Abstract
Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.
Highlights
Congestive Heart failure (CHF) is a clinical syndrome characterized by cardiac dysfunction and myocardial structural abnormality resulting in inability of the heart to eject sufficient blood to the metabolizing tissues
Smith and Lincoln [70] were the first to demonstrate in cultured vascular smooth muscle cells and mesangial cells that angiotensin II, and perhaps other vasoconstrictor Ca2+ mobilizing agents, may increase the degradation of cGMP, the 2nd messenger of atrial natriuretic peptide (ANP), by activation of Ca2+-dependent phosphodiesterase. This potential mechanism is of interest since we have demonstrated that urinary cGMP excretion is reduced in rats with aortocaval fistula (ACF); cGMP generation in isolated glomeruli from ACF rats as tested in vitro in response to ANP remains intact [69]
We have demonstrated that Omapatrilat, a drug belonging to the group of vasopeptidase inhibitors, improves both sodium balance and cardiac remodeling in rats with ACF and might be advantageous to ACE inhibitors for the treatment of decompensated congestive heart failure (CHF) [72]
Summary
Congestive Heart failure (CHF) is a clinical syndrome characterized by cardiac dysfunction and myocardial structural abnormality (e.g., hypertrophy and dilated cardiomyopathy) resulting in inability of the heart to eject sufficient blood to the metabolizing tissues. The progress that has been made so far and the expected future achievements in this field would not have been possible without the continuous development of experimental models of heart failure and hypertrophy in small and large animals, where each one has its unique advantages and limitations. Among these models, one can mention coronary ligation, aortic banding, salt-sensitive and spontaneous hypertension, toxic cardiomyopathy, rapid pacing, and aortocaval fistula (ACF) (for more details see [3]). The transition from large animals to rodents is of special value since powerful genomic tools such as transgenic and knockout technologies are available for the rat in addition to mice
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