação clínica, laboratorial, ergométrica e monitorização de pressão arterial (MAPA) e Holter de 24 horas foram realizadas no início do estudo e ao término de 6 semanas de cada intervenção. Resultados: Os pacientes em tratamento com trimetazidina apresentaram melhora significativa na classe funcional da angina (p<0,05), com diminuição significativa no número de episódios de crise anginosa por semana e na dose de nitrato sub-lingual utilizada (p<0,05). O tempo de início da isquemia no teste ergométrico foi maior após o uso da trimetazidina (229 ± 126 s no basal, 276 ± 101 s após o placebo e 348 ± 145 s após a trimetazidina; p<0,05). Não houve diferença nos níveis de pressão arterial, freqüência cardíaca e duplo-produto nas 24h, avaliadas concomitantemente com Holter e MAPA, ou no controle glicêmico e lipídico entre as intervenções. Conclusões: O uso da trimetazidina mostrou-se eficaz como tratamento coadjuvante da angina estável de difícil manejo em pacientes com DM tipo 2 em uso de múltiplos anti-anginosos, sem alteração de variáveis hemodinâmicas avaliadas nas 24 h. Estes dados ampliam o espectro de emprego da trimetazidina no manejo de pacientes sintomáticos e com limitadas opções de tratamento. / Aims: To evaluate the anti-ischemic and metabolic effect of trimetazidine in patients with refractory angina and type 2 diabetes (DM2) not eligible for revascularization and using at least two hemodynamic agents. Methods: Randomized, double-blind, crossover clinical trial conducted in 10 patients. Patients were randomized to receive trimetazidine (20 mg 3 times a day) or placebo for 6-week periods. Clinical and exercise evaluations, in addition to 24-h ambulatory blood pressure and Holter monitoring were carried out at baseline and at the end of each 6-week intervention period. Results: The patients receiving trimetazidine presented significant improvement in terms of angina functional class (p<0.05), with decrease in the number of weekly angina episodes at rest and in the sublingual nitrate dose (p<0.05). Time to 1 mm ST-segment depression was increased after trimetazidine use (229.2 ± 126.1 s at baseline, 276.3 ± 100.9 s after placebo and 347.5 ± 144.6 s after trimetazidine; p<0.001). No differences were observed between treatments group in terms of 24h-blood pressure, heart rate and ratepressure product as evaluated concomitantly with ambulatory blood pressure and Holter monitoring, or in terms of glycemic and lipid profile. Conclusions: The combined use of trimetazidine and haemodynamic agents was efficient to treat stable refractory angina in DM2 patients, significantly improving clinical and exercise parameters. The present data support the use of trimetazidine in the management of symptomatic patients with limited treatment options.