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The self-maintaining nature of ventricular fibrillation : contribution of L-type Ca²+ channels and Na+/Ca²+ exchange to cardiomyocyte Ca²+ overload in ventricular fibrillation : surface fluorescence study in isolated perfused rat hearts

Driamov, Sergey. The self-maintaining nature of ventricular fibrillation : contribution of L-type Ca²+ channels and Na+/Ca²+ exchange to cardiomyocyte Ca²+ overload in ventricular fibrillation : surface fluorescence study in isolated perfused rat hearts. 2004, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_6954

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Abstract

Approximately 40% of all deaths in Switzerland are due to cardiovascular diseases.1 An important part of these deaths happen because of life-threatening cardiac arrhythmias. Ventricular fibrillation (VF) is the most dangerous cardiac arrhythmia usually caused by ischemic heart disease and infarction. It also happens in apparently healthy individuals representing the most common cause of sudden death. The problem of high mortality associated with sudden cardiac death due to VF is relevant to all industrialized countries. In the United States, VF accounts for approximately 300,000 deaths per year.2 Currently the most important therapy is the implantable cardioverter-defibrillator (ICD). Recent clinical trials3 have expanded the indications for device therapy to overmillion patients in the US alone at a cost exceeding $50 billion if fully implemented.2 This consideration provides a strong motive to develop alternative new therapies that are comparably effective but less expensive and invasive.2 This requires a better understanding of VF pathogenesis at the molecular and cellular level. Therefore, our study was focused on elucidation of mechanisms of VF. It has been proposed that detrimental effects of VF are partially due to rapidly developing overload of cytosol of cardiac cells with Ca2+.4 The Ca2+ overload is responsible for maintaining of VF as well as for reinduction of VF after defibrillation5 and for the postVF left ventricular (LV) disfunction.6 It is not clear, however, through which pathways Ca2+ enters cells during VF. Here we studied the role of different ion transport systems, particularly, of L-type Ca2+ channels and sodium-calcium (Na+/Ca2+) –exchange, in initiation and maintenance of Ca2+ overload during VF. We applied drugs specifically blocking each of these Ca2+ transport systems in an isolated perfused rat heart model. We used nifedipine, a blocker of L-type Ca2+ channels and KB-R7943, a specific blocker of the reverse mode of Na+/Ca2+exchange. We induced VF in the hearts by rapid pacing and registered changes of intracellular Ca2+ concentration ([Ca2+]i) using surface fluorescence of the Ca2+ indicator indo-1. In order to get a better understanding of extend of Ca2+ overload during VF we calibrated fluorescence signal of indo-1 to [Ca2+]i. During the first two minutes of VF [Ca2+]i reached about double of the normal systolic concentration achieving ! 2000 -
2500 nM. With further VF duration [Ca2+]i elevated less rapidly and achieved ! 3000 nM.
We found that both L-type Ca2+ channels and Na+/Ca2+-exchange contribute to Ca2+
overload during VF. Specifically, when each of the drugs was perfused before VF
induction, nifedipine reduced the extend and especially the rate while KB-R7943 mostly
reduced the extend of Ca2+ accumulation in cardiomyocytes. Additionally, Na+/Ca2+-
exchange also contributes to maintenance of Ca2+ overload during VF because perfusion
of the hearts with KB-R7943 after VF has been induced also reduced [Ca2+]i. Finally, in
all groups of hearts perfused with the drugs, spontaneous terminations of VF
(defibrillations) were frequently observed. The spontaneous defibrillations did not happen
in untreated control hearts. These results enabled us to conclude that both L-type Ca2+
channels and Na+/Ca2+-exchange are important ways of Ca2+ entry into the
cardiomyocytes during VF. The L-type Ca2+ channels are more important for Ca2+ entry
into cardiomyocytes at the initial stage of VF. The Na+/Ca2+-exchange is also important at
the initial stage of VF but its contribution increases rapidly with progression of VF.
Advisors:Eberle, Alex N.
Committee Members:Hofbauer, Karl G. and Zaugg, Christian Ernst
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Endocrinology (Eberle)
UniBasel Contributors:Eberle, Alex N. and Hofbauer, Karl G.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6954
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:102
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 15:10

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