European Heart Journal Advance Access originally published online on June 13, 2009
European Heart Journal 2009 30(17):2155-2164; doi:10.1093/eurheartj/ehp240
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Abnormalities in intracellular Ca2+ regulation contribute to the pathomechanism of Tako-Tsubo cardiomyopathy
1 Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, D-61231 Bad Nauheim, Germany
2 Experimental Cardiology, Franz-Groedel-Institute of the Kerckhoff Heart Center, Bad Nauheim, Germany
3 Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
4 Department of Cardiology, Klinikum Oldenburg, Oldenburg, Germany
Received 23 June 2008; revised 15 March 2009; accepted 3 May 2009; online publish-ahead-of-print 13 June 2009.
* Corresponding author. Tel: +49 6032 996 2829, Fax: +49 6032 996 2827, Email: h.nef{at}kerckhoff-fgi.de
Aims: The Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction that has been assigned to excessive catecholamine levels after episodes of severe emotional or physical stress. Several studies have indicated that β-adrenoceptor stimulation is associated with alteration in gene expression of Ca2+-regulatory proteins. Thus, the present study investigated the gene expression of crucial proteins [sarcoplasmic Ca2+ ATPase (SERCA2a), sarcolipin (SLN), phospholamban (PLN), ryanodine receptor (RyR2), and sodium-calcium exchanger (NCX)] involved in the Ca2+-regulating system in TTC.
Methods and results: In 10 consecutive patients, TTC was diagnosed by coronary angiography, ventriculography, and echocardiography. Endomyocardial biopsies were taken during the phase of severely impaired left ventricular (LV) function and after functional recovery. Non-diseased LV tissue from three donor hearts not used for transplantation served as healthy controls. Expression levels of Ca2+-regulatory proteins were analysed by means of real-time PCR, western blot, and immunohistochemistry. SLN, predominantly expressed in the atrial component, showed a remarkable ventricular expression in TTC patients. Gene expression of SERCA2a was significantly down-regulated. Conversely, PLN/SERCA2a ratio was increased. For PLN, dephosphorylation was documented using western blot and immunostaining of PLN-Ser16 and PLN-Thr17. No changes could be documented for NCX and RyR2.
Conclusion: In TTC, ventricular expression of SLN and dephosphorylation of PLN potentially result in a reduced SERCA2a activity and its Ca2+ affinity. Thus, the TTC is associated with specific alteration of Ca2+-handling proteins, which might be crucial for contractile dysfunction.
Key Words: Tako-Tsubo cardiomyopathy • Apical ballooning • Calcium-handling proteins • Contractile dysfunction
These authors contributed equally to this work.