Uric Acid in Heart Failure: Controversy Factor in The Multiple Pathogenesis of The Disease Volume 1 - Issue 3
Alexander E Berezin*
Internal Medicine Department, State Medical University of Zaporozhye, Ukraine
Received: July 31, 2017; Published: August 03, 2017
Corresponding author:Alexander E. Berezin, Professor, MD, PhD, Private Clinic “Vita-Center”, 3, Sedova str, Senior Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovsky av, Zaporozhye, Ukraine
The majority of individuals with traditional cardiovascular risk factors contributing in heart failure (HF) risk exhibited increased serum
levels of uric acid. The role of SUA in HF manifestation appears to be controversial. First controversy affects the fact that SUA plays an
important role in inducing oxidative stress, inflammation, neuro humoral activation, and endothelial dysfunction. Being natural antioxidant
uric acid contributes in prevention of cell damage and thereby may restore vascular function leading to reversion of endothelial dysfunction.
Interestingly, there is a large body of evidence regarding that uric acid is able to regulate an activity of endogenous repair system through
epigenetic mechanisms and activation of intracellular signaling, such as STAT3 and Akt. Indeed, uric acid mediates a survival of endothelial
precursors, mediate their mobbing and differentiation, as well as coordinate a turn-over effect of metabolic memory phenomenon into repair
capability of cell precursors. Probably, these controversies could have taken into consideration when clinical results of several studies are
discussed. Although elevated SUA levels were found a strong predictor of adverse clinical outcomes in HF patients, there is assumption that
final result of elevated uric acid may depend on cooperation between metabolic and epigenetic factors contributing in HF evolution. The short
communication is depicted the importance of new clinical data to confirm the emerging reparative ability of SUA in HF and its role as promising
target for treatment in cardiac failure.
TThere is a large body of evidence regarding the role of serum
uric acid (SUA) in pathogenesis of cardiovascular diseases (CVD)
including heart failure (HF). Recent clinical studies and some
meta-analysis have shown that elevated SUA was associated with
an increased risk of incident HF, observed in majority of patients
with established chronic HF and relate to adverse clinical outcomes
in HF [1-4]. However, the impact of SUA on all-cause mortality and
HF-related death was insured by co-existing disease predominantly
hypertension, abdominal obesity, pred iabetes / diabetes mellitus,
kidney disease as well as female sex [2,5-7]. Whether SUA could
be an independent predictor of HF development is not fully
clear. Moreover, there are data clarifying that even asymptomatic
hyperuricemia associated strongly with long-term survival of CVD
patients and individuals with chronic kidney disease throughout
pre-dialysis period and whose who undergoing hemodialysis
procedures. In the Rotterdam Study high quartiles of normal rages
of SUA and mild increased SUA level were more closely related
to early-phase mechanisms of insulin resistance and diabetes mellitus rather than CV complications due to target organ damage
progression [5]. Thus, predictive value of SUA in different patients
at risk of HF is controversial and requires to be elucidated.
The potential molecular mechanisms that explain the role
of SUA in development and advance of HF are traditionally
structured in follow schematic consequences that are appeared to
be counter directed. On the one hand, the hyperuricemia causes
inflammation due to direct vascular injury and a production of
various inflammatory cytokines and monocyte chemo attractant
protein-1, inducing oxidative stress and activation of the local
rennin-angiotensin system [8,9]. Additionally, all these factors
lead to endothelial dysfunction by a reduction in endothelial levels
of vasodilator substances such as nitric oxide, inducing cellular
proliferation, accelerating atherosclerosis, activating insulin
resistance and microvascular inflammation [10]. On the other
hand, urates are physiological substrate for myeloperoxidase
acting as regulator of oxidative stress, but molecule of uric acid
may act as intracellular scavenger of free radicals diminishing pro-inflammatory effect and increasing cell survival [11]. Thus, SUA
links in vascular damage, endothelial dysfunction and oxidative
stress that play important role across all stages of HF development
and contributes in an impact of co-morbidities on risk of HF onset
and advance.
Another way that could probably explain the role of uric
acid in pathogenesis of HF relates to an ability of uric acid to
epigenetically regulate survival of endothelial precursors, mediate
their mobbing and differentiation, as well as coordinate a turnover
effect of metabolic memory into repair capability of cell
precursors [12,13]. Indeed, SUA independently and inversely
associated with number of circulating endothelial progenitor
cells in HF individuals [14]. Moreover, SUA contributed in shaping
of altered ability of endothelial precursors to activate by several
stimuli, release secretom, regulate endothelial reparation and
turn into mature endothelial cells [15,16]. Consequently, SUA may
consider as an endogenous regulator of vascular repair system that
undoubtedly opens new sign on the role of uric acid metabolism
as integrative asset explaining an impact of various comorbidities
on a risk of HF manifestation. As an evidence of the opinion it has
been allowed presenting data, which confirm higher predictive
value of elevated SUA in HF patients beyond etiology of disease,
cardiac pump function, traditional risk factors and estimated
glomerular filtration rate [17-19]. Interestingly, large numbers of
clinical and observational studies have shown that elevated SUA
levels are associated with reduced survival in in-patients and
out-patients with several phenotypes of chronic HF, as well as in
acute / actually decompensated HF [20-22]. In contrast, in recent
meta-analysis lowering SUA levels under treatment (allopurinol,
oxypurinol, febuxostat) did not predict improved surrogate clinical
outcomes in HF [23]. Moreover, there was not convincing evidence
regarding associations of SUA levels with increased risk of HF and
other disease at higher risk of HF (hypertension, impaired fasting
glucose or diabetes mellitus, chronic kidney disease, coronary heart
disease) and HF mortality [24].
All these facts clarify that SUA is multiple player with controversial
activities that concurrently contribute in HF pathogenesis [25]. SUA
modalities cannot be discussed as unconditionally harmful effects
supporting inflammation and cell death, but they may produce a
favorable result on reparative activity of endothelium and restoring
endothelium function and vascular integrity [26]. Whether SUA is a
therapeutic target to reduce HF risk in vulnerable population is not
fully clear and requires to be explained in the large clinical trials. In
conclusion, there is no an available evidence regarding only harmful
effect of SUA in vulnerable population patients at higher risk of
HF as well as in individuals with established HF irrespective left
ventricular ejection fraction or isolating diastolic abnormality. The
importance of new clinical data to confirm the emerging reparative
ability of SUA and its antioxidant activities across HF development
require to be cleared in large investigations. The results of these
trials would be intriguing and could open new perspective to use
xanthine oxidase inhibitors as adjuvant care in HF management.
ISSN: 2574 -1241
