2026-09-18T20:24:51Zhttps://gupea.ub.gu.se/server/oai/requestoai:gupea.ub.gu.se:2077/73802013-04-23T15:05:45Zcom_2077_283com_2077_17com_2077_10556col_2077_543col_2077_310col_2077_10557
Lindbom, Malin
2007-10-04T11:14:22Z
2007-10-04T11:14:22Z
2007-10-04T11:14:22Z
978-91-628-7317-2
http://hdl.handle.net/2077/7380
The failing heart is characterized by changes in structure, function and metabolism. All these changes are usually defined as
pathologic remodelling. An important part of this negative remodelling process is disturbances in the myocardial energy
metabolism. It has been demonstrated both in clinical and experimental studies that the failing heart contains low levels of
creatine(Cr), phosphocreatine (PCr) and adenosine-triphosphate (ATP). For the heart to be able to function and contract
normally, it needs energy in the form of ATP. ATP needs to be transported from sites of energy production to the sites of
energy utilization in the myocyte. The Creatine-kinas (CK) system is responsible for this energy transport. Previous studies
have shown that Cr depletion results in disturbed energy metabolism, which is associated with decreased PCr content,
decreased CK activity and compromised left ventricular dysfunction. But there is still limited knowledge about the role of
creatine and myocardial energy metabolism in the diseased heart. It is known that the heart that depends on exogenous lipids
for the oxidative production of ATP, and thereby for maintenance of normal cellular energy homeostasis. Recent studies have
however, reported that the heart synthesizes and releases its own endogenous apolipoprotein B (apoB). It has been proposed
that apoB may be involved in cardioprotection by means of elimination of toxic intracellular lipids.
The aim of this thesis were
• To investigate whether measures of intensive cardiac care applied to rats with acute myocardial infarction (MI)
would reduce mortality in this small animal model.
• To investigate in vivo the effects of Cr depletion in rats on left ventricular function and morphology, energy
metabolism, catecholamines and incidence of malignant ventricular arrhythmias during acute myocardial infarction.
• To investigate in vivo the effects of Cr depletion in mice on left ventricular function and morphology, energy
metabolism and myocardial lipids.
• To investigate importance of endogenous lipoproteins in the heart for cardiac function, morphology and survival in
the settings of acute and chronic myocardial infarction.
• To investigate acute and chronic effects of complete heart block (CHB) on cardiac function, morphology and
energy metabolism in a rat model.
In paper I we show that by applying simple methods like pre-treatment with anti-arrhythmia, prolonged respiratory support,
use of isoflurane gas anaesthesia, and treatment of MVA with electrical cardioversion, the mortality in the rat model of acute
MI is decreased by ~70 %.
In the rat model of Cr depletion we show that lack of myocardial Cr leads to disturbances in metabolism, morphology and
function of the heart, similar to those found in HF patients. The animals suffering from CR depletion show increased
incidence of arrhythmias and increased mortality in the setting of acute MI. We also showed that Cr depletion in mice leads
to similar disturbances as in the rat model. One very interesting new finding was the increased accumulation of triglycerides.
The most important finding in the mouse model was that the disturbances in the metabolism, structure and function of the
heart are completely reversible upon the normalization of the Cr levels. These findings indicate that Cr metabolism may be an
important target for pharmacological interventions in order to increase myocardial efficiency and structural integrity of the
failing heart.
In paper IV we showed that the over-expression of apolipoprotein B (apoB) in mice increased the survival post-MI, 2-fold.
This was associated with improved myocardial function in the apoB mice. It was also determined that the production of
endogenous apoB was increased acutely post-ischemia injury, but in long term it decreases to subnormal levels. These
findings indicate that the myocardial apoB system may be important in cardioprotection in pathophysiologic settings as
myocardial ischemia and HF.
CHB in rats lead to early, pronounced and sustained cardiac remodelling with the development of eccentric hypertrophy.
Howevere they did not develop left ventricular dysfunction and showed no signs of disturbed energy metabolism. Future
studies are needed here to elucidate the mechanism behind the beneficial cardiac remodelling post-CHB.
eng
I. Råmunddal T, Lorentzon M, Omerovic E. Decreased mortality in a rat model of acute postinfarction heart failure. Biochem Biophys Res Commun. 2006 Mar 10;341(2):459-63 ::pubmed::16446154
II. Lorentzon M., Råmunddal T., Bollano E., Soussi B., Waagstein F., Omerovic E. In vivo Effects of Myocardial Creatine Depletion on Left Ventricular Function, Morphology and Energy Metabolism – Consequences in Acute Myocardial Infarction. J Card Fail. 2007 Apr;13(3):230-7. ::pubmed::17448422
III. Lindbom M., Råmunddal T., Camejo G., Waagstein F., Omerovic E. In vivo effects of myocardial creatine depletion on left ventricular function, morphology and energy metabolism in mice. (Submitted)
IV. Råmunddal T., Lindbom M., Scharin-Täng M., Stillemark-Bilton P., Boren J., Omerovic E. Overexpression of apolipoprotein-B improves cardiac function and increases survival in mice with myocardial infarction. (Submitted)
V. Gizurarson S., Lorentzon M., Råmunddal T., Waagstein F., Bergfeldt L.,Omerovic E. Effects of complete heart block on myocardial function, morphology and energy metabolism in rats. Europace. 2007; 9(6): 411-6. ::pubmed::17507360
Energy metabolism
Creatine
Congestive heart failure
Myocardial infarction
Ventricular arrhythmias
Cardiac remodeling
apolipoprotein B
Lipid metabolism
Myocardial creatine metabolism in experimental infarction and heart failure
text
Doctoral thesis
Doctor of Philosophy (Medicine)
malin.lindbom@wlab.gu.se
18 october 2007, kl. 9.00, lecturehall 3rd floor, Guldhedsgatan 10A, Göteborg.
Göteborg University. Sahlgrenska Academy
Inst of Medicine. Dept of Molecular and Clinical Medicine
SA
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