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NHLBI WORKING GROUP ON CELLULAR AND MOLECULAR
MECHANISMS OF DIABETIC CARDIOMYOPATHY
July 16, 1998
MEETING SITE: BETHESDA, MARYLAND
MINUTES OF AND CONSENSUS RECOMMENDATIONS:
This document is a review of the current state of
knowledge and research in diabetic cardiomyopathy and recommendations for
future research initiatives. It summarizes presentations and discussions held
on the above date by a panel of scientific experts and NIH staff.
STATEMENT OF RATIONALE FOR THE WORKING GROUP
The development of heart failure in patients with
diabetes mellitus is a problem of major clinical and epidemiologic importance.
Heart failure can occur in patients with diabetes mellitus in the absence of
coexistent hypertension and/or hemodynamically significant epicardial coronary
artery stenoses (subsequently referred to as coronary artery disease).
Clinical reports in the 1970s first described such patients, who were
considered to have a diabetic cardiomyopathy, usually of a dilated
cardiomyopathy with low ejection fraction. Of far greater epidemiologic
importance, however, is the risk when diabetes mellitus is combined with
coronary artery disease and/or hypertension. Diabetes mellitus patients with
acute myocardial infarction have approximately twice the incidence of heart
failure and death compared to non-diabetic patients. Diabetes mellitus and
hypertension is also a potent combined risk factor for heart failure. Increased
risks for heart failure and death in patients with diabetes mellitus are
especially pronounced in women, African-Americans and certain Native Americans.
Many diabetes mellitus patients without overt heart disease have evidence of
subclinical myocardial abnormalities, including echocardiographic-Doppler
patterns suggestive of slowed relaxation and/or decreased compliance, abnormal
ultrasonic tissue characterization consistent with altered connective tissue,
and abnormal left ventricular functional responses during exercise. It is not
known whether these subclinical abnormalities are the substrate for the
subsequent development of heart failure, nor what factor(s) are responsible for
its pathogenesis.
Despite the obvious importance of diabetic
cardiomyopathy, a modern understanding of this complex, and very likely
multi-factorial, problem at the cellular and molecular level is lacking,
especially in patients. In addition, there has been little emphasis on
developing novel approaches to prevention and treatment.
The purpose of the Working Group was to discuss our
current understanding of diabetic cardiomyopathy, especially at the
cellular/molecular level, and identify the most promising and critical areas
for future research efforts in the field.
SUMMARY OF PREVIOUS RESEARCH
Early clinical studies of patients with apparent
diabetic cardiomyopathy were accompanied by very limited histologic examination
of tissue obtained by endomyocardial biopsy. Findings included increased PAS+
connective tissue (mainly perivascular), basement membrane thickening (also
with PAS+ material), and thickening of the walls of small arteries and
arterioles. These abnormalities were not striking in relation to the severity
of clinical disease. Replacement fibrosis in particular was not a prominent
feature, arguing against myocardial necrosis as a major causative factor. At
about the same time, the epidemiologic importance of diabetes mellitus as a
risk factor for heart failure was first recognized, initially through
observations made in the Framingham Study. Subsequent clinical research, most
of which was accomplished in the 1980s through the early 1990s, included the
following major contributions:
- Careful pathologic examination of post-mortem
tissue from patients with diabetes mellitus and advanced heart disease,
typically in combination with coronary artery disease and/or hypertension.
These patients had substantial cardiac hypertrophy and enlargement with major
increases in connective tissue and replacement fibrosis. Although it was
impossible to sort out their relative contributions, the concept that evolved
from these studies was that diabetes mellitus and coronary artery disease/
hypertension were synergistic in increasing the risk of heart failure and
death. This concept continues to the present day.
- Epidemiologic studies of the natural history of
acute myocardial infarction in patients with coexistent diabetes mellitus.
These revealed remarkably high mortality and risk for development of heart
failure. Women, African-Americans, and some Native Americans appear to be at
especially high risk. Despite modern treatment, more recent studies continue to
reveal excess morbidity and mortality from acute myocardial infarction in
patients with diabetes mellitus.
- Non-invasive studies utilizing
echocardiography-Doppler, radionuclide ventriculography, and stress testing in
patients with diabetes mellitus without overt heart disease. These
revealed abnormalities of relaxation and/or compliance, ultrasonic tissue
characterization, and abnormally small increases in contractile functional
parameters during exercise in, surprisingly, large numbers of patients. The
incidence of these abnormalities appeared to be independent of diabetes type
(insulin dependent vs non-insulin dependent), but was positively correlated
with the presence of other complications of diabetes mellitus such as
neuropathy, nephropathy, and retinal vasculopathy.
These clinical observations stimulated work in
experimental models of diabetes mellitus. By far the most extensively employed
model was, and continues to be, streptozotocin (STZ)-induced diabetes mellitus
in the rat. Rats given STZ for weeks to months develop hypoinsulinemic diabetes
mellitus, consistent depression of contraction, and, most especially,
relaxation. Effects on "passive" diastolic compliance have been variable. These
contractile abnormalities were correlated with several alterations in
excitation-contraction coupling, ion transport and exchange, including
prolongation of the action potential, and depressed sarcoplasmic reticular
calcium pumping and sarcolemmal Na/Ca exchange. Abnormalities of the
contractile machinery have also been detected in mechanical studies in skinned
strips, in addition to a V1 to V3 isomyosin switch.
STZ-diabetes mellitus is a reliable,
well-characterized model. However, results are confounded by the fact that STZ
is a general toxin which causes several other abnormalities in addition to
diabetes mellitus, for example, hypothyroidism. Several other models of mild
diabetes mellitus in rats, sometimes in combination with hypertension, have
been studied, but in much more limited fashion. Alloxan is another toxin which
has been used to produce diabetes mellitus, mainly in large mammals and more
long-term preparations. Interestingly, these animals seem to have abnormalities
of diastolic compliance in association with changes in the connective tissue
matrix that are more prominent than defects in contractile performance.
Taken together, the clinical and experimental work
have led to only limited insights into the mechanism(s) of diabetic
cardiomyopathy. The direct effects of abnormal carbohydrate metabolism and
excessive fatty acid oxidation have been implicated as an important proximate
cause of diabetic cardiomyopathy in STZ treated rats. Free radical production
with altered lipid content of membranes is one postulated mechanism. However,
several other consequences of abnormal carbohydrate metabolism, for example,
depressed pyruvate dehydrogenase activity and inadequate energy availability,
have also been proposed to account for diabetic cardiomyopathy. Possible
molecular/genetic mechanisms involved in diabetic cardiomyopathy in
STZ-diabetes mellitus have in general not been well characterized.
Microvascular disease and protein glycation/glycosylation, important mechanisms
of complications in patients with diabetes mellitus, do not have particularly
good counterparts in experimental models. The direct effects of hyperglycemia
are also difficult to characterize in intact animals. Thus, the roles of these
major components of diabetes mellitus in causation of diabetic cardiomyopathy
have been particularly difficult to evaluate.
There has also been virtually no progress in
characterizing the cellular and molecular features of diabetic cardiomyopathy
in patients, much less their mechanisms. Defining cardiac changes in diabetic
humans is obviously extremely important in light of the fact that diabetes is a
chronic disease, not well represented by animal models. Moreover, it remains
unclear whether there are differences between insulin dependent and non-insulin
dependent forms of diabetes mellitus and what role insulin resistance plays in
its development.
Finally, there remains some skepticism, particularly
amongst clinicians, as to whether a distinct diabetic cardiomyopathy actually
exists. The "conventional wisdom" is that if diabetic cardiomyopathy does exist
its cause is diabetic vasculopathy, possibly of the microvasculature, despite
the fact that there is no more support for this mechanism than for any of the
other known complications of diabetes mellitus. The Working Group came to a
rapid consensus that there is a wealth of evidence supporting the existence of
diabetic cardiomyopathy as a major and distinct complication of diabetes
mellitus, although there remain more questions than answers with regard to the
underlying pathogenesis and pathophysiology.
AREAS OF CURRENT RESEARCH REVIEWED BY THE WORKING
GROUP
Transformation of Normal to Abnormal Myocardium by
Diabetes Mellitus: Role of Hyperglycemia and Protein Kinase C
Activation There are multiple manifestations of diabetes mellitus that
could potentially cause diabetic cardiomyopathy, including hyperglycemia per
se, altered carbohydrate metabolism (increased fatty acid oxidation, altered
energy metabolism), extracellular and intracellular protein glycosylation, and
microvascular disease. A central, unresolved issue in the pathogenesis of
diabetic cardiomyopathy is the relative contributions of specific
manifestations of diabetes mellitus (e.g., hypo- or hyperinsulinemia,
hyperglycemia, increased fatty acid oxidation, dyslipidemia) vs secondary
effects of these manifestations on cell signaling (e.g., protein kinase C
activation) and/or gene expression. In rodent models of diabetes mellitus (STZ,
BB/Wor), concentric remodeling and hypertrophy of the left ventricle may be
observed in association with "diastolic dysfunction". Increased expression of
atrial natriuretic peptide and upregulation of angiotensin converting enzyme
activity suggest that this process shares a number of features with other
causes of pathologic hypertrophy.
One potential mechanism of diabetic cardiomyopathy is
activation of protein kinase C as a response to hyperglycemia. Protein kinase C
very likely has a critical signaling role in cardiac hypertrophy by virtue of
its effects on angiotensin converting enzyme activity, nitric oxide synthase,
the MAP kinase/early gene response system, and contractile proteins. In rodent
models of diabetic cardiomyopathy, total protein kinase C activity is modestly
increased. Preliminary data with respect to isoform specificity suggest that
the -isoform may be selectively upregulated in STZ-diabetes mellitus, but other
isoforms are selectively elevated in other forms of heart failure. Upregulation
occurs before rather than after the appearance of left ventricular dysfunction.
A mechanism that may serve as another source of diacylglycerol and amplify
protein kinase C upregulation is activation of tyrosine kinase secondary to
protein kinase C activation of angiotensin converting enzyme and increased
angiotensin II production. Tyrosine kinase also activates the MAP kinase
system. Finally, although phospholipase D activity is found to be decreased in
diabetic myocardium, phosphotidate phosphohydrolase activity is increased,
providing another source of diacylglycerol.
Low-dose ethanol is known to inhibit diacylglycerol
and tyrosine kinase while upregulating protein kinase C. Treatment of
STZ-diabetes mellitus rats with low-dose ethanol appears to prevent the
structural changes and protein kinase C upregulation induced by STZ. Thus,
complex signaling relationships between protein kinase C, tyrosine kinase ,
angiotensin converting enzyme, and MAP kinase may be involved in both
structural and biochemical changes during STZ-diabetes mellitus.
Exposure of isolated cardiac myocytes in a cell
culture system to hyperglycemia is one approach to this aspect of diabetic
cardiomyopathy, which allows stringent control of conditions and testing of
discrete hypotheses. Maintaining cardiac myocytes in a hyperglycemic
environment for only 1-2 days results in alterations in cellular
electrophysiology and excitation-contraction coupling that are remarkably
similar to those observed with short-term experimental diabetes mellitus.
Specifically, the cellular action potential is prolonged, and cytosolic calcium
clearing and relaxation are impaired. Suggested mechanisms include
up-regulation of Ca2+ currents, down-regulation of K+
currents and Na/Ca exchange, and/or depressed sarcoplasmic reticulum
calcium ATPase (SERCA-2) activation. The signaling pathway appears to involve
N-linked glycosylation of certain proteins as well as elevated protein kinase C
activity. Interfering with the processing of glucosamine or the inhibition of
protein kinase C prevents these hyperglycemia-induced abnormalities. The
effects of hyperglycemia on the myocyte do not seem to be caused by increased
osmolarity, and they can be attenuated by certain antidiabetic agents (e.g.,
metformin and troglitazone) but not by others (e.g., glyburide). Here again,
preliminary evidence implicates a role for hyperglycemia-induced up-regulation
of protein kinase C activity, in addition to intracellular glycosylation and
changes in intracellular calcium concentration. One or more of these factors
may then trigger changes in gene expression and potentially a host of other
alterations in protein function.
Activation and upregulation of the signal transduction
pathway involving diacylglycerol and protein kinase C has also been observed in
human cardiomyopathy unrelated to diabetes mellitus. In diabetes mellitus, in
addition to hyperglycemia, protein glycosylation and oxidative stress may also
activate this pathway. As indicated, protein kinase C influences a multiplicity
of cellular functions, including production of extracellular matrix, cytokines,
contractile protein function, calcium handling and contractility, and growth
responses (early response genes, MAP kinase). In heart failure, there is
evidence that the isoform, and possibly the isoform, of protein kinase C are
preferentially increased. To assess the consequences of increased protein
kinase C- activity, both a specific inhibitor and a transgenic mouse that
overexpresses protein kinase C- have been studied. The inhibitor may be capable
of preventing some of the complications of experimental diabetes mellitus.
Overexpression of protein kinase C- results in development of a cardiomyopathy
characterized by hypertrophy, loss of myocytes, fibrosis and markedly depressed
contractile function. mRNA for collagen, TGF-, -myosin heavy chain, ANF and
c-fos are all increased. Thus, activation of protein kinase C is of
considerable interest as a potential mechanism of diabetic cardiomyopathy.
Transgenic Models of Altered Glucose Metabolism:
Role of the GLUT4 Transporter The glucose transporter protein, GLUT4,
is normally the major glucose transport system. In insulin resistant diabetes
mellitus, especially in association with obesity, reduced insulin transport
into skeletal muscle and fat cells is the major metabolic defect. To better
understand factors that regulate whole body insulin sensitivity and glucose
transport, gene knockout technology has been employed to produce mice with one
null allele of GLUT4 (+/-) and with a complete knockout of the GLUT4 gene
(-/-).
GLUT4 +/- mice develop a pattern closely resembling
human type 2 diabetes mellitus. As expected, these animals have reduced GLUT4
expression and glucose transport in muscle and adipose tissue, in addition to
reduced glycolysis and glycogen synthesis. In an outbred genetic background,
severe insulin resistance (quantified by euglycemic/hyperinsulinemic clamps)
and a number of other pathologic changes noted in human type 2 diabetes
mellitus are present, including hypertension, myocardial tissue changes
consistent with a cardiomyopathy, and renal glomerular lesions. These changes
occur in males only. Females are able to normalize glucose transport through as
yet uncertain mechanisms. The phenotype in these animals is strongly dependent
on age, progressing from normoglycemia/insulinemia, to
normoglycemia/hyperinsulinemia, to hyperglycemia/insulinemia. Unlike human type
2 diabetes mellitus, GLUT4 +/- mice do not become obese, although their
adipocytes are enlarged. Thus, the GLUT4 +/- mouse has considerable potential
for understanding the development of diabetic cardiomyopathy in
insulin-resistant diabetes mellitus independent of coincident obesity.
Interestingly, GLUT4 -/- mice, while exhibiting
relatively subtle abnormalities of glucose and lipid metabolism including
abnormal glucose clearance from the blood, do not become diabetic and do not
display the sorts of diabetic complications seen in +/- mice. This is accounted
for by upregulation of both the GLUT1 transporter and most likely another, as
yet poorly characterized transport mechanism. Surprisingly, the -/- mice
develop severe cardiac hypertrophy in the absence of hypertension, and yet have
improved recovery of function following global ischemia-reperfusion when
compared to the heterzygous animals. GLUT4 -/- animals, while not diabetic, may
provide clues to interactions between abnormal transport mechanisms and stimuli
for cardiac hypertrophy, as well as protection from ischemia.
Apoptosis and Ventricular Remodeling in Diabetes
Mellitus Multiple abnormalities of both excitation-contraction coupling
and the contractile machinery have been documented in STZ-diabetes mellitus,
but a role for apoptosis in this model of diabetes mellitus has not previously
been sought. This is pertinent in view of increasing evidence of apoptosis in
other forms of cardiomyopathy. In addition, the relatively modest
histopathologic changes in STZ-diabetes mellitus suggest the possibility of
cell dropout due to apoptosis.
In preliminary studies designed to assess whether
significant amounts of apoptosis occur after one month of STZ-diabetes mellitus
in the rat, heart to body weight ratios were increased, but absolute heart
weight was decreased because body weight fell faster than heart weight.
Morphologic analysis revealed a 10% decrease in myocyte mass despite a 13%
increase in myocyte cell volume. This apparent inconsistency was due to a
remarkable, 28% decrease in total myocyte number in the left ventricle. As in
previous studies of STZ-diabetes mellitus, histologic changes were modest.
Studies using both TdT and Taq analyses of apoptosis suggest that both calcium
and pH dependent DNAases are activated, and that necrosis may also occur
despite the absence of histologic sequelae. Parallel in vitro studies in
cultured myocytes suggest that hyperglycemia per se may be a stimulus for
increased apoptosis. These preliminary studies suggest a previously
unappreciated role for apoptosis and cell necrosis in STZ-induced diabetic
cardiomyopathy.
The high mortality after acute myocardial infarction
in diabetic patients is generally considered to be caused by an increased risk
of heart failure. One possible explanation is that myocardial necrosis is
superimposed on a pre-existing cardiomyopathic process, which reduces cardiac
reserve. Another is that the remodeling process after acute myocardial
infarction differs in patients with diabetes mellitus. An interaction of
post-acute myocardial infarction remodeling and apoptosis is of interest
because factors known to be operative in diabetes mellitus such as altered
insulin levels, oxidative stress and growth factors, also influence apoptosis.
This interaction has been studied in vitro using a
tissue culture model in which neonatal myocytes are first exposed to high
glucose concentrations for three days followed by a hypoxic period as a
surrogate for ischemia. High glucose treatment results in markedly reduced
apoptosis following hypoxia. This is at least in part a generic response to
osmotic stress. An alternative mechanism of protection may be related to
hyperglycemia-induced changes in expression and/or phosphorylation (by tyrosine
kinase) of BCL-2, which is known to be pro-apoptotic. It is unclear at present
whether glucose protection against hypoxic apoptosis in vitro is relevant to in
vivo remodeling in either a positive or negative fashion.
Role of Insulin-Like Growth Factor-1 in Diabetic
Cardiomyopathy Insulin-like growth factor-1 (IGF-1) promotes cardiac
growth, exerts positive effects on contractility and relaxation, promotes
relaxation of vascular smooth muscle, and is a potentially important
paracrine/autocrine factor in the myocardium. IGF-1 is produced by both
vascular smooth muscle cells and cardiac myocytes and is subject to multiple
regulatory influences. In vascular smooth muscle, its effects appear to be
mediated by increased nitric oxide production. In contrast, hyperglycemia
decreases nitric oxide production. In rat papillary muscle preparations and
isolated ventricular myocytes, IGF-1 causes dose-dependent increases in tension
development/shortening and calcium transients, but does not alter
relaxation parameters. These effects are attenuated by nitric oxide synthase
inhibition. In STZ-diabetes mellitus rats (5-7 days), the above-mentioned
effects of IGF-1 are not observed, suggesting an intrinsic defect at the level
of the myocyte whose mechanism is unknown at present. Similarly, short-term
STZ-diabetes mellitus results in loss of effects of IGF-1 on vascular muscle,
although normal responses to norepinephrine and KCl are retained. Since IGF
receptors are up-regulated in this model, the signaling pathway must be
disrupted downstream of the receptors. The possibility that paracrine/autocrine
factors (e.g., IGF-1) contribute to the development of diabetic cardiomyopathy
is an area that has received little previous attention.
Characterization of Diabetic Cardiomyopathy in
Human Myocardium Hemodynamic and endomyocardial biopsy assessment of
patients with heart failure presumed due to diabetic cardiomyopathy has been
mentioned previously, as have noninvasive studies in patients without overt
evidence of heart disease. There has been no assessment of abnormalities of
myocardial function in patients with combined diabetes mellitus and coronary
artery disease, who are at high risk for heart failure and death if they suffer
acute myocardial infarction. Advances in tissue preservation now allow
assessment of the in vitro mechanical performance of strips of left ventricular
myocardium obtained via epicardial biopsy during surgery or from explanted
hearts. Studies performed in myocardial tissue from patients with mitral
regurgitation and dilated cardiomyopathy (without diabetes mellitus) reveal a
key functional abnormality, depression of the force-frequency relation (FFR).
The positive FFR probably results from increased calcium cycling as contraction
frequency is increased and is a key mechanism whereby ventricular function is
augmented during exercise. Depression of the FFR has been strongly correlated
with depressed sarcoplasmic reticular calcium pumping and decreased expression
of SERCA-2. Recently, this approach has been applied to patients with combined
diabetes mellitus and coronary artery disease who requires coronary artery
bypass surgery. Patients selected for study had normal left ventricular
contraction pattern, and no history of prior acute myocardial infarction or
hypertension. They were compared to matched bypass surgery patients without
diabetes mellitus. Left ventricular myocardial strips were stimulated to
contract isometrically at varying contraction frequencies. In patients with
combined diabetes mellitus and coronary artery disease, contractile performance
is normal at rest, but the FFR is depressed compared to patients with coronary
artery disease alone. The extent of depression is intermediate between coronary
artery disease patients and mitral regurgitation/diabetes mellitus. Preliminary
results of simultaneous calcium transient measurements indicate that the
amplitude of the transient decreases in parallel with force measurements,
implicating abnormal calcium handling as a mechanism of FFR depression. These
results represent the first in vitro documentation of an underlying
cardiomyopathy in patients with combined diabetes mellitus and coronary artery
disease, and may provide a mechanism whereby contractile performance is
impaired, especially during stress, resulting in a high incidence of heart
failure after acute myocardial infarction.
Novel Therapeutic Approaches to Diabetic
Cardiomyopathy 0000Until recently, the only therapy envisioned for
prevention and treatment of the complications of diabetes mellitus has been
tight control of blood glucose with insulin and/or oral hypoglycemic regimens.
Results in general have been inconclusive. The recent introduction of agents
that directly increase sensitivity to insulin (e.g., metformin and
troglitazone) offer one new approach. Looking toward the future, application of
gene therapy is of course of great interest. The ultimate efficacy of gene
therapy will be linked to better understanding of the underlying
pathophysiology of diabetic cardiomyopathy. Some recent developments with
implications for gene therapy are indicative of the sorts of novel approaches
that might be employed.
One alteration in calcium handling proteins identified
in rodent models of diabetes mellitus is decreased activity of SERCA-2. SERCA-2
is also depressed in non-diabetic failing myocardium. A number of possibilities
exist to explain this and other alterations in calcium handling, including
reduced insulin signaling at the myocyte level, hyperglycemia per se, increased
fatty acid oxidation and free radical production with damage to membrane
lipids, and cytokine-mediated effects (e.g., interleukin-6 decreases SERCA-2
expression). Increasing SERCA-2 activity is therefore a potential novel
therapeutic approach to diabetic cardiomyopathy. To test this hypothesis, the
effects of STZ-induced diabetes on contractile function in isolated hearts and
papillary muscle strips have been tested in transgenic mice that overexpress
SERCA-2. SERCA-2 overexpression resulted in partial restoration of function
compared to wild type mice treated with STZ, supporting this as a therapeutic
modality. Advances in in vivo viral transfection techniques offer the
possibility of transfecting large numbers of myocytes with transgenes that
would be particularly useful in treating the dysfunction (e.g., by interfering
with the inhibitory action of phospholamban on SERCA-2).
Recently, transgenic mice with modification of genes
encoding proteins of oxidative metabolism have been developed. These animals
may shed light on the relation between altered energy metabolism and depressed
contractile function in diabetic cardiomyopathy and conceivably suggest targets
for treatment. New genetic screening approaches to identify small molecules
with potential use as drugs to protect the heart from metabolic injury are also
of considerable interest. For example, a group of peptides selected for high
affinity binding to DnaK, the bacterial orthologue of mammalian hsp70,
demonstrate marked cytoprotection during substrate deprivation. Based on their
binding affinity, this may be related to enhanced chaperone activity.
Since skeletal muscle insulin-resistance is a major
risk factor contributing to metabolic disturbances of diabetes mellitus,
insight into the cellular mechanisms associated with these changes and the
effects of drug interventions and exercise may greatly enhance the ability to
treat and prevent diabetic cardiomyopathy. An example of this is the
identification of intracellular signaling links between the firing of motor
nerves controlling the activity of skeletal muscles and transcription of genes
encoding proteins that are differentially expressed in Type I vs Type IIb
muscle fibers. These discoveries could lead to novel approaches to increasing
insulin sensitivity and beneficial effects with respect to diabetic
cardiomyopathy.
CONSENSUS RECOMMENDATIONS OF THE WORKING GROUP
As indicated in the introductory comments above, the
Working Group agreed that diabetic cardiomyopathy is an extremely important and
complex problem and that very little progress has been made in understanding
its underlying pathophysiology, specific manifestations and natural history in
patients, and treatment. The Group especially wished to dispel any questions as
to the existence of diabetic cardiomyopathy as a distinct entity and the notion
that it is not worth detailed investigation because it is simply a consequence
of diabetes mellitus-related vasculopathy. Vascular disease may certainly be a
cause of diabetic cardiomyopathy, but this in no way diminishes its importance
and/or the need for more knowledge in this area. The Group was particularly
struck by the fact that poor outcomes due to cardiovascular disease in patients
with diabetes mellitus, especially those due to heart failure, are associated
with angioplasty as compared to coronary bypass surgery. In consideration of
the above, the Working Group strongly recommends that diabetic cardiomyopathy
be targeted as an area for special emphasis in research funding and supports
the timely development of a Request for Applications (RFA) to support future
investigations. The Working Group also felt that this is an area in which
collaborative, multidisciplinary research is especially appropriate. The
Working Group agreed that the following constitute the most promising areas for
funding:
- Research designed to identify basic mechanisms
of disease and novel therapeutic interventions using innovative molecular and
cellular approaches. Emphases should be on distinguishing and elucidating
the contributions of direct "toxic" effects of diabetes mellitus from those due
to altered gene expression. Correspondingly, the roles of altered organelle and
protein function vs cell death (either by necrosis or apoptosis) in the
pathophysiology of diabetic cardiomyopathy should also be established. A great
deal of effort should be focussed on the fundamental reasons for gender,
racial, and ethnic variations in diabetes mellitus and associated
cardiomyopathy.
- The development and utilization of experimental
models with high relevance to human disease should be encouraged and used to
answer specific, mechanistic questions. Examples are: animals with insulin
resistance as a single risk factor and in combination with other risk factors
(e.g., hypertension and/or obesity), models that are particularly amenable to
testing novel therapeutic interventions, and longer-term models that better
simulate human disease.
- Delineation of the connections between altered
intracellular signaling, including those related to glucose transport and
protein kinase C activation, and altered contractile function and cell death.
These mechanisms of disease have been largely unappreciated by
investigators working in the field until relatively recently.
- A better understanding of the relation between
altered energy metabolism and myocardial function in diabetes mellitus in
particular and heart failure in general. Is there the possibility of a
unifying hypothesis related to abnormal fatty acid oxidation and what are the
key metabolic factors that contribute to diabetic cardiomyopathy? What is the
relation between "diastolic dysfunction" and energy metabolism?
- Elucidation of the mechanisms contributing to
the modification of cardiac responses to ischemia -reperfusion and oxidative
stress in diabetes mellitus. Is this the key factor in the high mortality
of acute myocardial infarction in patients with diabetes mellitus? Does
substrate utilization in the diabetic heart influence responses to ischemia and
reperfusion?
- Research designed to better characterize the
epidemiology and pathophysiology of diabetic cardiomyopathy in patients.
Recognizing the limitations of short-term animal models in relation to a
chronic and extraordinarily complex human disease, it is critical to better
characterize organ level and myocardial cellular/molecular alterations in
patients with diabetes mellitus. In vitro studies employing tissue
from patients and modern, non-invasive assessments of myocardial function and
metabolism (magnetic resonance spectroscopy/imaging, PET scanning,
echocardiography-Doppler and ultrasonic tissue characterization) are likely to
be most fruitful in delineating human natural history and pathophysiology.
Non-cardiac markers of diabetic cardiomyopathy (e.g., skeletal muscle
alterations, retinal vasculopathy) should also be sought. Clues gained from
these types of studies could be used to test mechanistic hypotheses relevant to
human disease. Other key areas are whether there are meaningful differences
between type 1 and type 2 diabetes mellitus and quantification of gender,
racial and ethnic differences. Establishment of a registry of patients with
diabetic cardiomyopathy based on noninvasive markers might be useful in
delineating genetic markers of diabetic cardiomyopathy and identifying high
risk patients, tracking disease incidence and natural history and providing a
framework for intervention trials.
- Clinical trials to test specific
interventions. These could be designed to track clinical endpoints (death,
development of heart failure) and/or non-invasive markers as delineated above.
The list of potential interventions is large, for example, "tight control" of
blood glucose, insulin sensitizers, protein kinase C inhibitors and ACE
inhibitors, and is likely to increase in the future. A useful strategy might be
to establish a mechanism to perform relatively short-term, feasibility studies
followed by larger trials with longer term clinical endpoints when indicated.
Last Updated April 2011
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