Abstract-In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying 125 I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT 1 and AT 2 on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT 1 density on failing myocytes did not differ from that of NF myocytes, with preserved AT 1 /AT 2 ratio. Conversely, AT 1 density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT 1 density does not change on failing myocytes, and (3)

Abstract-Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [ 3 H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (PϽ0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (PϽ0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (PϽ0.01), whereas cardiac [ 3 H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise. Key Words: insulin-like growth factor-I Ⅲ norepinephrine Ⅲ sympathetic nervous system Ⅲ exercise Ⅲ hypertrophy, left ventricular T he heart sustains an increased hemodynamic load by adjusting its mass independently of whether the enhanced workload is due to physiological activity or to pathological alterations in the cardiovascular system. There is much evidence that the development of myocardial hypertrophy results from the interaction of mechanical forces (the increased workload) and cardiac growth factors. The hemodynamic overload leads to myocardial cellular stretch and strain that in turn induce gene expression of cardiac growth factors. 1,2 In regularly trained healthy subjects, both isotonic and isometric exercise cause cardiac changes resulting in modifications of the ventricular chambers and in a notable enhancement of heart performance. These modifications, called physiological hypertrophy or athlete's hypertrophy, are required for sustaining the tremendous increase in cardiac output during exercise. Cardiac growth factors involved in the development of physiological hypertrophy in humans are still unknown, and their knowledge might also be relevant for better understanding the mech...

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