Abstract
Increasing evidence points to insulin resistance as a primary
etiologic factor in the development of nonischemic heart failure
(HF). The myocardium normally responds to injury by altering
substrate metabolism to increase energy efficiency. Insulin
resistance prevents this adaptive response and can lead to further
injury by contributing to lipotoxicity, sympathetic up-regulation,
inflammation, oxidative stress, and fibrosis. Animal models have
repeatedly demonstrated the existence of an insulin-resistant
cardiomyopathy, one that is characterized by inefficient energy
metabolism and is reversible by improving energy use. Clinical
studies in humans strongly support the link between insulin
resistance and nonischemic HF. Insulin resistance is highly
prevalent in the nonischemic HF population, predates the development
of HF, independently defines a worse prognosis, and predicts
response to antiadrenergic therapy. Potential options for treatment
include metabolic-modulating agents and antidiabetic drugs. This
article reviews the basic science evidence, animal experiments, and
human clinical data supporting the existence of an "insulin-
resistant cardiomyopathy" and proposes specific potential
therapeutic approaches.

Introduction
Insulin resistance, often manifested clinically through the features
of the metabolic syndrome or type II diabetes mellitus, has reached
epidemic levels in the U.S. and many nations throughout the world.
[1,2] Heart failure (HF) will eventually affect 1 in 5 Americans and
is responsible for the consumption of an extraordinary proportion of
health care resources.[3-5] Although a relationship between these 2
diseases has been long-recognized, it has classically been
attributed to the increased prevalence of myocardial ischemia in
patients with insulin resistance and to the fact that HF itself
causes whole-body insulin resistance.[6,7] We propose a more
fundamental link between insulin resistance and HF, one independent
of coronary artery disease. The theories/evidence for this link as
well as potential treatment options will be reviewed in this article.

A link between insulin resistance and HF has been noted for more
than a century. In 1881, Leyden[8] noted that HF is a "frequent and
noteworthy complication of diabetes mellitus," and Mayer[9,10]
speculated 7 years later that "heart disease in diabetes can be
traced to an abnormality in metabolism." In 1974, Kannel et al.[11]
found that men with cardiomyopathy were more than twice as likely as
matched control subjects to have diabetes mellitus, with women more
than 5 times as likely. Surprisingly, this link between diabetes and
HF actually grew stronger when patients with ischemic heart disease
were excluded. Other descriptions of a specific "diabetic
cardiomyopathy" continued to emerge in the 1970s.[12,13]

Subsequent studies have confirmed the existence, at the very least,
of a strong correlation between diabetes and nonischemic
cardiomyopathy, with a dramatically increased prevalence of diabetes
in the dilated cardiomyopathy population.[12,14-21] In newly
diagnosed patients with HF, this increase in prevalence might be up
to 4 times as high.[14] Each 1% increase in hemoglobin A1c is
associated with an 8% increased risk of HF, even after adjusting for
other factors, including coronary artery disease.[22] Importantly,
the increased prevalence of abnormal structure and frank HF is seen
with insulin resistance even when not accompanied by frank diabetes
mellitus.[18,21-23] Patients with nonischemic cardiomyopathy are not
only more insulin-resistant than a healthy control population but
also are more insulin-resistant than patients with coronary artery
disease.[24]

Abnormalities in diastolic function independent of ischemic heart
disease are very commonly observed in patients with insulin
resistance and diabetes mellitus and can be favorably impacted by
improved glycemic control.[25,26] Hypertension, left ventricular
hypertrophy, and left ventricular dysfunction are strongly
correlated with insulin resistance and the subsequent development of
HF.[17,18,27-29]

We have examined the prevalence of subclinical insulin resistance in
patients with nonischemic cardiomyopathy compared with a matched
control population, excluding patients with known pre-existing
diabetes. The cardiomyopathy population was not only significantly
more insulin resistant than matched control subjects (Fig. 2) but
also had a very high prevalence of frank glucose dysmetabolism when
challenged with an oral glucose load.[21] When patients with known
diabetes were included, 59% of cardiomyopathy patients had frank
glucose dysmetabolism,[21] even higher than another study examining
a mixed ischemic/nonischemic population, which found a prevalence of
43%.[19]

Epidemiological evidence suggests more than simply a correlation
between insulin resistance and HF, demonstrating that insulin
resistance precedes HF rather than occurring as a consequence of it.
A study of 1,187 Swedish patients without prior HF found that
insulin resistance predicts the subsequent development of HF,
independent of all established risk factors, including diabetes
mellitus itself.[18] Another study found higher proinsulin levels (a
surrogate marker for insulin resistance) in patients who
subsequently developed HF than in control patients 20 years before
their HF was diagnosed.[30]

Insulin resistance and diabetes portend a worse prognosis in HF. The
prognostic impact of insulin resistance is independent of other
variables, including peak oxygen consumption (VO2max) and left
ventricular ejection fraction (LVEF), implying that insulin
resistance is pathogenic rather than simply a marker for worsened HF.
[19,31]

The presence/absence of diabetes mellitus is more than 7 times as
potent a risk factor for mortality in the nonischemic cardiomyopathy
population as in the ischemic population.[4] Indeed, the highest-
risk subgroup from a recent study was the diabetic/nonischemic
population (relative risk [RR] 1.79 vs. the nondiabetic/nonischemic
population), as compared with the nondiabetic/ischemic population
(RR 1.07) or even the diabetic/ischemic population (RR 1.11).[4]

Preliminary evidence also suggests that the presence of insulin
resistance predicts response to therapy, especially antiadrenergic
therapy. The potent adrenergic-blocking medication carvedilol, the
only beta-blocker approved for HF that does not worsen insulin
resistance, is 3 times as likely to cause a dramatic improvement in
left ventricular function in the nonischemic cardiomyopathy
population as in the ischemic cardiomyopathy population.[32]
Intriguingly, this degree of response to antiadrenergic therapy can
be predicted by the severity of baseline abnormalities in myocardial
glucose uptake.[33]