Nonmyocardial production of ST2 protein in human hypertrophy and failure is related to diastolic load.
OBJECTIVE
This study was designed to investigate: 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; and the 3) expression of ST2, membrane-anchored ST2L, and its ligand, interleukin (IL)-33, in myocardium, endothelium, and leukocytes from patients with left ventricular (LV) pressure overload and congestive cardiomyopathy.


BACKGROUND
Serum levels of ST2 are elevated in heart failure. The relationship of ST2 to hemodynamic variables, source of ST2, and expression of ST2L and IL-33 in the cardiovascular system are unknown.


METHODS
Serum ST2 (pg/ml; median [25th, 75th percentile]) was measured in patients with LV hypertrophy (aortic stenosis) (n = 45), congestive cardiomyopathy (n = 53), and controls (n = 23). ST2 was correlated to N-terminal pro-brain natriuretic peptide, C-reactive protein, and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. The levels of ST2, ST2L, and IL-33 were measured (reverse transcriptase-polymerase chain reaction) in myocardial biopsies and leukocytes. The ST2 protein production was evaluated in human endothelial cells. The IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium.


RESULTS
The ST2 protein was elevated in aortic stenosis (103 [65, 165] pg/ml, p < 0.05) and congestive cardiomyopathy (194 [69, 551] pg/ml, p < 0.01) versus controls (49 [4, 89] pg/ml) and correlated with B-type natriuretic peptide (r = 0.5, p < 0.05), C-reactive protein (r = 0.6, p < 0.01), and LV end-diastolic pressure (r = 0.38, p < 0.03). The LV ST2 messenger ribonucleic acid was similar in aortic stenosis and congestive cardiomyopathy versus control (p = NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. The IL-33 protein was expressed in coronary artery endothelium. Leukocyte ST2L and IL-33 levels were highly correlated (r = 0.97, p < 0.001).


CONCLUSIONS
In human hypertrophy and failure, serum ST2 correlates with the diastolic load. Though the heart, endothelium, and leukocytes express components of ST2/ST2L/IL-33 pathway, the source of circulating serum ST2 is extra-myocardial.
Bartunek
Jozef
J
Translational Cardiology Unit, Cardiovascular Center and Cardiovascular Research Center, OLV Hospital, Aalst, Belgium.
Delrue
Leen
L
Van Durme
Frederik
F
Muller
Olivier
O
Casselman
Filip
F
De Wiest
Bart
B
Croes
Romaric
R
Verstreken
Sofie
S
Goethals
Marc
M
de Raedt
Herbert
H
Sarma
Jaydeep
J
Joseph
Lija
L
Vanderheyden
Marc
M
Weinberg
Ellen O
EO
D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D003971:Diastole; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000503:physiopathology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000097:blood / Q000378:metabolism*
C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D011956:Receptors, Cell Surface; D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein