Cardiac growth factors in human hypertrophy - Relations with myocardial contractility and wall stress

The aim of the present study was to investigate whether and which cardiac g rowth factors are involved in human hypertrophy, whether growth factor synt hesis is influenced by overload type and/or by the adequacy of the hypertro phy, and the relationships between cardiac growth factor formation and vent ricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aort ic stenosis (n=26) or regurgitation (n=15) and controls (n=12). Gene expres sion and cellular localization was investigated in ventricular biopsies usi ng reverse transcriptase-polymerase chain reaction and in situ hybridizatio n. Cardiac hypertrophy with end-systolic wall stress <90 kdyne/cm(2) was as sociated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aort ic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was corr elated to the mean velocity of circumferential fiber shortening (r=0.86, P< 0.001) and ET-1 formation to relative wall thickness (r=0.82, P<0.001). Whe n end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET-1 synthesis by c ardiomyocytes was no longer detectable, and only angiotensin (Ang) II was g enerated, regardless of the type of overload. The mRNA level for angiotensi nogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang Il formation was positively correlated to end-systolic stress (r =0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001), Multivariate st epwise analysis selected end-systolic stress as the most predictive variabl e and left ventricular end-diastolic pressure as the independent variable f or Ang II formation (r=0.93, P<0.001). In conclusion, the present results i ndicate that the course of human left ventricular hypertrophy is characteri zed by the participation of different cardiac growth factors that are selec tively related both to the type of hemodynamic overload and to ventricular function.