After 6 years of multifactorial risk intervention, there is significant and persistent improvement in lipoprotein levels and physical work capacity, which results in a significant retardation of disease progression. These beneficial effects appear to be largely due to chronic physical exercise.

Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI.

Abstract-The evolutionary conserved Wnt signaling pathway regulates cardiogenesis. However, members of the Wnt pathway are also expressed in the adult heart. Although Wnt-signaling is quiescent under normal conditions, we noticed activation on pathological stress of the heart, such as chronic afterload increase. To examine the role of Wnt signaling on the postnatal heart, we modified the expression and function of the Wnt regulator dishevelled 1 (Dvl-1) both in transgenic mice with cardiac-specific overexpression of Dvl-1 (Dvl-1-Tg) and in cultured cardiac myocytes. Dvl-1-Tg mice (3 months) had severe cardiac hypertrophy (heart weight:body weight ratio: 5.2Ϯ0.3 mg/g wild-type [WT] versus 6.4Ϯ0.7 mg/g Dvl-1-Tg; PϽ0.01), an increase in cardiomyocyte size (86% increase in Dvl-1-Tg compared with WT; PϽ0.01) and marked raise of atrial natriuretic factor expression (12-fold increase versus WT; PϽ0.01). Hypertrophy was associated with left ventricular dilatation in Dvl-1-Tg and a reduction of ejection fraction (4.4Ϯ0.1 mm versus 5.5Ϯ0.2 mm, 80Ϯ2% and 43Ϯ4% in WT versus Dvl-1-Tg, respectively; PϽ0.01). Transgenic animals died prematurely before 6 months of age. Both canonical as well as noncanonical Wnt signaling branches were activated in the Dvl-1-Tg animals. Small interfering RNA-mediated depletion of Dvl-1 was used to further characterize the role of Dvl-1 in cardiac myocytes. Whereas baseline parameters were unaltered, ␤-adrenergic hypertrophic response was abrogated in Dvl-1 knockdown cardiac myocytes, indicating a mandatory role in ␤-adrenergic stimulation. Therefore, activation of Wnt signaling is sufficient and critical for the induction of myocardial hypertrophy and cardiomyopathy. Key Words: Wnt signaling Ⅲ cardiac hypertrophy Ⅲ experimental heart failure A fter conditions of increased wall stress, the myocardium may adopt by a process called remodeling. Left ventricular remodeling is considered to be a maladaptive process characterized by myocyte hypertrophy, an increase in myocardial fibrosis, and left ventricular dilatation. Remodeling may induce clinically overt heart failure and contributes to increased mortality after myocardial infarction. Other than standard heart failure medications, there are no treatment options available targeted to maladaptive remodeling. On pathological stress, the heart reactivates a number of signaling pathways, which traditionally were thought to be operational primarily in the developing organism. The Wnt pathway is an evolutionary conserved signaling mechanism with a critical function in tumor growth 1 and cardiogenesis. 2,3 However, members of the Wnt pathway are also expressed in the normal adult heart. 4 -7 Thus, for example, the Frizzled (Fz) class of cell surface receptors of Wnt proteins, including Fz1 and Fz2, is expressed in human myocardium. 7 In infarcted hearts, Fz2 expression is considerably enhanced, 8 and in failing ventricles of humans, mRNA levels of secreted Fz-related proteins 3 and 4, which are endogenous Wnt antagonists, are elevated, leading to attenuat...

To examine the relationship between exercise intensity and activation of coagulation and fibrinolysis, we measured markers of thrombin, fibrin, and plasmin formation in 12 male subjects (mean 24+/-4 yr (SD)) before and after running on a treadmill for 1 h at two different intensities corresponding to moderate (82% maximal heart rate (HR), 68% VO2max) and very heavy (94% maximal HR, 83% VO2max) exercise. During moderate exercise plasma levels of tissue plasminogen activator (t-PA) antigen rose from 3.7+/-0.5 (mean+/-SE) to 14.6+/-1.8 ng x mL[-1] (P < 0.01) and of plasmin-alpha-antiplasmin (PAP) complexes from 2.1+/-0.3 to 4.2+/-0.7 nmol x L[-1] (P < 0.01), whereas prothrombin fragment 1+2 (PTF1+2), thrombin-antithrombin III (TAT) complexes and fibrinopeptide A (FPA) did not change significantly. In response to very heavy exercise, mean plasma levels of t-PA antigen and PAP complexes exceeded the upper limit of normal values 2.5- (P < 0.01) and two-fold (P < 0.01), respectively, while significant increases of plasma levels of PTF1+2 (P < 0.01), TAT (P < 0.05), and FPA (P < 0.01) occurred within the range of normal. We conclude that in healthy young individuals, exercise-induced activation of coagulation is well balanced by activation of the fibrinolytic system, since moderate exercise results in increased plasmin formation only, while at very heavy exercise generation of plasmin seems to exceed that of thrombin and fibrin.