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RESEARCH PROGRAM
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Research Units
Similar research programs:
- 1 - Genomic and non genomic effects of DITPA (partial T3 analogue) on cardiac function, endothelium dependent vasodilation and metabolic profile in experimental animals and in patients affected by heart failure, with or without low-T3 syndrome.
- 2 - Clinical, genetic and molecular markers of susceptibility to atrial fibrillation: an integrated approach to the prevention and treatment of the arrhythmia and its complications.
- 3 - Cancer Treatment Related Cardiotoxicity Involves Resident Myocardial Progenitor Cells
- 4 - Early cardiovascular damage in obese children and adolescents: the identification of genetic and/or metabolic risk factors may allow precocious diagnosis and improve the quality of future life
- 5 - PLEIOTROPIC MOLECULAR EFFECTS OF PHOSPHODIESTERASE 5 INHIBITION
- 6 - Study of aldosterone genomic effects in cellular and in vivo models.
- 7 - Animal models of normal and pathological development and differentiation of the central nervous system
- 8 - Parkinson’s disease and dopaminergic stimulation: cardiovascular, behavioural and vigilance’s alterations
- 9 - EFFECTS OF PHOSPHODIESTERASE TYPE 5 INIBITORS (PDE5i) ON SEXUAL, ENDOCRINE AND VASCULAR HEALTH
- 10 - MOLECULAR AND CELLULAR MECHANISMS OF CARDIAC REMODELING AND NEW APPROACHES TO THERAPY.
Scientific and education field classification
International Patent Classification
- HUMAN NECESSITIES
- MEDICAL OR VETERINARY SCIENCE; HYGIENE
- DIAGNOSIS; SURGERY; IDENTIFICATION (analysing biological material G01N, e.g. G01N33/48; obtaining records using waves other than optical waves, in general G03B42/00)
- THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- MEDICAL OR VETERINARY SCIENCE; HYGIENE
Geographical classification
- Region: Campania
Bibliografia
1. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 108:2941-2948,20032. Marceille JR, Goins JA, Soni R, Biery JC, Lee TA. Chronic heart failure-related interventions after starting rosiglitazone in patients receiving insulin. Pharmacotherapy 24:1317-22,2004
3. Bristol-Meyer Squibb Company. Glucophage and Glucophage XR prescribing information, 2002
4. Tang WHW, Francis GS, Hoogwert BJ, Young JB. Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure. J Am Coll Cardiol 41:1394-1398,2003
5. Buse JB. Glitazones and heart failure: critical appraisal for the clinician. Circulation 108:e57,2003
6. Rajagopalan R, Rosenson RS, Fernandes AW, Khan M, Murray FT. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Clin Ther 26:1400-1410,2004
7. Inzucchi SE, Masoudi FA, Wang Y, Kosiborod M, Foody JM, Setaro JF, Havranek EP, Krumholz HM. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: insights from the National Heart Care Project. Diabetes Care 28:1680-1689,2005
8. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111:583-590,2005
9. St John Sutton M, Rendell M, Dandona P, Dole JF, Murphy K, Patwardhan R, Patel J, Freed M. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 25:2058-2064,2002
10. Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46:433-439,1997
11. Zhu P, Lu L, Xu Y, Schwartz GG. Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation 101:1165-1171,2000
12. Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K. Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker fatty rat heart. Diabetes 51:1110-1117,2002
13. Wayman NS, HattoriY, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 16:1027-1040,2002
14. Yue T-L, Bao W, Gu J-L, Cui J, Tao L, Ma X-L, Ohlstein EH, Jucker BM. Rosigltazone treatment in Zucker diabetic fatty rats is associated with ameliorated cardiac insulin resistance and protectin from ischemia/reperfusion-induced myocardial infarction. Diabetes 54:554-562,2005
15. Abdelrahman M, Sivarajah A, Thiemermann C. Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock. Cardiovasc Res 65:772-781,2005
16. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S. The PPARgamma-activator rosiglitazone does not alter remodelling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 58:632-637,2003
17. McCormack J, Johns K, Tildesley H. Metformin’s contraindications should be contraindicated. CMA J 173:502-504,2005
18. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet 352:854-865,1998
19. Cittadini A, Stromer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat. A combined in vivo and in vitro evaluation. Circulation 93:800-809,1966
20. Cittadini A, Isgaard J, Monti MG, Casaburi C, Di Gianni A, Serpico R, Iaccarino G, Sacca L. Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol 41:2154-63,2003
21. Cittadini A, Monti MG, Isgaard J, Casaburi C, Stromer H, Di Gianni A, Serpico R, Saldamarco L, Vanasia M, Saccà L. Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure. Cardiovasc Res 58:555-564,2003
22. Palmieri EA, Benincasa G, Di Rella F, Casaburi C, Monti GM, De Simone G, Chiarotti L, Palombini L, Bruni CB, Saccà L, Cittadini A. Differential expression of TNF-alpha, IL-6, and IGF-1 by graded mechanical stress in normal rat myocardium. Am J Physiol 282:H926-934,2002
23. D’Ascia C, Cittadini A, Monti GM, Riccio G, Saccà L. Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-{alpha} expression, and apoptotic death in failing human myocardium. Eur Heart J 27:201-206,
2006
Keywords
ROSIGLITAZONE, METFORMIN, SHHF RAT, INSULIN-RESISTANCE, ISOLATED WHOLE HEART, HEART FAILURE, HYPERTENSION, OBESITY, DIABETESEffects of Rosiglitazone and Metformin on the Development and Progression of Chronic Heart Failure in a model of insulin-resistance and heart failure
Università degli Studi di Napoli "Federico II"Abstract
The thiazolidinediones (TZDs) rosiglitazone and pioglitazone represent a relatively new class of insulin-sensitizing agents, recommended for the treatment of type 2 diabetes. TZDs have been extensively investigated with regard to their metabolic effects, but to a lesser extent as to their interaction with heart structure and function. Understanding of this interaction is particularly relevant for several reasons: 1) type 2 diabetes is marked by increased incidence of cardiovascular complications, including myocardial infarction, heart failure, and stroke, and these events account for more than 70% of mortality in diabetic patients; 2) TZDs use has been even associated with first appearance of symptoms of heart failure. Consequently, it is recommended to use TZDs cautiously in patients with CHF. Data from large cohorts of patients with type 2 diabetes have shown that TZD therapy is associated with significantly lower incidence of heart failure as compared with insulin therapy and that the association of TZD and metformin results in lower mortality in patients discharged after hospitalization for acute myocardial infarction. As with TZDs, the current contraindication to metformin use in diabetes associated with CHF causes some frustration to clinicians who want to exploit the many beneficial effects of the drug in their diabetic patients. Again, the real question is whether the postulated risks of metformin use in CHF are greater than or even outweighed by the benefits. The >>>Principal Investigator
Luigi Saccà Università degli Studi di NAPOLI "Federico II"Research Objectives
The main objective of this study is to explore the effect of rosiglitazone as monotherapy and the combination of rosiglitazone and metformin on progressive cardiac remodelling and dysfunction, and subsequent CHF in an animal model of insulin resistance and metabolic syndrome. The model employed will allow us to get insights into the cellular and molecular mechanisms underlying the cardiac interaction of rosiglitazone and metformin. In particular, the study will generate data regarding the effect of the drugs on myocardial structure and ventricular geometry (cell size, interstitial fibrosis, and capillary density) and the expression of regulatory proteins of contractility and cardiomyocyte survival (SERCA2, cytokines, apoptosis, etc)Significance of the Project
The effects of TZDs on the heart have been the object of several studies. Most of them suffer from the limitation inherent in acute experiments carried out in the isolated perfused heart or in the ischemia-reperfusion model. Clearly, in these conditions TZDs have a reduced potential to fully exert their effects, given the impossibility for TZDs to affect the metabolic environment as they do in the clinical reality.
On the other hand, little attention has focused on the effects of TZDs on progressing heart failure and even less on the crucial question whether TZDs impact on the biology of CHF in diabetic or severe insulin resistant models. The current approach has the potential to provide >>>
Timescale
12 monthsNational and international background
The thiazolidinediones (TZDs) rosiglitazone and pioglitazone represent a relatively new class of insulin-sensitizing agents, largely recommended for the treatment of type 2 diabetes. TZDs have been extensively investigated with regard to their metabolic effects, but to a lesser extent as to their interaction with heart structure and function. Full understanding of this interaction is particularly relevant for several reasons: 1) type 2 diabetes is marked by increased incidence of cardiovascular complications, including myocardial infarction, heart failure, and stroke, and these events account for more than 70% of mortality in diabetic patients; 2) TZDs use in patients with diabetes associated with chronic heart failure (CHF) may exacerbate heart disease, and this is more likely to occur when TZDs are administered in combination with insulin (1); 3) in some patients, TZDs use has been even associated with first appearance of symptoms of heart failure (2). Consequently, it is recommended to use TZDs cautiously in patients with class I or II NYHA, whereas in patients with class III or IV NYHA, TZDs should not be used at all (1).The current guidelines pose a major clinical dilemma, given the rising prevalence of the association between diabetes and CHF. The matters are further complicated by the fact that also metformin, another key agent in the treatment of type 2 diabetes, has received warning against prescription in patients with CHF that requires pharmacological >>>
