Importance of sympathetic activation for the expression of Na+-Ca2+ exchanger in end-stage failing human myocardium.
OBJECTIVE
In end-stage heart failure, an alteration in the expression of the Na+-Ca2+ exchanger has been reported. Regulation of its expression is largely unknown. We sought to find out whether Na+-Ca2+ exchanger in human heart failure is regulated by sympathetic activation. In addition, since Na+-Ca2+-exchange is electrogenic, we conjectured whether increased expression of Na+-Ca2+ exchanger is associated with an increased incidence of cardiac arrhythmias.


RESULTS
Twenty-three patients suffering from end-stage cardiac failure were examined in the hours preceding cardiac transplantation. Plasma levels of norepinephrine, epinephrine, atrial natriuretic peptide, renin activity, aldosterone, tumour necrosis factor (TNF)-alpha, and TNF-receptors were measured. All parameters were elevated relative to 21 healthy control subjects. As determined by immunoblots, protein levels of the Na+-Ca2+ exchanger were increased by 56% and protein levels of sarcoplasmic reticulum (SR) Ca2+-ATPase were decreased by 20% in left ventricles of the explanted failing hearts. A significant correlation between protein and neurohumoral levels was exclusively found for the Na+-Ca2+ exchanger with norepinephrine (r=0.64; P=0.01). Recent Holter ECGs revealed that patients with sustained or non-sustained ventricular tachycardia (more than three consecutive beats) had significantly higher Na+-Ca2+ exchanger protein and plasma norepinephrine levels than patients with a maximum of two consecutive beats (Na+-Ca2+ exchanger: 109+/-10 vs 83+/-7, n=11 each, P<0.05; norepinephrine: 1359+/-159 vs 656+/-88 pg. ml(-1), n=9 each, P<0.001).


CONCLUSIONS
Sympathetic activation may enhance the expression of Na+-Ca2+ exchanger in end-stage heart failure. The data support the hypothesis that increased Na+-Ca2+-exchange could favour malignant ventricular arrhythmias.
Schillinger
W
W
Zentrum Innere Medizin, Abt. Kardiologie und Pneumologie, Universität Göttingen, Germany.
Schneider
H
H
Minami
K
K
Ferrari
R
R
Hasenfuss
G
G
D001692:Biological Transport; D006328:Cardiac Catheterization; D016022:Case-Control Studies; D002395:Catecholamines / Q000032:analysis / Q000096:biosynthesis*; D015331:Cohort Studies; D015716:Electrocardiography, Ambulatory; D005260:Female; D006333:Heart Failure / Q000175:diagnosis* / Q000201:enzymology* / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D011300:Preoperative Care; D011336:Probability; D012016:Reference Values; D012720:Severity of Illness Index; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000502:physiology*
D002395:Catecholamines; D000254:Sodium-Potassium-Exchanging ATPase