THE historic vineyards of Bordeaux
and the elegant Château Giscours
were the stunning backdrops to a
recent gathering of Europe’s
foremost veterinary cardiologists.
The occasion was a
symposium, hosted by
Ceva Animal Health,
bringing together
specialists in human
and animal science to
discuss the role of
aldosterone in heart
failure and the
therapeutic benefit of
blocking its activity.
Cardiologists’
interest in aldosterone
has largely been
stimulated by the fact
that the aldosterone
antagonists, spironolactone and
eplerenone, substantially reduce
cardiovascular mortality in humans.
These benefits are not related to any
diuretic or blood pressure effect of
aldosterone blockade, but appear to be a
consequence of blocking the
mineralocorticoid receptors (MR) that
mediate the remodelling activity of
aldosterone.
Scientific understanding of the role
of aldosterone and its receptors in the
heart was the subject of the
symposium’s first two presentations,
which were given by Dr Nicolette
Farman and Dr Frédérick Jaisser from
the French National Institute of Health
and Medical research (INSERM) in
Paris.
Their research group has been
pivotal in showing that MR are
expressed in cardiomyocytes and in
endothelial and smooth muscles cells of
coronary blood vessels, the aorta and
resistance arteries. Although the exact
function of aldosterone and MR in
these tissues is poorly understood, it is clear that over-activation of MR
contributes to the progression of heart
disease and failure.
Aldosterone is known to have a
profibrotic effect and chronic activation of
MR has been
associated with cardiac
fibrosis, endothelial
dysfunction and
vascular wall
remodelling. These
effects are, however,
seen regardless of
plasma aldosterone
concentrations and are
independent of blood
pressure, suggesting
that it is increased
expression and/or
activation of MR, rather than
hyperaldosteronism, that is responsible for cardiovascular pathology.
The pathogenic role of these receptors in cardiac tissues is highlighted
by the observation that blocking MR
with low doses of spironolactone
prevents cardiac and vascular
remodelling in humans and a variety of
animal models of heart failure. This
includes dogs, with a recent study
showing that spironolactone reduces
atrial fibrosis and prevents conduction
defects in dogs with congestive heart
failure induced by rapid ventricular
pacing.1
Conundrum re-examined
The science linking experimental MR
studies with clinical benefits was further
explored by Dr Johann Bauersachs from
the University Hospital in Würzburg,
Germany.
He began by re-examining the
conundrum that, while aldosterone
induces cardiac fibrosis and plasma
levels predict the risk of mortality in
humans suffering acute myocardial
infarction or congestive heart failure,
benefits from MR antagonists are seen
in patients with normal aldosterone
concentrations.
Dr Bauersachs’ own research has
shown that cardiac MR expression is
increased in heart failure patients,
thereby indicating that it is over-
expression of the receptor, rather than
increased production of aldosterone,
that is deleterious.
Other contributing factors might
include activation of MR by
glucocorticoids, oxidative stress, and
changes in gene expression – so-called
“foetal switching” – in the failing heart.
The relevance of experimental models to canine clinical disease was
debated during this and the subsequent
presentation from Professor Robert
Hamlin of Ohio State University. While
models cannot truly replicate either
myxomatous mitral valve disease
(MMVD) or dilated cardiomyopathy,
both speakers argued that the pathology
of end stage heart failure is similar
regardless of the cause and that canine
models, including those in which heart
failure is induced by rapid pacing,
chordectomy or micro-embolism, do
have value.
MR antagonists
Developments in the use of MR
antagonists in humans were reviewed by
Professor Bertram Pitt from the
University of Michigan School of
Medicine, who led clinical studies
demonstrating that spironolactone
reduces three-year mortality by over
30% in patients with chronic severe
heart failure.
He stressed that clinical benefits are
greater the sooner that therapy is
started and are in addition to other
cardiac therapies, including angiotensin
converting enzyme (ACE) inhibitors,
angiotensin II receptor antagonists, β
blockers, loop diuretics and digoxin.
On-going studies are examining the
efficacy of spironolactone in patients
with mild heart failure and Professor
Pitt expressed the firm belief that, in
the future, MR antagonists will play a
key role in preventing many forms of
heart failure.
The spotlight then switched to
veterinary experiences with
spironolactone and Dr Claudio
Bussadori from Milan, Italy, who is
dually qualified as a veterinarian and
medical doctor, described a large
clinical trial of spironolactone in dogs
with moderate to severe mitral valve
regurgitation caused by MMVD.
A total of 221 dogs entered into a
double-blinded, placebo-controlled
study that took place in 32 veterinary
practices across France, Germany,
Belgium and Italy. The dogs received
either spironolactone at a dose of
2mg/kg/day or placebo, and were
monitored for 15 months. All dogs
were concurrently receiving an ACE
inhibitor and approximately 50% were
on frusemide.
The primary end points were
cardiac-related death or euthanasia, or
severe worsening of disease.
Analysis of clinical trials such as this spironolactone study is complicated
and can be difficult to understand, but
was expertly explained by Professor
John Bland from the Department of
Health Statistics at the University of
York.
His analysis revealed that the
estimated survival rates for dogs treated
with placebo or spironolactone at 15
months were 66% and 84%,
respectively (P<0.05). The hazard ratio,
which is an indication of the efficacy of
treatment, was 0.45 (P<0.05).
This meant that there was a 55%
reduction in the risk of death or
worsening of cardiac disease in dogs
treated with spironolactone.
When only cardiac death or
euthanasia were considered, the survival
rate for spironolactone-treated dogs
was 92%, compared with 73% for the
placebo group (P<0.01), and there was
a 69% reduction in risk of mortality
(P<0.05).
Substantially greater
Putting these results in context,
Professor Bland indicated that the
magnitude of benefit was such that,
had it been a human clinical trial, the
study would have been stopped on
ethical grounds so that all patients
could receive spironolactone.
The 69% reduction in 15-month
mortality is substantially greater than
that seen in the equivalent human
study, which amounted to 31% over
three years.2
In closing proceedings, Mark
Prikazsky, the president and CEO of
Ceva Santé Animale, remarked that the
symposium was inspired by the
philosophy of “one medicine” and the
advances that might be accrued by
exchanging expertise between human
and veterinary fields.
Judging from the buzz over dinner
later that night, it certainly achieved
that goal and left all those who
attended with new thoughts and ideas
to take back to both the laboratory
and clinic.
- Yang, S-s., et al. (2008) Effects of
spironolactone on electrical and
structural remodeling of atrium in
congestive heart failure dogs. Chinese
Medicine Journal 121: 38-42. - Pitt, B., et al. (1999) The effects of
spironolactone on morbidity and
mortality in patients with severe heart
failure. New England Journal of Medicine
341: 709-717.
