A possible new pathway in the development of heart failure has been suggested,
by the observation that plasma levels of the novel protein resistin are raised
in people who go on to develop the condition [1].

The study, published in the March 3, 2009, issue of the Journal of the American
College of Cardiology, was conducted by a team led by Dr David Frankel
(Massachusetts General Hospital, Boston).

They analyzed data from the Framingham Offspring Study and found that resistin,
a protein produced in adipose tissue, was strongly associated with an increased
risk of new-onset heart failure. "The specific mechanism whereby resistin
promotes heart failure remains to be elucidated, but our findings suggest that
novel mechanisms promoting heart failure remain yet to be discovered," the
researchers conclude.

Senior author Dr James Meigs (Massachusetts General Hospital) commented to
heartwire that resistin can now be considered a new marker of risk for the
development of heart failure. "We cannot say from this study if it is causal or
not, as this was an observational study and can be considered only as hypothesis
generating. But we did show a very strong association, even after controlling
for many other risk markers, which suggests that resistin could be part of an
alternative pathway in the development of heart failure that has not been
previously recognized," he added.

Meigs explained that obesity and insulin resistance are known to be linked to
higher rates of heart failure, but the mechanism is not well understood. Also,
in obese people, the fat tissue is infiltrated with inflammatory macrophage
cells to a much greater extent than in individuals of normal weight, and these
macrophages secrete resistin. "In this study, we looked at people before they
developed heart failure and found that elevated levels of resistin precede and
predict the onset of heart failure. We are seeing relative risks of 2 to 4,
which is a very strong effect. We made every effort to get rid of the
association, but it was still there, which leads us to suspect that there could
be something real here. Our results raise a lot of questions about what resistin
does. Are there other ways in which people develop heart failure related to
obesity that we have not yet understood?" he noted.

Meigs says this paper does not address the idea of measuring resistin as a risk
marker for heart failure. "My hunch is that it would not be particularly
helpful. The big question is whether this would add anything to existing
information, and what we have seen with most new biomarkers is that they have a
hard time adding information to that already supplied by the things we already
measure such as blood pressure, left ventricular function, atrial natriuretic
peptide levels, etc.

"I think the chief value of our findings is that they suggest a new target for
heart-failure research. It is particularly interesting that resistin was an
independent predictor of heart failure, even after controlling for CRP levels,
which is intriguing, as both these substances are markers of inflammation. This
suggests that resistin may have other actions on the heart independent of
inflammation," he said.

Meigs said it was far too soon to be thinking about antiresistin drugs. "This
research is at such an early stage. We need to find out exactly what resistin is
doing first, but if we find that it does play a role in the development of heart
failure, this could lead to new prevention strategies."

In the study, the researchers measured levels of two proteins produced in fat
tissue, resistin and adiponectin, in 2739 individuals without heart failure
taking part in the Framingham Offspring Study. During six years of follow-up, 58
participants developed new-onset heart failure.

After adjusting for age, sex, blood pressure, antihypertensive treatment,
diabetes, smoking, lipid levels, coronary heart disease, valvular heart disease,
left ventricular hypertrophy, and glomerular filtration rate, the researchers
found that people in the highest tertile for resistin levels were four times
more likely to develop heart failure than those in the lowest tertile, and those
in the middle tertile were two to three times as likely to develop the
condition.

Additional adjustment for body-mass index, insulin resistance, CRP, and B-type
natriuretic peptide did not substantively weaken this association. In contrast,
concentrations of adiponectin were not associated with heart failure.

In an accompanying editorial [2], Drs Malcolm Arnold (University of Western
Ontario, London, ON) and Richard Gilbert (University of Toronto, ON) note that
there is still much to learn about the complex interrelationships between
dysglycemia, obesity, and insulin resistance, but their impact on heart failure
and the cardiovascular system is becoming clearer, with inflammation emerging as
a possible unifying mechanism. "Ongoing interdisciplinary research will
hopefully provide us with a better understanding of these emerging risk factors
and potential therapeutic targets that will allow us to see the full and correct
picture rather than just individual parts," they conclude.

One of the authors of the current study has received honoraria from
Sanofi-Aventis and serves on advisory boards for Pfizer and Bayer. Meigs
currently has research grants from GlaxoSmithKline and serves on safety boards
for GlaxoSmithKline and Lilly.


Frankel DS, Vasan RS, D'Agostino RB, et al. Resistin, adiponectin, and risk of
heart failure. The Framingham Offspring Study. J Am Coll Cardiol 2009;
53:754¡V762. Abstract
Arnold JMO and Gilbert RE. Novel risk factors for heart failure. When the whole
may be greater than the sum of its parts. J Am Coll Cardiol 2009; 53:763-764.
Abstract