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CLINICAL RESEARCH: BIOMARKERS IN HEART FAILURE

Nonmyocardial Production of ST2 Protein in Human Hypertrophy and Failure Is Related to Diastolic Load

Jozef Bartunek, MD, PhD^_*,,_*, Leen Delrue, PhD^_*,, Frederik Van Durme, MD^_*, Olivier Muller, MD, PhD^_*, Filip Casselman, MD, PhD, Bart De Wiest, RN, Romaric Croes, MD^||, Sofie Verstreken, MD^_*, Marc Goethals, MD^_*, Herbert de Raedt, MD^_*, Jaydeep Sarma, MD, PhD^_*, Lija Joseph, MD^¶, Marc Vanderheyden, MD^_*, and Ellen O. Weinberg, PhD^¶,_*

^_* Cardiovascular Center and Cardiovascular Research Center, OLV Hospital, Aalst, Belgium
Translational Cardiology Unit, OLV Hospital, Aalst, Belgium
Department of Cardiovascular Surgery, OLV Hospital, Aalst, Belgium
Department of Pathology, OLV Hospital, Aalst, Belgium
^|| Department of Pathology, St. Blasium Hospital, Dendermonde, Belgium
^¶ Boston Medical Center, Boston, Massachusetts

Manuscript received May 12, 2008; revised manuscript received August 26, 2008, accepted September 22, 2008.

^_* Reprint requests and correspondence: Dr. Jozef Bartunek, Cardiovascular Center and Cardiovascular Research Center, Moorselbaan 164, 9300 Aalst, Belgium (Email: jozef.bartunek{at}olvz-aalst.be).

^_* Dr. Ellen O. Weinberg, Boston Medical Center, EBRC Room 704, 650 Albany Street, Boston, Massachusetts 02118 (Email: eweinbe{at}bu.edu).

Objectives: 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.

Key Words: interleukins • ST2 • hypertrophy • heart failure • natriuretic peptides • endothelium-derived factors

Abbreviations and Acronyms   AS = aortic stenosis   AU = arbitrary units   BNP = B-type natriuretic peptide   CCM = congestive cardiomyopathy   EDP = end-diastolic pressure   hsCRP = high sensitivity C-reactive protein   IL = interleukin   LV = left ventricular   mRNA = messenger ribonucleic acid   NT-proBNP = N-terminal pro-brain natriuretic peptide

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J. Am. Coll. Cardiol. 2008 52: A29. [Full Text] [PDF]