INTRODUCCIÓN: REVISIÓN CRITICA DEL PROBLEMA

CAPÍTULO IV
it was based mainly on clinical trials, and differences in HF management,
especially with more prevalent use of devices (in fact, 3.7% of our patients had an
implanted cardioverter– defibrillator compared to 1.7% of the 11,232 patients
included in all 6 SHFS derivation and validation cohorts). Thus, novel markers with
proved and validated prognostic predicting capacity may be useful to improve
former risk scores.
In the present study, sRAGE was associated with worse outcomes in addition to
and independently of SHFS. sRAGE, the soluble form of RAGE, is a product of
alternative splicing of the gene for RAGE (endogenously secreted RAGE) and
cleavage of membrane-bound RAGE (cleaved RAGE) 275 . sRAGE has been
recently related to oxidative stress and inflammation 269 and, as we described, to
coronary heart disease in patients with CHF 264 . In this study we demonstrated its
association with worse prognosis (mortality and hospitalization rate), which is
consistent with work by Koyama et al 175 and to our knowledge the only study on
this issue. There are some hypotheses that justify this finding. Experimental
studies have demonstrated that activation of RAGE by its ligands may trigger
reactive oxygen species generation 276 , inflammation 269 , remodeling, and growth
factor signaling and/or distinct events 271 , which in the aggregate may lead to cell
death and HF. Our hypothesis is that sRAGE plasma levels in patients with HF
reflect increased activity of the AGE-RAGE axis.
Outpatients with CHF in the present study attended a tertiary reference unit and
thus were treated optimally with almost 90% receiving prescriptions for
angiotensin–aldosterone system blockers and B-blockers and 3.7% with
implantable cardioverter– defibrillators/cardiac resynchronization therapy. High
levels of sRAGE were associated with a fourfold increase in risk of cardiac death
and cardiac events. It is also worth mentioning that almost 25.9% of patients
presented normal LVEF, which is a proportion considerably larger than in the
study of Koyama et al 175 .There was no significant association between sRAGE
and LVEF, and the prognostic impact of the former marker was independent of
systolic function in our study. There is experimental evidence that may explain the
deleterious role of RAGE in HF with normal LVEF 230 . Overexpression of RAGE
decreased systolic and diastolic intracellular calcium concentrations and caused
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