Cardiac Growth Factors in Human Hypertrophy

Abstract

Abstract-The aim of the present study was to investigate whether and which cardiac growth factors are involved in human hypertrophy, whether growth factor synthesis is influenced by overload type and/or by the adequacy of the hypertrophy, and the relationships between cardiac growth factor formation and ventricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aortic stenosis (nϭ26) or regurgitation (nϭ15) and controls (nϭ12). Gene expression and cellular localization was investigated in ventricular biopsies using reverse transcriptase-polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end-systolic wall stress Ͻ90 kdyne/cm 2 was associated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was correlated to the mean velocity of circumferential fiber shortening (rϭ0.86, PϽ0.001) and ET-1 formation to relative wall thickness (rϭ0.82, PϽ0.001). When end-systolic wall stress was Ͼ90 kdyne/cm 2 , IGF-I and ET-1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin (Ang) II was generated, regardless of the type of overload. The mRNA level for angiotensinogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang II formation was positively correlated to end-systolic stress (rϭ0.89, PϽ0.001) and end-diastolic stress (rϭ0.84, PϽ0.001). Multivariate stepwise analysis selected end-systolic stress as the most predictive variable and left ventricular end-diastolic pressure as the independent variable for Ang II formation (rϭ0.93, PϽ0.001). In conclusion, the present results indicate that the course of human left ventricular hypertrophy is characterized by the participation of different cardiac growth factors that are selectively related both to the type of hemodynamic overload and to ventricular function. (Circ Res. 1999;85:57-67.) Key Words: myocardial hypertrophy Ⅲ aortic valve disease Ⅲ endothelin-1 Ⅲ insulin-like growth factor-I Ⅲ angiotensin II

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

“…10 Although the precise pathophysiological role of ET-1 in heart failure remains uncertain, it has been suggested that ET-1 is secreted from cardiomyocytes or nonmyocytes and acts as a local autocrine or paracrine hormone to produce vasoconstriction, positive inotropy, and hypertrophy. 24,25 There are several studies showing beneficial effects of the ET receptor blockade on survival, hemodynamic parameters, and histological remodeling. [11][12][13] This study has demonstrated for the first time that long-term treatment with an ET A receptor antagonist prevents electrical remodeling such as reduction of I to , I K , and I Ca,L and prolongation of APD in ventricular cells and improves QT prolongation in the ECG of cardiomyopathic hamsters.…”

Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

“…The reduction in cardiac contractility characterizing the transition from hypertrophy to failure in patients with aortic valve disease was indeed found to be associated with reduced cardiac production of IGF-I and ET-1 [4], notwithstanding the progressive increase in Ang II cardiac generation. In patients with heart failure, the progressive reduction in contractility, marked by the increase in left ventricular stress, was finally associated with reduced cardiac production of growth factors (IGF-I and ET-1) and progressive increase in Ang II cardiac generation [5].…”

“…The study protocol complies with the principles of the Helsinki declaration, was approved by our institution, and all patients gave their informed written consent to participate in the study. Echocardiographic and hemodynamic measurements were performed as previously described [4].…”

“…IGF-I and preproET (ppET)-1 mRNA expression and peptides released in the conditioned media were measured with reverse transcriptase-PCR and radioimmunoassay (Peninsula Lab, San Carlos, California, USA) as previously described in detail [4,5].…”

“…Early growth factor formation following the application of mechanical stimuli is also mediated by Ang II as suggested by the observation that the inhibition of type I receptors for Ang II inhibited early growth factor (ET-1 and angiotensinogen) overexpression in stretched myocytes in vitro [1] and in experimental models of acute cardiac overload in vivo [2,3]. However, in patients with aortic valve disease, the progression from compensatory hypertrophy to heart failure is characterized by reduced gene expression of ventricular myocytes and cardiac formation of insulin-like growth factor-1 (IGF-I) and ET-1 [4], notwithstanding a significant increase in cardiac Ang II generation [4]. The capability of myocytes to express IGF-I and ET-1 following Ang II stimulation is finally lost in ventricular myocytes isolated from failing explanted human hearts [5].…”