Objectives Aims were to investigate 1) relationships between serum ST2 levels and hemodynamic/neurohormonal variables; 2) myocardial ST2 production; 3) expression of ST2, membrane-anchored ST2L, and its ligand, IL-33, in myocardium, endothelium and leukocytes from patients with LV pressure overload and congestive cardiomyopathy. Background Serum levels of ST2 are elevated in heart failure. Relationship of ST2 with 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]) was measured in patients with LV hypertrophy (aortic stenosis, AS, N=45), congestive cardiomyopathy (CCM N=53), and Controls (N=23). ST2 was correlated to NT-pro BNP, CRP and hemodynamic variables. Coronary sinus and arterial blood sampling determined myocardial gradient (production) of ST2. ST2, ST2L and IL-33 were measured (RT-PCR) in myocardial biopsies and leukocytes; ST2 protein production was evaluated in human endothelial cells. IL-33 protein expression was determined (immunohistochemistry) in coronary artery endothelium Results ST2 was elevated in AS (103[65-165], p<0.05) and CCM (194[69-551], p<0.01) vs. Controls (49[4-89]) and correlated with BNP (r=0.5; p<0.05), CRP (r=0.6; p<0.01) and LV EDP (r=0.38, p<0.03). LV ST2 mRNA was similar in AS and CCM vs. Control (NS). No myocardial ST2 protein gradient was observed. Endothelial cells secreted ST2. 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 hypertrohy and failure, serum ST2 correlates with 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.

In patients with AS, BNP appears to be regulated not only by systolic but also by diastolic load. This supports the hypothesis that myocardial stretch modulates BNP production in human pressure overload hypertrophy/failure.

In HF patients with electromechanical cardiac dyssynchrony, functional improvement related to CRT is associated with favorable changes in established molecular markers of HF, including genes that regulate contractile function and pathologic hypertrophy.

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ET in resynchronized CHF patients is feasible and further enhances exercise tolerance. Patients with severe CHF should be prescribed an exercise training programme after implantation in order to maximize the expected benefit.