Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling

Abstract

Abstract-Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6-and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit ϩ cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.

Fluorescence Tomography and Magnetic Resonance Imaging of Myocardial Macrophage Infiltration in Infarcted Myocardium In Vivo

“…Individual differences in the response to cytokine therapy in the postinfarction setting have been reported recently, 38 and magnetofluorescent imaging of myocardial macrophage infiltration in vivo could thus allow the timing, dose, and efficacy of a particular therapy to be quantitatively assessed and individualized. The prolonged retention of internalized MNPs by macrophages, however, may limit the utility of these nanoparticles for repeated serial imaging of myocardial macrophage infiltration.…”

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction

“…The anti-remodeling effect of doxycycline was independent from both the infarct size (as measured by troponin I peak or CK-MB peak) and LV wall stress (as indirectly expressed by pro-BNP peak), which are the two most important drivers of the post-infarct remodeling process [30], and from advanced age that may critically contribute to remodeling process [31]. Moreover, doxycycline appears to have more impact on LV remodeling than the cornerstone of post-MI anti-remodeling therapy probably because the unquestionable favorable clinical effect of the latter drugs in patients with acute MI depends on mechanisms other than inhibiting the LV dilation [32], especially in the successfully reperfused patients [33].…”

The immune system and cardiac repair

“…Thus, the injurious potential of inflammatory mediators in patients with myocardial infarction may have been overstated due to extrapolation from young animals to human patients. In addition, senescent ischemic hearts show impairment of important cardioprotective pathways involving TNF-α [339] and PDGF-AB [340] and have a decreased anti-apoptotic response to administration of GranulocyteColony Stimulating Factor (G-CSF) and SCF [341] in comparison with young animals.…”