Stress-inducerad hjärtsvikt Sjukdomsmekanismer och behandling

Transkript

1 Forskningsprojekt Stress-inducerad hjärtsvikt Sjukdomsmekanismer och behandling Elmir Omerovic MD, PhD Björn Redfors MD

2 Projekthandledare Björn Redfors, Elmir Omerovic Epost Projekttitel Patofysiologi och behandling vid stress-inducerad kardiomyopati Sammanfattning Stress-inducerad kardiomyopati (SIK) är ett stressutlöst nyligen uppdagat syndrom där patienten kliniskt ter sig som vid akut hjärtinfarkt, med central bröstsmärta, andningspåverkan och illamående. Även EKG och hjärtskademarkörer indikerar hjärtinfarkt (ST-höjning, förhöjda troponin-nivåer). Trots att en stor del av vänster kammare är helt utslagen i SIK (som vid en stor hjärtinfarkt) är kranskärlen ej förträngda. Den kardiella funktionsnedsättningen beror istället på kraftigt förhöjda katekolamin-nivåer som tros direkt eller indirekt orsaka hjärtskada. Patienterna drabbas ofta av allvarlig hjärtsvikt, kardiogen shock eller arytmier och riskerar att dö. Hjärtat kan t.o.m. brista (SIK kallas också "broken heart syndrome"). SIK är vanligt förekommande och drabbar ffa kvinnor. För närvarande finns ingen behandling för SIK. Patienterna behandlas istället som om de led av hjärtinfarkt. Det finns evidens för att sådan behandling kan vara direkt skadlig. Vi har etablerat djurmodeller för att studera patofysiologin samt olika behandlingsmetoder. Projektet går ut på att tillsammans med våra doktorander studera effekten av olika farmaka på hjärtfunktionen och överlevnaden i SIK modellerna Vetenskaplig frågeställning Hur svarar hjärtat vid stress-inducerad kardiomyopati på den behandling som för närvarande ges, d.v.s. behandling för hjärtinfarkt och/eller hjärtsvikt? Vad är den optimala behandlingen vid stress-inducerad kardiomyopati? Praktiskt genomförande Studenten deltar i de moment han/hon finner mest intressanta (se nedan) samt utför självständigt vissa utvalda metoder och bidrar således personligen till gruppens resultat. Vi träffas på veckobasis (åtminstone) för vetenskapliga diskussioner och utvärdering av våra metoder. Ekokardiografi (ultraljudsundersökning av hjärtfunktionen) och invasiva hemodynamiska mätningar (mätningar av trycket inuti hjärtat och ute i artärerna) utförs i våra djurmodeller. Hjärtvävnad analyseras sedan med hjälpa av olika metoder (histologi, immunohistokemi, PCR, etc). Vi utför även cell experiment där hjärtmuskelceller utsätts för katekolaminer samt olika interventioner. Nedan följer en detaljerad beskrivning av forskningsprojektet (på engelska)

3 AIMS OF THE STUDY Our aims are to study the pathophysiology and treatment of stress-induced cardiomyopathy (SIC). We are specifically interested in the role of lipotoxicity in the pathogenesis of SIC. BACKGROUND What is stress-induced cardiomyopathy and why should we study this syndrome? Stress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is a novel syndrome most frequently affecting women[1] and first reported in Japan in 1991[2]. The characteristic hallmark of SIC is a development of a peculiar type of reversible left ventricular (LV) dysfunction with extensive akinesis affecting 2/3 of apical segments[3] ( apical ballooning ). This leads to severe cardiac dysfunction that may cause fulminant heart failure (HF), cardiogenic shock and literally heart rupture leading to death. However, in many cases the patients recover very quickly. The pathophysiology leading to myocardial dysfunction of this magnitude and the remarkable recovery process are not well understood, suggesting an important knowledge gap in our understanding of cardiovascular physiology and medicine. In February 2005 we discovered at our hospital what we believe is the first documented case of SIC in Sweden. Since then we have treated 160 such patients; at the moment this is one of the largest and the fastest growing cohorts in the world. Despite increasing awareness about SIC in clinical medicine, our knowledge about this syndrome is rather limited. The epidemiology and health consequences of SIC in Sweden are largely unknown. What we know, based on preclinical and clinical observations[4, 5], is that intensive catecholamine overstimulation of myocardium may be responsible for the development of myocardial dysfunction. What we don t know is how SIC affects prognosis, how we should treat these patients, which mechanisms are involved in the development of cardiac dysfunction, and which pathways are responsible for effective healing. SPECIFIC AIMS What is the pathophysiology behind SIC and what is the optimal treatment for this condition? This syndrome was first described in 1990 in Japanese women and has a strong association with severe emotional stress[3, 6]. Its epidemiology is largely unknown, but initial estimates suggest that it could be present in ~4% of all patients with acute chest pain. The pathogenesis and the reason why it affects mostly women are

4 unknown. Could it result from an interaction between some yet unknown stimuli present in modern society and biological predisposition of certain individuals? Are the mechanisms behind takotsubo pathophysiology operable in acute heart failure and cardiogenic shock two common syndromes associated with high mortality? Our results from the takotsubo registry in Gothenburg reveal that only 6 patients (6%) in the cohort are non-swedish (person born outside Sweden or with both parents born outside Sweden), the finding that contrasts with the fact that ~28% of all inhabitants in Gothenburg are non-swedish. This suggests the presence of ethnical (genetic?) predisposition to develop takotsubo among Swedish population. Direct experimental evidence shows that intense catecholamine stimulation leads to myocardial lipid accumulation[7] and disturbed myocardial lipid metabolism in takotsubo patients[8]. Our working hypothesis is that severe (emotional) stress paralleled by intense neurohormonal (catecholamines[3]) activation causes derangement in myocardium (lipid accumulation[7]) resulting in progressive cell dysfunction and cell death. The patients develop characteristic apical 'ballooning' (Fig. 5) representing severe left ventricular dysfunction that may result in heart failure, cardiogenic shock and literally heart rupture leading to death. We propose that an adequate apob response may attenuate and/or prevent the development of takotsubo cardiomyopathy. This syndrome is also intriguing from the aspect of 'recovery' and cardioprotection. The majority of patients recover normal cardiac function within days, and thus it will be valuable to elucidate which genetic programs are activated during the recovery phase. To address this question, gene-array analysis, lipidomics and electron microscopy will be performed on myocardial biopsies obtained from patients in the acute and the recovery phase. These experiments will provide a genetic fingerprint of the population as well as information about which genes and gene products are upregulated/downregulated during the two distinct phases, and may identify future targets for cardioprotective intervention. Adenosine treament? Adenosine is an endogenous cardioprotective mediator with substantial anti-catecholaminergic effects[9], and signals through at least four distinct receptors[10]. In the clinic, adenosine has been widely used for many years, both as a therapeutic regimen and as a diagnostic tool, and has an established safety-profile and a large therapeutic window[11]. It has been shown to be cardioprotective in several different experimental animal models[12] of ischemia-reperfusion, and it has been shown to decrease infarct-size in humans[13]. We hypothesize that adenosine is able to prevent myocardial lipid accumulation and deterioration of cardiac function in a mouse model of isoprenaline-induced cardiotoxicity. METHODS Female and male rats and mice will be exposed to infusion of catecholamines. Our new state of the art echocardiographic equipment will be the cornerstone in establishing relevant rat and mouse models of SIC and in assessing cardiac function and morphology in vivo. In addition, advanced hemodynamic and electrophysiological techniques will be employed to give detailed information of the cardiac function.

5 Furthermore, Langendorff in vitro heart perfusion system will be established to provide further information of cardiac function. Myocardial tissue will then be used for further evaluation. Myocardial lipids, catecholamines and adrenergic receptors will be analyzed quantitatively and qualitatively by HPLC and receptor assay, while myocardial tissue will be examined with electron microscopy and gene-array during acute and recovery phase. Detailed time-dependent relationship between cardiac function and myocardial lipid content will be studied. These experiments will elucidate whether lipotoxicity is involved in the pathogenesis of takotsubo cardiomyopathy. The experiments will also delineate potential gender disparities in these models. In addition, we aim to evaluate the effect of various pharmacological agents on the cardiac function in these experimental models. As of yet there is no specific treatment strategy for takotsubo cardiomyopathy. Our experiments will show whether patients with takotsubo have distinct differences in myocardial lipid and energy metabolism at gene and organ levels and may provide an elegant explanation for takotsubo cardiomyopathy. IMPORTANCE Stress-induced cardiomyopathy is a new disease entity that may be present in a substantial proportion of patients with acute chest pain and heart failure, but the mechanisms involved and its epidemiology and prognosis are largely unknown. Our project has the potential to significantly increase our understanding of this syndrome and to provide specific pharmacological treatment. REFERENCES 1. Akashi, Y.J., et al., Stress cardiomyopathy. Annu Rev Med, : p Dote, K., et al., [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases]. J Cardiol, (2): p Wittstein, I.S., et al., Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med, (6): p Ueyama, T., et al., Catecholamines and estrogen are involved in the pathogenesis of emotional stress-induced acute heart attack. Ann N Y Acad Sci, : p Abraham, J., et al., Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists. J Am Coll Cardiol, (15): p Grawe, H., M. Katoh, and H.P. Kuhl, Stress cardiomyopathy mimicking acute coronary syndrome: case presentation and review of the literature. Clin Res Cardiol, (3): p

6 7. Jodalen, H., R. Lie, and S. Rotevatn, Effect of isoproterenol on lipid accumulation in myocardial cells. Res Exp Med (Berl), (3): p Kurisu, S., et al., Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction. J Am Coll Cardiol, (5): p Dobson, J.G., Jr., Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3',5'-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Circ Res, (5): p Headrick, J.P., et al., Adenosine and its receptors in the heart: regulation, retaliation and adaptation. Biochim Biophys Acta, (5): p Karamitsos, T.D., et al., Tolerance and safety of adenosine stress perfusion cardiovascular magnetic resonance imaging in patients with severe coronary artery disease. Int J Cardiovasc Imaging, (3): p Liu, G.S., et al., Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation, (1): p Ross, A.M., et al., A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol, (11): p