EDITORIAL
European Heart Journal (2014) 35, 413–415
doi:10.1093/eurheartj/eht562
A direct link between haemodynamic failure
and inflammatory activation in heart failure:
the simplified approach to heart failure and to
creation of life
Wolfram Doehner*
Centre for Stroke Research Berlin, and Department of Cardiology, Virchow Klinikum, Charité-Universitätsmedizin Berlin, Germany
Online publish-ahead-of-print 9 January 2014
This editorial refers to ‘Peripheral venous congestion causes
inflammation, neurohormonal and endothelial cell activation’†, by P.C. Colombo et al. on page 448
‘Simplicity does not precede complexity, but follows it’
Alan Perlis
The classical pathophysiological concept of heart failure (HF) is, of
course, the failing pumping force of the myocardium leading to
poor tissue perfusion and subsequent functional failure of a range
of tissues and organs. The logical consequence, to treat this
problem by medically enforced stronger myocardial contractility,
failed dramatically, however, as mortality in the long run was even
increased with treatment by catecholamines or phosphodiesterase
inhibitors. The reasoning from these clinical findings together with
further studies formed the basis for the paradigm of neuroendocrine
activation as a major underlying principle of HF above and beyond
haemodynamic failure. The neurohormonal hypothesis of HF as proposed 20 years ago by Milton Packer1 soon became established as a
cornerstone of HF pathophysiology. In fact, all of today’s medical
treatment concepts in chronic HF with proven benefits on prognosis
target neurohormonal activation in some way.
This insight was only the first step that opened an era of huge
advances in understanding the complexity of the pathophysiology
of heart failure. Beyond the haemodynamic failure and neuroendocrine activation, further paradigms were uncovered as contributing
to clinical symptoms, to progression, and to mortality of HF. As
one prominent feature, inflammatory immune activation was recognized to occur in HF, adding further complexity by linking haemodynamic, endothelial, and metabolic dysfunction (Figure 1). Moreover,
it soon became apparent that it is not only the myocardium itself which
is the target and promoter of the disease. On the contrary, multiple systemic effects involve peripheral tissues and organs in feedback loops
of disease progression. Clearly, chronic HF should be regarded as a
systemic disease with secondary dysfunctions, e.g. of the kidneys,
skeletal muscles, bone marrow, intestine, endothelium, and others
that contribute to the downward spiral of symptomatic and prognostic deterioration.2
Sound evidence emerged that increased proinflammatory cytokine levels account for a latent systemic immune activation even in
stable and compensated ambulatory HF patients. Tumour necrosis
factor-a, interleukin-1, and interleukin-6 are the most prominent
cytokines implicated in HF progression. A range of cell types have
been identified to secrete cytokines under pathological conditions
such as HF, with local (autocrine and paracrine) or systemic effects.
However, the origin of elevated cytokine plasma levels in HF
remained a matter of debate, and several hypotheses are discussed.
First, the failing heart itself can express proinflammatory cytokines.
Indeed, increased cytokine expression and spillover from the overburdened myocardium into the systemic circulation has been
observed.3 Secondly, tissue hypoxia may result in increased cytokine
production on a systemic level, as suggested mostly from cell studies
and experimental animal models. Thirdly, intestinal hypoxia and/or
congestion may result in compromised intestinal barrier function and
subsequent increased translocation of gut flora lipopolysaccharides.4,5
Most of today’s insights into the role and mechanisms of cytokines
in HF were achieved from intense research during the 1990s. A series
of interventional trials tested the convincing concept that lowering
cytokines in HF may improve morbidity and/or mortality in CHF
patients. Disappointingly, the RECOVER, RENAISSANCE, and
ATTACH trials were unable to show a clinical benefit of targeting
increased cytokine levels in chronic HF.6,7 A number of
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/eht456.
* Corresponding author. Center for Stroke Research Berlin, CSB, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel: +49 30 450 553 507,
Fax: +49 450 553951, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
414
Editorial
Figure 1 Evolving pathophysiological principles of HF and current treatment concepts. CRT, cardiac resynchronization therapy; HTX, heart transplantation; LVAD, left ventricular assist device; H-ISDN, hydralazine and isosorbide dinitrate; MR antagonists, mineralocorticoid receptor antagonists.
methodological issues of the trials were discussed to explain the
negative results.8 However, the failure of anticytokine therapies in
HF may also be explained by the complexity of the signalling effects
that go well beyond the activation of immune cells and that are far
from being understood.9 The fact that cytokines came into action
very early in the evolution of multicellular organisms early in the
Cambrian period (540 million years ago) suggests that these molecules may confer a significant survival benefit on the organism.
Despite such considerations, further research in this field tailed off
after the negative treatment trials mentioned above.
Colombo et al. now take up the thread again as they report on a
direct link between peripheral venous congestion and local release
of inflammatory mediators.10 Using a simple yet robust clinical
model, they could show a direct and mechanistic link between
acute venous congestion even without ischaemia and inflammation,
with increased cytokine release and modification of key proinflammatory genes.
The study, despite its rather simple protocol and plain test setting,
nevertheless provides convincing results regarding direct inflammatory activation by increased pressure load. Of course the test
settings are a huge simplification of the true pathophysiological conditions since relevant factors such as older age, chronic HF-induced
neurohormonal activation, and accumulation of secretory products
due to renal impairment were not accounted for. Also the perplexing short period of 75 min of pressure overload compared with the
prolonged chronicity in chronic HF for months and the unphysiologically high level of venous pressure increase (+30 mmHg
compared with ,10 mmHg above normal in most patients with
chronic HF) would by no means realistically mimic the conditions
in chronic patients. With this in mind, to find significant activation
of inflammatory gene signatures and cytokine secretion in such simplified conditions supports the applicability of the hypothesis even
more strongly.
In fact, it is simplification in the setting that is sometimes needed to
shed light on highly inter-related and seemingly inextricable conditions. One may be reminded of another fascinating example of a
highly simplified experimental setting that resulted in nothing less
than the proof of one of nature’s finest hours: the Miller –Urey experiment that proved the abiogenetic creation of life on earth.
Searching for the miracle of organic life developing from anorganic
precursors, in 1953 Stanley Miller and Harold Urey conducted an experiment that simulated the conditions thought to be present on the
early earth. They used as few ingredients as water, methane,
ammonia, and hydrogen as presumed components of the early atmosphere, poured all these into a sterile glass flask, and added heat
and electric sparks resembling extensive volcanic and thunderstorm
activity. Being a student of chemistry at the University of Chicago,
Stanley Miller could wait no longer than one night for these ingredients to work on what may have required several hundred millions of
years in the original setting. Opening the flask he was nevertheless
able to identify as many as three of the 20 proteinogenic amino
acids. After this highly simplified initial experiment, of course, multiple repeated tests around the world were performed that uniformly
confirmed the principal approach by Miller and Urey. Increasing
Editorial
complexity of the settings resulted in ever higher organic molecules
deriving from anorganic precursors including sugars, purines, porphyrins, and eventually even adenosine triphosphate (ATP). With
the drastic simplification of the experimental conditions the scientists
were able to prove a principle that was unsuccessfully sought after by
a large scientific community with highly complex hypotheses and
experiments.
The paradigm of proinflammatory immune activation in HF as
reported by Colombo and colleagues may of course not exactly resemble the creation of life on earth. However, the reductive approach of the
experiment may help to refocus on a principle of experimental work.
With better understanding of the pathways and the effects of inflammatory activation in HF, novel therapeutic concepts may arise
to continue the story that was put to rest after the RECOVER and RENAISSANCE trials. Today’s medical treatment strategies in HF with
prognostic improvement rely nearly exclusively on the inhibition of
neuroendocrine overactivation. This concept had been developed
in the late 1980s. Since then, none of the more recent pathophysiological paradigms that were correctly identified as contributing to HF
progression successfully translated into a guideline-relevant therapeutic concept.
Several metabolic strategies to improve energy efficacy are currently pursued and with iron i.v. therapy a first step towards metabolic interventions in HF has been made.11 Both metabolic treatments
and anti-inflammatory concepts are promising candidates for novel
treatment options in HF. More work in these fields is warranted to
extend our therapeutic armamentarium beyond the current standards of neuroendocrine inhibition.
Conflict of interest: none declared.
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