Target Discovery and Validation Reviews and Protocols

270 Iversen and Sørensen
witnessed important new contributions in terms of revascularization regimens,
e.g., coronary artery bypass surgery and angioplasty. However, in spite of these
advances, the prognosis of the heart failure patient remains dismal with high
morbidity and mortality (3).
Although the heart failure syndrome is generally characterized primarily as
a hemodynamic disorder with impaired left ventricular function as the main
hallmark, we are still short of a comprehensive understanding of the pathology
of this debilitating disorder. Refinement of tools for measuring minute concentrations
of biologically active molecules as well as the advent of genetically
altered mice has changed our view of heart failure as a mere circulating disorder
to that of a possible inflammatory condition. In line with this changed
view, several cytokines seem to play important roles in the pathogenesis of
heart failure, at least in experimental models. Hence, in particular, the proinflammatory
cytokine tumor necrosis factor (TNF)α, and also the interleukins
(IL)-1β and -18, seem to exert cardiodepressive effects in various in vitro and
in vivo settings (4–6).
Paralleling this development is the recognition that patients with heart failure
also suffer from conditions related to an impairment of bone marrow function,
in particular, hematopoiesis. Although not well documented in the past, it has
been a clinical experience that the hemoglobin concentrations of these patients
usually are somewhat reduced. Based on autopsies, Bohm (7) concluded that
a gelatin transformation of the bone marrow was more frequent among patients
deceased from heart failure. Later, epidemiological studies concluded that
anemia significantly predicted a worsened outcome among heart failure patients
who were anemic compared with those with normal hemoglobin levels (8,9).
The crucial question is whether the anemia has a true negative impact on
the development and progression to overt heart failure or whether it simply
is a result of a deteriorating bone marrow function because of the failing
heart (10).
Although wild mice and rats can survive almost any climatic condition,
their laboratory relatives have lost the genetic background for this adaptability.
When animals are bred for experimental use, one major concern is to produce
individuals or populations with a minimum genetic variance, which makes
the animals sensible to even small changes in the environment that may influence
the outcome of the experiments. Examples of factors that may influence on the
experimental results are physical parameters, such as temperature, humidity,
light cycle, and chemical factors (see Notes 1–4), and also social factors, such
as human contact, cage design, and animal interactions. Control of the most
important of these factors may reduce “the background noise” in animal experiments
and make it possible to obtain statistically significant results with a
limited number of animals.