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Mechanism of Disease New!
The failing heart -an engine out of fuel
Neubauer S.
N Engl J Med. 2007 Mar 15;356(11):1140-51.Review. No abstract available |
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| This review describes in depth cardiac energy metabolism, the methods used for its assessment and evaluates the role of impaired energy metabolism in heart failure with its implication for novel therapies. |
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| The paper points out that deprivation of an adequate amount of energy causes mechanical failure of the heart and thus plays a major role in the mechanism of heart failure. |
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| This review focus on : |
- The complexity of cardiac energy metabolism by underlying the role of the main components of the process: substrate utilization, oxidative phoshorylation and ATP transfer and utilization.
- The techniques available to assess the cardiac energy metabolism.
- The changes that occurs for each component in different stages of heart failure.
- Implication for the treatment of heart failure. Different strategies for metabolic intervention are described. The modulation of cardiac energy metabolism, by selective inhibition of fatty acid oxidation with FLAVEDON MR, shows major clinical benefits in the treatment of ischemic heart failure patients. FLAVEDON MR "improves left ventricular function over a period of 6 months in elderly patients; an 18-month study confirmed this finding in patients with heart failure due to a previous myocardial infarction."
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| Protective effect of an acute oral loading dose of Trimetazidine on myocardial injury following percutaneous coronary intervention. |
| Abstract |
Bonello L, Sbragia P, Amabile N, Com O, Pierre S, Levy S, Paganelli F.
Heart. 2007 May 8; [Epub ahead of print] |
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| This study demonstrates that pre-treatment with an acute oral loading dose of FLAVEDON MR before PCI limits myocardial damage, as shown by a lower total amount of troponin Ic release after coronary angioplasty. |
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| The results support the effectiveness of pre-treatment with FLAVEDON MR against ischemic reperfusion damage during angioplasty. |
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| [The best of cardiac rehabilitation in 2006] |
| Verges B, Iliou MC, Corone S, Pierre B, Meurin P, Fischbach M, Pavy B, Carre F, Feige JM, Brion R, Douard H; Groupe de Travail Evaluation Fontionnelle et Readaptation des Cardiaques. |
| Arch Mal Coeur Vaiss. 2007 Jan;100 Spec No 1:89-94. French. |
| Abstract |
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| This review paper on cardiac rehabilitation highlights the benefits of optimimizing medical treatment with FLAVEDON MR before starting exercise training. As the authors have stated, "The combination of trimetazidine with exercise training provides greater improvements in functional capacity, left ventricular function and the endothelium-dependent relaxation of the brachial artery than exercise training alone in patients with ischaemic cardiomyopathy referred for cardiac rehabilitation." Thus, treating the metabolic consequences of ischemia with FLAVEDON MR, by ensuring optimal symptom control and improvement of cardiac function, leads to synergic benefits to the cardiovascular system. |
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| Trimetazidine inhibits cardiomyocyte apoptosis in a rabbit model of ischemia-reperfusion. |
| Ruixing Y, Wenwu L, Al-Ghazali R. |
| Transl Res. 2007 Mar;149(3):152-60. |
| Abstract |
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| This study demonstrates that FLAVEDON MR pre-treatment before myocardium reperfusion decreases apoptotic index and malondialdehyde concentration, and increases serum superoxide dismutase levels in an animal model of ischemia-reperfusion. Similar results have been recently reported in patients undergoing cardiac surgery (Iskesen I et al. Circ J. 2006;70(9):1169-73). Thus, in patients scheduled for revascularization, FLAVEDON MR pre-treatment might play an important role in the protection of myocardium against ischemia reperfusion damage. |
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| Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease. |
| Marazzi G, Wajngarten M, Vitale C, Patrizi R, Pelliccia F, Gebara O, Pierri H, Ramires JA, Volterrani M, Fini M, Rosano GM. |
| Int J Cardiol. 120 (2007) 79-84 |
| Abstract |
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This study shows that in diabetic patients with coronary artery disease, FLAVEDON MR on top of standard care significantly reduces silent and symptomatic episodes of myocardial ischemia, as well as total ischemic burden. This study confirms the interest of FLAVEDON MR in the treatment of diabetic patients with coronary artery disease since repeated myocardial ischemia may cause deterioration in left ventricular function and thus, progression to diabetic ischemic cardiomyopathy.
So authors conclude that:
"our group and others have recently reported a reduction in cumulative events in patients with ischemic heart failure in whom trimetazidine was added on top of standard therapy further supporting the importance of this drug on top of standard care in the treatment of patients with ischemic heart failure." |
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| A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. |
| Fragasso G, Palloshi A, Pucetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A. |
| J Am Coll Cardiol. 2006 Sep;48(5):992- 8. |
| Abstract |
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The study shows that 13-month treatment with FLAVEDON MR on top of optimal standard therapy improves functional class and left ventricular function in patients with Heart Failure.
Moreover, brain natriuretic peptide (BNP) levels they significantly decreased in patients treated with FLAVEDON MR whereas they did not change in the conventional therapy group. |
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| Optimizing cardiac fatty acid and glucose metabolism as an approach to treating heart failure. |
| Lopaschuk GD. |
| Semin Cardiothorac Vasc Anesth. 2006 Sep;10(3):228-30. |
| Abstract |
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| This review highlights the growing evidence ".that in the failing heart, shifting metabolism away from a preference for fatty acids toward more carbohydrate oxidation can improve contractile function and slow the progression of pump failure". In fact, long term studies with FLAVEDON MR (a 3-KAT inhibitor) have demonstrated a significant improvement in left ventricular ejection fraction, both in short and long term as well as at rest or during a dobutamine stress test compared with placebo. As stated by the author, "The clinical improvement in heart failure.is associated with a switch in myocardial metabolism away from fatty acid oxidation towards more glucose uptake and carbohydrate oxidation." |
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| Trimetazidine improves post-ischemic recovery by preserving endothelial nitric oxide synthase expression in isolated working rat hearts. |
| Di Napoli P, Chierchia S, Taccardi AA, Grilli A, Felaco M, Caterina RD, Barsotti A. |
| Nitric Oxide. 2006 Sep 12; [Epub ahead of print] |
| Abstract |
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| This study confirms that the major anti-ischemic effect of FLAVEDON MR, which can be observed in the absence of any hemodynamic action, improves post-ischemic recovery during reperfusion and limits most of the detrimental effects of ischemia and reperfusion on cardiomyocytes and endothelial cells. |
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| Trimetazidine reduces oxidative stress in cardiac surgery. |
| Ihsan Iskesen, MD; Osman Saribulbul, MD; Mustafa Cerrahoglu, MD; Ahmet Var, MD; Yunus Nazli, MD; Hayrettin Sirin, MD. |
| Circ J. 2006 Sep;70(9):1169-73. |
| Abstract |
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| The study confirms that pretreatment with FLAVEDON MR reduces the Ischemia Reperfusion damage during cardiac surgery. |
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| Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. |
| Fragasso G, Perseghin G, DeCobelli F, Esposito A, Palloshi A, Lattuada G, Scifo P, Calori G, Del Maschio A, Margonato A. |
| Eur Heart J. 2006 Apr;27(8):942-8. |
| Abstract |
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| FLAVEDON MR increases PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate intracellular levels. This beneficial effect of FLAVEDON MR may certainly be associated with the improvement in functional class and left ventricular function. |
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| Trimetazidine in angina combination therapy - the TACT study: Trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. |
| Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, Rumiantzeva EG, Fitileva TB. |
| Am J Ther. 2005 Jan-Feb;12(1)35-42. |
| Abstract |
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| In TACT study, FLAVEDON MR has proven to ensure fully additional antianginal efficacy in angina patients uncontrolled by monotherapy with beta-blockers or long-acting nitrates . The combination of FLAVEDON MR with beta-blockers or long-acting nitrates significantly improves exercise stress test parameters and angina symptoms compared with placebo. |
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| Comparison of trimetazidine plus sildenafil to chronic nitrates in the control of myocardial ischemia during sexual activity in patients with coronary artery disease. |
| Rosano G, Marazzi G, Patrizi R, Cerquetani E, Vitale C, Volterrani M, Fini M, Mercuro G. |
| Am J Cardiol 2005; 95:327-331. |
| Abstract |
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| FLAVEDON MR and sildenafil is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long term nitrate therapy maybe safely switched to Flavedon therapy when therapy for erectile dysfunction is required. |
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| Effects of Trimetazidine on Myocardial Perfusion and the Contractile Response of Chronically Dysfunctional Myocardium in Ischemic Cardiomyopathy: A 24-Month Study |
| El-Kady T, El-Sabban K, Gabaly M, Ahmed Sabry A, Abdel-Hady S. |
| Am J Cardiovasc Drugs.2005;5:271-278. |
| Abstract |
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| The study results demonstrate that the metabolic intervention with FLAVEDON MR ensures an effective angina symptom relief and improves left ventricular function and myocardial perfusion. All these benefits were obtained with an excellent long-term tolerability profile. |
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| Long-term cardioprotective action of Trimetazidine and potential effect on the inflammatory process in patients with ischemic dilated cardiomyopathy. |
| Di Napoli P, Taccardi AA, Barsotti A. |
| Heart 2005;91:161-165 |
| Abstract |
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| The study shown that 18-month treatment with FLAVEDON MR added to the standard therapy improves functional status of the patients. Moreover, C-reactive protein plasma concentrations (CRP) remained stable throughout the study in FLAVEDON MR group suggesting that inflammatory response was limited in patients treated with FLAVEDON MR. |
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| Previous Studies |
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| Gupta R, Sawhney JPS and Narain VS.
Treatment of stable angina pectoris with trimetazidine
modified release in indian primary-care practice.
Am J Cardiovasc Drugs 2005;5(5):325-329 |
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| Vitale C, Wajngaten M, Sposato B et
al. Trimetazidine improves left ventricular
function and quality of life in elderly patients
with coronary artery disease. Eur Heart
J. 2004;25:1814-1821 |
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Genissel P et al. Assessment of the sustained
release properties of a new oral formulation
of trimetazidine in pigs and dogs and confirmation
in healthy human volunteers. Eur J Drug Metab
Pharmacokinet. 2004;29:61-68.
Abstract |
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| Fragasso G, De-Cobelli F, Esposito A et al.
Improved myocardial high-energy phosphate metabolism
induces by partial free fatty acid inhibition
in patients with heart failure J Am Coll
Cardiol. 2004;43(5 Suppl. A):1088-121. |
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| Rosano GM, Vitale C, Sposato B et al.
Effect of free fatty acid inhibition on left
ventricular function in diabetic patients with
coronary artery disease J Am Coll Cardiol.
2004;43(5 Suppl. A):1001-9. |
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| Rosano GM, Patrizi R, Marazzi G et al.
Comparative effect of trimetazidine plus sildenafil
versus nitrates in the control of myocardial
ischemia during sexual activity J Am Coll
Cardiol. 2004;43(5 Suppl. A):1023-94. |
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| Paloshi A, Fragasso G, Silipigni C et al.
Partial fatty acid inhibition by trimetazidine
improves left ventricular function in patients
with heart failure of different etiologies J
Am Coll Cardiol. 2004;43(5 Suppl. A):1088-115. |
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Kölbel F, Bada V. Trimetazidine in geriatric
patients with stable angina pectoris: the TIGER
study. Int J Clin Pract. 2003;57:867-870.
Abstract |
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Sellier P, Broustet JP. Assessment of
anti-ischemic and anti-anginal effect at trough
plasma concentration and safety of trimetazidine
MR 35 mg in patients with stable angina pectoris.
Am J Cardiovasc Drugs. 2003;3:361-369.
Abstract |
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Barré J. Pharmacokinetic profile of a
modified-release formulation of trimetazidine
(TMZ MR 35 mg) in the elderly and patients with
renal failure. Biopharm Drug Dispos.
2003;24:159-164.
Abstract |
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Manchanda SC. Treatment of stable angina
with low dose diltiazem in combination with
the metabolic agent trimetazidine. Int J
Cardiol. 2003;88:83-89.
Abstract |
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Marzilli M, Klein W. Efficacy and tolerability
of trimetazidine in stable angina: a meta-analysis
of randomized, double-blind, controlled trials.
Coron Artery Dis. 2003;14:171-179.
Abstract |
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| Rosano G. et al. Trimetazidine improves
left ventricular function and quality of life
in elderly patients with coronary artery disease.
Eur Heart J. 2004;6:1-8. |
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Fragasso G. et al. Short- and long-term
beneficial effects of trimetazidine in patients
with diabetes and ischemic cardiomyopathy. Am
Heart J. 2003;146:e18-e25.
Abstract |
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Rosano G. et al. Trimetazidine improves
left ventricular function in diabetic patients
with coronary artery disease : a double-blind
placebo-controlled study. Cardiovasc Diabetol.
2003;2:16.
Abstract |
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| Romano M et al. Trimetazidine in patients
with previous myocardial revascularization and
left ventricular dysfunction. An exercise testing
and radionuclide study. It J Pract Cardiol.
2003;0:29-36. |
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