6 General discussion
6.1 Clinical implications and future perspectives
Clinical implications of this study involve novel targets in the search of better treatment of complications due to diabetic cardiomyopathy, including FOXO3a, Sirt1 and p38. Here I have shown beneficial effects of oral treatment with levosimendan in reducing ventricular remodelling in diabetic cardiomyopathy.
Since marketing authorisation, the use of levosimendan has increased steadily and is now approved in 47 countries worldwide. Today levosimendan is widely used in cardiac emergency units and is recoginsed as an alternative for the management of decompensated heart failure. Its off-label use is also gaining ground, including use in states such as septic shock, perioperative cardiac support and ischemic heart disease and cardiogenic schock.
78 7 Conclusions
The aims of the studies were to investigate in more detail the molecular mechanisms ofdiabetic cardiomyopathy in spontaneously diabetic Goto-Kakizaki rats, a model of type 2 diabetes. Specifically I examined the role of Sirt1 – p53 and Akt – FOXO3a pathways in the advent of ventricular remodelling. Ventricular remodelling in diabetic rats was further aggravated by experimental myocardial infarction. In this model of post-MI heart failure and ventricular remodelling I studied the cardiovascular effects of oral calcium sensitizer therapy with levosimendan. The main findings in the studies were:
I. Ventricular remodelling in diabetic GK rats was associated with increased LVH, systolic dysfunction and increased apoptotic signalling and activation of the FOXO3a pathway. The study further suggested a role for Sirt1 in growth and counteracting apoptosis in diabetic cardiomyopathy.
II. Post-myocardial infarction in GK rats was associated with increased LVH, sustained cardiomyocyte apoptosis and interstitial fibrosis. This study established the initial finding that FOXO3a activation was associated with Akt dephosphorylation after MI and that Sirt1 – p53 deacetylation was increased post-MI. Furthermore, the data indicated that p38 MAPK protein phosphorylation was increased after MI in GK rat hearts.
III. A 12 –week regimen of oral levosimendan exerted beneficial effects on ventricular remodelling by decreasing cardiomyocyte apoptosis, hypertrophy and markers of cellular senescence. The study provided a role for levosimendan in the treatment of diabetes-induced ventricular remodelling in post-MI heart failure.
IV. The beneficial effects of levosimendan on systolic function and ventricular remodelling were evident at 4 weeks post-MI. The effects were associated with changes in the gene expression profile in the diabetic GK rat myocardium including downregulation of the hydroxyprostaglandin dehydrogenase 15 (Hpgd) gene and the mammalian target of rapamycin (mTOR) gene.
79 8 Acknowledgements
The studies were carried out during the 6 –year period between 2004 and 2010 at the department of Pharmacology, Institute of Biomedicine, University of Helsinki. I would like to express my gratitude to my supervisor and mentor Eero Mervaala from whom I received the initial spark for science and the resilience to continue. I would like to thank professor emeritus Heikki Vapaatalo for valuable advice throughout the years and for reviewing my thesis. I want to express my sincere thanks to Esa Korpi, professor and head of the department, for urging me to finish my thesis. Docent Risto Kerkelä and docent Pasi Tavi are acknowledged for reviewing my thesis.
My co-authors and research colleagues, Marjut Louhelainen, Saara Merasto, Essi Martonen, Satu Penttinen, Ilkka Aahos, Ville Kytö, Ismo Virtanen, Hanna Forsten, Johanna Raivio, Petri Kaheinen, Ilkka Tikkanen, Jouko Levijoki, Piet Finckenberg, Markus Storvik, Päivi Lakkisto, Jarkko Lakkisto and Hanna Leskinen are gratefully thanked for their expertise and irreplaceable help. A great deal of my work would not have been possible without the valuable help from Mrs. Anneli von Behr. I would like to acknowledge Sari Laakkonen, Nada Bechara-Hirvonen and Eeva Harju. Thanks to Anthony Bishopp for reviewing the language in my thesis. For many interesting and stimulating conversations I would like to acknowledge Taru Pilvi, Juha Ketonen, Teemu Aitta-Aho, Elli Leppä and all other PhD students at the department of Pharmacology. I want to thank my colleagues at Fimea including Marja-Leena Nurminen and Erkki Palva.
I want to extend my gratitude to all my childhood friends and a great thanks to my rock climbing partners throughout the years for providing a way of life; As Long &
Middendorf say in the book called “Big Walls”: “on the high crag we feel our life acutely”. Also, I want to thank all my friends in Turku during my studies in Åbo Akademi and afterwards.
80
I want to acknowledge my father Jukka and mother Catharina, for being there for me all the time, and for looking after my family when times have been hectic with the thesis. And most importantly I want to thank my family, my wife Sofia whose patience has been amazing throughout this project and for looking after the rest of the family. I want to acknowledge my sons Benjamin, Fredrik and Viktor, you are the joys in my life and the best kids a father could wish for.
Erik Vahtola in Espoo, February 2011.
81 9 References
Abuissa H, Jones PG, Marso SP, O’Keefe JH Jr. (2005). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta analysis of randomized clinical trials. J Am Coll Cardiol 46(5):821-6.
Abrams P, Levitt Katz LE. (2011). Metabolic effects of obesity causing disease in childhood. Curr Opin Endocrinol Diabetes Obes 18(1)23-7.
Adamopoulos S, Parissis JT, Iliodromitis EK, Paraskevaidis I, Tsiapras D, Farmakis D, Karatzas D, Gheorghiade M, Filippatos GS, Kremastinos DT. (2006). Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol 98(1):102-6.
Akao M, Ohler A, O’Rourke B, Marbán E. (2001). Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res 88(12):1267-75.
Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart.
Circ Res 100(10):1512-21.
Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, Sadoshima J. (2004). Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95(10):971-80.
Aneja A, Tang WH, Bansilal S, Garcia MJ, Faroukh ME. (2008) .Diabetic cardiomyopathy:
insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 121(9):748-57.
Antila S, Sundberg S, Lehtonen LA. (2007). Clinical pharmacology of levosimendan. Clin Pharmacokinet 46(7):535-52.
Antoniades C, Tousoulis D, Koumallos N, Marinou K, Stefanadis C. (2007).
Levosimendan: beyond its simple inotropic effects in heart failure. Pharmacol Ther 114(2):184-97.
Anversa P, Nadal-Ginard B. (2002). Myocyte renewal and ventricular remodelling. Nature 415(6868):240-3.
Avendano GF, Agarwal RK, Bashey RI, Lyons MM, Soni BJ, Jyothirmayi GN, Regan TJ.
(1999). Effects of glucose intolerance on myocardial function and collagen-linked glycation. Diabetes 48(7):1443-7.
Bader M, Ganten D. (2008). Update on tissue renin-angiotensin systems. J Mol Med 86(6):615-21.
82
Bader M, Peters J, Baltatu O, Müller DN, Luft FC, Ganten D. (2001). Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research. J Mol Med 79(2-3):76-102.
Banfor PN, Preusser LC, Campbell TJ, Marsh KC, Polakowski JS, Reinhart GA, Cox BF, Fryer RM. (2008). Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine and milrinone on vascular resistance, indexex of cardiac function and O2 consumption in dogs. Am J Physiol Heart Circ Physiol 294(1):H238-48.
Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, Hare JM. (2003). Disruption of leptin signalling contributes to cardiac hypertrophy independently of body weight in mice.
Circulation 108(6):754-9.
Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC, Kittleson MM, Minhas KM, Berkowitz DE, Wei C, Hare JM. (2006). Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res 98(1):119-24.
Becker K. (2001). Principles and practice of endocrinology and metabolism. 3rd ed.
Lippincott Williams and Wilkins.
Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, Zhang D, Cooksey RC, McClain DA, Litwin SE, Taegtmayer H, Severson D, Kahn CR, Abel ED. (2002).
Insulin signalling co-ordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 109(5):629-39.
Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J. (2009). Evidence for
cardiomyocyte renewal in humans. Science 324(5923):98-102.
Bers DM, Despa S. (2009). Cardiac myocyte and Ca2+ and Na+ regulation in normal and failing hearts. J Pharmacol Sci 100(5):315-22.
Bertoni AG, Tsai A, Kasper EK, Brancati FL. (2003). Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care 26(10):2791-5.
Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, Dincer UD, Besch HR Jr.
(2003). Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes 52(7):1825-36.
Bisbis S, Bailbe D, Tormo MA, Picarel-Blanchot F, Derouet M, Simon J, Portha B. (1993).
Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver. Am J Physiol 265(5 Pt 1):E807-13.
Bitar MS, Wahid S, Pilcher CW, Al-Saleh E, Al-Mulla F. (2004). Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats. Horm Metab Res 36(8):542-9.
Bojestig M, Nystrom FH, Arnqvist HJ, Ludvigsson J, Karlberg BE. (2000). The renin-angiotensin-aldosterone system is suppressed in adults with type 1 diabetes. J Renin Angiotensin Aldosterone Syst 1(4):353-6.
83
Boost KA, Hoegl S, Dolfen A, Czerwonka H, Scheiermann P, Zwissler B, Hofstetter C.
(2008). Inhaled levosimendan reduces mortality and release of proinflammatory mediators in a rat model of experimental ventilator-induced lung injury. Crit Care Med 36(6):1873-9.
Boudina S, Abel ED. (2006). Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda) 21:250-8.
Boudina S, Abel ED. (2010). Diabetic cardiomyopathy, causes and effects. Rev Endocr Metab Disord 11(1):31-9.
Brooks BA, Franjic B, Ban CR, Swaraj K, Yue DK, Celermajer DS, Twigg SM. (2008).
Diastolic dysfunction and abnormalities of the microcirculation in type 2 diabetes. Diabetes Obes Metab 10(9):739-46.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857-68.
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303(5666):2011-5.
Bugger H, Abel ED. (2009). Rodent models of diabetic cardiomyopathy. Dis Model Mech 2(9-10):454-66.
Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. (2002). Hyperglycemia-induced apoptosis in mouse myocardium: cytochrome C-mediated caspase-3 activation pathway. Diabetes 51(6):1938-48.
Chandler MP, Morgan EE, McElfresh TA, Kung TA, Rennison JH, Hoit BD, Young ME.
(2007). Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol Heart Circ Physiol 293(3):H1609-16.
Cheng ZJ, Vaskonen T, Tikkanen I, Nurminen K, Ruskoaho H, Vapaatalo H, Muller D, Park JK, Luft FC, Mervaala EM. (2001). Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. Hypertension 37(2):433-9.
Cho H, Tai HH. (2002). Thiazolidinediones as a novel class of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors. Arch Biochem Biophys 405(2):247-251.
Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW, Guatimosim S, Lederer WJ, Matlib MA. (2002). Defective intracellular Ca(2+) signalling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol Heart Circ Physiol 283(4):H1398-408.
Current Care guideline for diabetes, the Finnish Medical Society Duodecim. Updated 15.9.2009. www.kaypahoito.fi
84
de Kloet AD, Krause EG, Woods SC. (2010). The renin angiotens system and the metabolic syndrome. Physiol Behav 100(5):525-34.
Despas F, Trouillet C, Franchitto N, Labrunee M, Galinier M, Senard JM, Pathak A.
(2010). Levosimendan improves hemodynamics functions without sympathetic activation in severe heart failure patients: direct evidence from sympathetic neural recording. Acute Card Care 12(1)25-30.
Desrois M, Sidell RJ, Gauguier D, King LM, Radda GK, Clarke K. (2004). Initial steps of insulin signalling and glucose transport are defective in the type 2 diabetic rat heart.
Cardiovasc Res 61(2):288-96.
Devereux RB, Roman MJ, Parancias M, O’Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. (2000). Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 101(19):2271-6.
Dobrin JS, Lebeche D. (2010). Diabetic cardiomyopathy: signaling defects and therapeutic approaches. Expert Rev Cardiovasc Ther 8(3):373-91.
Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy S, Cannon CP, Antman EM. (2007). Diabetes and mortality following acute coronary syndromes. JAMA 298(7):765-75.
Dong F, Zhang X, Yang X, Esberg LB, Yang H, Zhang Z, Culver B, Ren J. (2006).
Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice. J Endocrinol 188(1):25-36.
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. (2000). A novel angiotensin converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87(5):E1-9.
Dorn GW 2nd, Force T. (2005). Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115(3):527-37.
Dorn GW 2nd. (2007). The fuzzy logic of physiological cardiac hypertrophy. Hypertension 49(5):962-70.
Dorn GW 2nd. (2009). Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81(3):465-73.
Dubin A, Maskin B, Murias G, Pozo MO, Sottile JP, Barán M, Edul VS, Canales HS, Estenssoro E. (2006). Effects of levosimendan in normodynamic endotoxaemia: a controlled experimental study. Resuscitation 69(2):277-86.
Eguchi K, Boden-Albala B, Jin Z, Rundek T, Sacco RL, Homma S, Di Tullio MR. (2008).
Association between diabetes mellitus and left ventricular hypertrophy in a multiethnic population. Am J Cardiol 101(12):1787-91.
85
El-Omar MM, Yang ZK, Phillips AO, Shah AM. (2004). Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus. Basic Res Cardiol 99(2):133-41.
van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ. (2005).
Myocyte apoptosis in heart failure. Cardiovasc Res 67(1):21-9.
Erdei N, Papp Z, Pollesello P, Edes I, Bagi Z. (2006). The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol 148(5):696-702.
Falkenhahn M, Franke F, Bohle RM, Zhu YC, Stauss HM, Bachmann S, Danilov S, Unger T. (1995). Cellular distribution of angitotensin-converting enzyme after myocardial infarction. Hypertension 25(2):219-26.
Fang ZY, Prins JB, Marwick TH. (2004). Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 25(4):543-67.
Fang ZY, Schull-Meade R, Leano R, Mottram PM, Prins JB, Marwick TH. (2005).
Screening for heart disease in diabetic subjects. Am Heart J 149(2):349-54.
Feuvray D, Darmellah A. (2008). Diabetes-related metabolic perturbations in cardiac myocyte. Diabetes Metab 34S3-9.
Ferrario CM, Iyer SN. (1998). Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. Regul Pept 78(1-3):13-8.
Finck BN, Lehman JJ, Leone TC, Welch MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. (2002). The cardiac phenotype induced PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109(1):121-30.
Finckenberg P, Inkinen K, Ahonen J, Merasto S, Louhelainen M, Vapaatalo H, Müller D, Ganten D, Luft F, Mervaala E. (2003). Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways. Am J Pathol 163(1)355-66.
Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J.
(2001). Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50(10):2363-75.
Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, Kajstura J. (2000).
Mycocyte death in streptozotocin-induced diabetes in rats is angiotensin II –dependent.
Lab Invest 80(4):513-27.
Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L. (2002). Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO) study: a randomised double-blind trial. Lancet 360(9328):196-202.
Franke TF, Kaplan DR, Cantley LC. (1997). PI3K: downstream AKTion blocks apoptosis.
Cell 88(4):435-7.
86
Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. (2000). Myocardial cell death in human diabetes. Circ Res 87(12):1123-32.
Galderisi M, Anderson KM, Wilson PW, Levy D. (1991). Echocardiographic evidence for the existence of a distinct diabetic cardiomyopathy (the Framingham study). Am J Cardiol 68(1):85-9.
Galli J, Fakhrai-Rad H, Kamel A, Marcus C, Norgren S, Luthman H. (1999).
Pathophysiological and genetic characterization of the major diabetes locus in GK rats.
Diabetes 48(12):2463-70.
Ganten D, Minnich JL, Granger P, Hayduk K, Brecht HM, Barbeau A, Boucher R, Genest J. (1971). Angiotensin-forming enzyme in brain tissue. Science 173(991):64-5.
Gao F, Yue TL, Shi DW, Christopher TA, Lopez BL, Ohlstein EH, Barone FC, Ma XL.
(2002). p38 MAPK activation reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression blockade of PMN accumulation. Cardiovasc Res 53(2):414-22.
Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P. (2003). Mitochondrial potassium transport: the role of the mitochondrial ATP-sensitive K(+) channel in cardiac function and cardioprotection. Biochim Biophys Acta 1606(1-3):1-21.
Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau MT, Portha B, James MR, Penicaud L, Lathrop M, Ktorza A. (1996). Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 12(1):38-43.
Giordano FJ. (2005). Oxygen, oxidative stress, hypoxia and heart failure. J Clin Invest 115(3):500-8.
González-Vílchez F, Ayuela J, Ares M, Pi J, Castillo L, Martín-Durán R. (2005). Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients. Int J Cardiol 101(1):53-8.
Goto Y, Kakizaki M, Masaki N. (1976). Production of spontaneous diabetic rats by repetition of selective inbreeding. Tohoku J Exp Med 119(1):85-90.
Gruhn N, Nielsen-Kudsk JE, Theilgaard S, Bang L, Olesen SP, Aldershvile J. (1998).
Coronary vasorelaxant effect of levosimendan, a new inodilator with calcium-sensitizing properties. J Cardiovasc Pharmacol 31(5):741-9.
Grönholm T, Cheng ZJ, Palojoki E, Eriksson A, Bäcklund T, Vuolteenaho O, Finckenberg P, Laine M, Mervaala E, Tikkanen I. (2005). Vasopeptidase inhibition has beneficial cardiac effects in spontaneously diabetic Goto-Kakizaki rats. Eur J Pharmacol 519(3):267-76.
Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. (1998). Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339(4):229-34.
87
Haigis MC, Sinclair DA. (2010). Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253-95.
von Harsdorf R, Li PF, Dietz R. (1999). Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99(22):2934-41.
van der Heide LP, Hoekman MF, Smidt MP. (2004). The ins and outs of FoxO shuttling:
mechanisms of FoxO translocation and transcriptional regulation. Biochem J 380:297-309.
Henriksen EJ, Diamond-Stanic MK, Marchionne EM. (2010). Oxidative stress and etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med [Epub ahead of print].
Hoit BD, Castro C, Bultron G, Knight S, Matlib MA. (1999). Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats. J Card Fail 5(4):324-33.
Hori M, Nishida K. (2009). Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res 81(3):457-64.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191-6.
Huang H, Tindall DJ. (2007). Dynamic FoxO transcription factors. J Cell Sci 120(15):2479-87.
Ingelsson E, Sundström J, Arnlöv J, Zethelius B, Lind L. (2005). Insulin resistance and risk for congestive heart failure. JAMA 294(3):334-41.
Joffe II, Travers KE, Perreault-Micale CL, Hampton T, Katz SE, Morgan JP, Douglas PS.
(1999). Abnormal cardiac function in the streptozotocin-induced non-insulin dependent diabetic rat: non-invasive assessment with Doppler echocardiography and contribution of the nitric oxide pathway. J Am Coll Cardiol 34(7):2111-9.
Kaheinen P, Pollesello P, Levijoki J, Haikala H. (2004). Effects of levosimendan and milrinone on oxygen consumption in isolated guinea pig heart. J Cardiovasc Pharmacol 43(4):555-61.
Kannel WB. (1976). The Framingham study. Br Med J 2(6046):1255.
Kaplan P, Babusikova E, Lehotsky J, Dobrota D. (2003). Free radical-induced protein modification and inhibition of Ca2+ ATPase of cardiac sarcoplasmic reticulum. Mol Cell Biochem 248(1-2):41-7.
Karason K, Sjöström L, Wallentin I, Peltonen M. (2003). Impact of blood pressure and insulin on the relationship between body fat and left ventricular structure. Eur Heart J 24(16):1500-5.
Kerbaul F, Garibold V, Giorgi R, Makkaoui C, Guieu R, Fesler P, Gouin F, Brimioulle S, Collart F. (2006). Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure. Crit Care Med 35(8):1948-54.
88
Kersten JR, Montgomery MW, Pagel PS, Warltier DC. (2000). Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg 90(1):5-11.
Khatter JC, Sadri P, Zhang M, Hoeschen RJ. (1996). Myocardial angiotensin II (Ang II) receptors in diabetic rats. Ann N Y Acad Sci 793:466-72.
Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ., Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI. (2004). Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. J Clin Invest 113(5):756-63.
Kimura KD, Tissenbaum HA, Ruvkun G. (1997). daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277(5328):942-6.
Kivikko M, Lehtonen L, Colucci WS. (2003). Sustained haemodynamic effects of intravenous levosimendan. Circulation 107(1):81-6.
Kompa AR, See F, Lewis DA, Adrahtas A, Cantwell DM, Wang BH, Krum H. (2008). Long-term but not short-Long-term p38 mitogen-activated protein kinase inhibition improves cardiac function and reduces cardiac remodelling post-myocardial infarction. J Pharmacol Exp Ther 325(3):741-50.
Kopustinskiene DM, Pollesello P, Saris NE. (2004). Potassium-specific effects of levosimendan on heart mitochondria. Biochem Pharmacol 68(5):807-12.
Koudona E, Xanthos T, Bassiakou E, Goulas S, Lelovas P, Papadimitriou D, Tsirkos N, Papadimitriou L. (2007). Levosimendan improves initial outcome of cardiopulmonary resuscitation in a swine model of cardiac arrest. Acta Anaesthesiol Scand 51(8):1123-9.
Kytö V, Saraste A, Saukko P, Henn V, Pulkki K, Vuorinen T, Voipio-Pulkki LM. (2004).
Apoptotic cardiomyocyte death in fatal myocarditis. Am J Cardiol 94(6):746-50.
Lagouge M, Argmann C, Gerhart-Hines Z, Mezjane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. (2006).
Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109-22.
Lavoie JL, Sigmund CO. (2003). Minireview: overview of the renin-angiotensin system-an
Lavoie JL, Sigmund CO. (2003). Minireview: overview of the renin-angiotensin system-an