Objective: Cardiotrophin-1 (CT-1) is an interleukin-6-related cytokine with known hypertrophic and protective actions upon cardiac myocytes. We provide here the first report of cardiac tissue and plasma levels of CT-1 in human and experimental hypertension, demonstrate cardiac CT-1 secretion stimulated by ventricular stretch, and characterise molecular forms of CT-1 in tissue and plasma.
Methods: CT-1 levels in human and rat plasma and in rat cardiac tissue extracts were determined by specific radioimmunoassay (RIA). Cardiac CT-1 secretion during ventricular stretch was studied in isolated, perfused hearts. Molecular forms of CT-1 were identified using RIA coupled with high performance liquid chromatography (HPLC). Results are given as mean+/-SEM.
Results: Plasma levels of CT-1 in patients with untreated hypertension (UTH, 606+/-18 pmol/L, n=24) were significantly higher than those in age-and BMI-matched normotensive volunteers (NT, 546+/-12 pmol/L, n=31, P<0.01 vs. UTH). CT-1 levels in matched patients with treated hypertension (THT, 618+/-10 pmol/L, n=35) were similar to those in UTH patients, but higher than in NT controls (P<0.01). Plasma CT-1 demonstrated a weak but significant correlation with systolic blood pressure in all patients (r=0.241, P<0.05, n=90). In contrast, CT-1 levels in male, 40-week-old, NT-WKY rats (1295+/-98 pmol/L) were significantly higher than those in matched UTH-SHR (937+/-31 pmol/L, P<0.01). In both WKY and SHR rats, atrial tissue concentrations of CT-1 were 8-fold higher than ventricular levels. Left ventricular tissue CT-1 protein concentrations were significantly higher in 40-week-old SHR compared with age-matched WKY (SHR 12.6+/-0.5 fmol/g vs. WKY 9.5+/-0.8 fmol/g, P<0.01). Ventricular stretch of Langendorff perfused, isolated WKY/SHR hearts resulted in significant, acute release of CT-1 and BNP. HPLC coupled with specific RIA revealed CT-1 in human/rat plasma, isolated rat heart perfusate, and rat heart tissue extracts to consist of complex, high molecular weight forms.
Conclusions: This is the first report to show increased levels of plasma CT-1 in hypertensive disease. CT-1 is a unique cardiac cytokine whose release is stimulated by ventricular stretch. The atrium contains the highest levels of the protein. The stored and circulating molecular form of CT-1 is complex, which may modulate its in vivo role in cardiovascular disease.