diabetic cardiomyopathy reviews.circ res

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Indu G. Poornima, Pratik Parikh and Richard P. ShannonDiabetic Cardiomyopathy : The Search for a Unifying Hypothesis

Print ISSN: 0009-7330. Online ISSN: 1524-4571Copyright 2006 American Heart Association, Inc. All rights reserved.is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation Research

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This Review is part of a thematic series on Adipocyte Signaling in the Cardiovascular System, which includes the

following articles:

Adipose Tissue, Inflammation, and Cardiovascular Disease

Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin Resistant Adipose Tissue

Diabetic Cardiomyopathy: The Search for a Unifying Hypothesis

Adipocyte Signaling and the Vasculature

PPARActivation and Effects on the Vasculature Phillip Scherer, Guest Editor

Diabetic CardiomyopathyThe Search for a Unifying Hypothesis

Indu G. Poornima, Pratik Parikh, Richard P. Shannon

AbstractAlthough diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known

as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular

systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all

been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects

of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides

important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac

structure and function. (Circ Res. 2006;98:596-605.)

Key Words: insulin resistance diabetic cardiomyopathy diastolic function cardiac hypertrophy

The conventional wisdom holds that diabetes causes myo-cardial contractile dysfunction through accelerated ath-erosclerosis and hypertension. Much less appreciated and

more controversial is the notion that diabetes mellitus affects

cardiac structure and function, independent of blood pressure

or coronary artery disease. Diabetic cardiomyopathy is a

clinical condition, diagnosed when ventricular dysfunction

develops in patients with diabetes in the absence of coronary

atherosclerosis and hypertension.14 Despite the potential

importance of this disease entity, the complex and multifac-

torial nature of the cellular and molecular perturbations that

predispose to altered myocardial structure and function re-main incompletely understood.

The epidemiological link between diabetes mellitus and the

development of heart failure, independent of atherosclerotic

cardiovascular disease, has been evident for the better part of

three decades. The increased risk of heart failure persists in

the diabetic patients after considering age, blood pressure,

weight, cholesterol, as well as history of coronary artery

disease.5,6 Notably, there is a significant association between

diabetes and diastolic dysfunction leading to congestive heart

failure in the absence of impaired systolic function.7,8 More

recently, patients with unexplained idiopathic dilated cardio-

myopathy were found to be 75% more likely to have diabetes

than age matched controls.9 The association between diabetes

and cardiomyopathy was strongest among individuals with

microvascular complications of diabetes that parallels the

duration and the severity of hyperglycemia. However, it has

been difficult to ascertain from these epidemiological corre-lations the causal relationship between the commonly ob-

served metabolic abnormalities and the specific cardiac phe-

notype. In this review, we provide an update of our current

understanding of the complexities of diabetic cardiomyopa-

thy with a special emphasis on the relationship between the

Original received May 11, 2005; resubmission received October 27, 2005; revised resubmission received December 27, 2005; accepted January 18,

2006.From the Department of Medicine, Allegheny General Hospital, Pittsburgh; and the Drexel University College of Medicine, Philadelphia, Pa.Correspondence to Richard P. Shannon, MD, Department of Medicine, Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212. E-mail

[email protected] 2006 American Heart Association, Inc.

Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/01.RES.0000207406.94146.c2

596

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metabolic perturbations that accompany diabetes and the

cellular consequences leading to altered myocardial structure

and function.

Cellular Mechanisms Predisposing toDiabetic Cardiomyopathy

The 3 characteristic metabolic disturbances evident in diabetic

states are hyperlipidemia (usually in the form of increasedtriglycerides and nonesterified fatty acids [NEFAs]) and early

hyperinsulinemiafollowed by pancreatic -cell failure, leading

eventually tohyperglycemia. Type 1 diabetes differs principally

from type 2 diabetes in that it is unaccompanied by a period of

hyperinsulinemia and is characterized by early- as opposed to

late-onset hyperglycemia. Alterations in body mass (obesity)

and adipocytokines (leptin, adiponectin) have also been impli-

cated in the cardiovascular pathophysiology observed in diabe-

tes. As such, the effects of increased NEFAs, altered insulin

action, and hyperglycemia can be considered triggers to the

cardiac phenotype in diabetes. An understanding of the cellular

effects of these metabolic disturbances on cardiomyocytes

should be useful in predicting the structural and functional

cardiac consequences.

Extensive cellular and molecular studies have identified

putative mediators, effectors, and targets of these metabolic

triggers in the pathogenesis of cardiac dysfunction in diabetes

(Figure 1). We review the cellular signaling pathways asso-

ciated with these metabolic triggers that lead to altered

myocardial structure and function.

Increased NEFAsNEFAs play a critical role in triggering the development of

cellular insulin resistance but also have been implicated in the

development of myocardial contractile dysfunction. NEFAsplay a central role in altering cellular insulin signaling

through several mechanisms leading to insulin resistance and

compensatory hyperinsulinemia1012 (Figure 2). In turn, hy-

perinsulinemia is an important trigger to the development of

cardiac hypertrophy in diabetic cardiomyopathy (see below).

NEFAs induce the activation of atypical protein kinase C

(PKC) , a serine/threonine kinase that phosphorylates and

subsequently activates IB kinase. IB kinase phosphorylates

serine residues on insulin receptor substrate-1 (IRS-1), inhib-iting its ability to bind SH2 domains of the p85 regulatory

subunit of phosphatidylinositol 3-kinase (PI3K), impairing

insulin signal transduction.12 Although this mechanism is

active in skeletal muscle and adipose tissue, it has been less

clear whether similar mechanisms are apparent in cardiac

muscle.

Increases in intracellular NEFAs can also alter insulin

signaling without affecting IRS-1/PI3K activation (Figure 2).

Akt-1 activation is critically dependent on the generation of

phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) to

bind the N-terminal pleckstrin domain and activate mem-

brane bound kinases responsible for the phosphorylation of

serine and threonine residues on Akt-1 that confer catalytic

and regulatory properties.1316 NEFAs are natural ligands for

the nuclear receptor, peroxisome proliferator-activated recep-

tor (PPAR) , and can induce the upregulation of the

phosphatase and tensin homolog deleted on chromosome 10

(PTEN) which dephosphorylates PtdIns(3,4,5)P3, preventing

the activation of Akt-1.16

NEFAs can directly alter myocardial contractility indepen-

dent of altered insulin action by increasing NEFA flux into

the myocardium.17 Recent evidence18 suggests that increases

in fatty acyl coenzyme A (CoA) esters within cardiac myo-

cytes may modulate the contractile state of the myocardium

by opening of the KATP channel. Activation of the KATPchannel leads to shortening of the action potential and

Figure 1. The relationship between dia-betic metabolic disturbances (triggers)and the mediators, effectors, and intra-cellular targets that lead to a diabeticcardiomyopathic phenotype.

Poornima et al Diabetic Cardiomyopathy 597

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reduces transsarcolemmal calcium flux and subsequently

myocardial contractility.

Finally, the increased intracellular accumulation of NEFAs

may directly contribute to cell death under circumstances in

which accumulating intracellular NEFAs do not undergo

oxidation. The reaction between palmityol-CoA, an intracel-

lular intermediate of NEFAs, and serine leads to the genera-

tion of the sphingolipid ceramide, and this reaction may be

facilitated by the cytokine, tumor necrosis factor (TNF) .19

Ceramide can induce cellular apoptosis through the inductionof nuclear factor B, caspase 3 activation, and cytochrome c

release and can inhibit DNA repair by blocking poly (ADP

ribose) polymerase.20 Under these circumstances, increased

NEFAs are said to cause lipotoxicity.17 Although lipotoxicity

has been implicated in the reduction in pancreatic -cell

reserves, the relevance of these findings in the myocardium

remain controversial.

Thus, NEFAs play a central role not only in inducing

cellular insulin resistance but also in directly affecting myo-

cardial contractility and, under specific circumstances, in the

promotion of cardiomyocyte cell death.

HyperinsulinemiaCellular insulin resistance may presage frank diabetes by a

decade or more and requires compensatory increases in

plasma insulin levels to maintain glucose homeostasis in the

face of impaired cellular insulin action, principally in skeletal

muscle and liver.10 The nature and extent of the cellular

insulin resistance may be selective to certain organ systems

and may vary in terms of the metabolic, mitogenic, prosur-

vival, and vascular actions of insulin.

How then can hyperinsulinemia cause cardiac hypertro-

phy2124 if the cellular actions of insulin are attenuated? The

paradox is reconciled by the recognition that systemic hyper-

insulinemia may accentuate cellular insulin action in insulinresponsive tissues, such as the myocardium, that do not

manifest cellular insulin resistance. In this regard, the mito-

genic actions of insulin on myocardium during chronic

systemic hyperinsulinemia bear directly the commonly ob-

served finding of cardiac hypertrophy in diabetic

cardiomyopathy.2123

There are at least 3 cellular mechanisms whereby hyper-

insulinemia mediates cardiomyocyte hypertrophy (Figure 3).

Acutely, insulin stimulates growth through the same PI3K/

Akt-1 pathway by which it mediates glucose uptake. Akt-1

phosphorylates and inactivates glycogen synthases kinase-3(GSK-3), a well-recognized inhibitor of nuclear transcrip-

tion governing the hypertrophic process via the nuclear factor

in activated lymphocytes (NFAT-3).25,26 In addition, Akt-1

Figure 2. Role of increased NEFAs in the

pathogenesis of cellular insulin resis-tance. There are several putative mecha-nisms including the induction of atypicalPKC, phosphorylation, and activation ofIB kinase which serine phosphorylatesand deactivates IRS-1. NEFAs may alsoactivate the phosphatase PTEN,decreasing the tris-inositol phosphatesto which the pleckstrin domain of Akt-1binds. Finally, NEFAs can contribute toceramide production, triggering cellularapoptosis.

Figure 3. Alternative pathways whereby compensatory hyperin-sulinemia contributes to myocyte hypertrophy through the sym-pathetic nervous system activation and MAP kinase/ERK path-

ways at a time when insulin receptor mediated Akt-1 activationis impaired.

598 Circulation Research March 17, 2006



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activates the mammalian target of rapamycin (mTOR) that

activates the p70 ribosomal subunit S6kinase-1, leading to

increased protein synthesis.2730 However, these mitogenic

actions mediated through the insulin receptor may be miti-

gated when insulin signaling through the PI3K/Akt-1 path-

way is impaired during chronic hyperinsulinemiaHowever, chronic hyperinsulinemia may augment myocar-

dial Akt-1 activation indirectly through increased sympa-

thetic nervous system activation.26,3133 Recent evidence sug-

gests that chronic Akt-1 activation in cardiac myocytes is

mediated through 2-adrenergic receptors via protein kinase

A and Ca2-calmodulin dependent kinase (CaMK),26 and

these mechanisms may predominate when insulin signaling is

attenuated through the PI3K pathway.

In addition, there are other insulin-mediated, but Akt-1

independent, pathways that may be operative, most notably

the extracellular signal-regulated kinase (ERK)/mitogen-acti-

vated protein (MAP) kinase pathways.34,35

Significant cellu-lar evidence exists for an insulin-induced activation of the

p38 MAP kinase pathway,34 as well as prenylation of both

Rho and Ras in the setting of hyperinsulinemia, leading to

myocyte hypertrophy and expansion of the extracellular

matrix (Figure 3). These redundant pathways provide a strong

mechanistic basis for the development of cardiac hypertrophy

associated with chronic hyperinsulinemia as an early accom-

paniment of type 2 diabetes, even though the glucoregulatory

effects of insulin are attenuated.

HyperglycemiaThe mechanism whereby hyperglycemia mediates tissue in-

jury through the generation of reactive oxygen species hasbeen elucidated largely through the work of the Brownlee and

colleagues.3638 Hyperglycemia leads to increased glucose

oxidation and mitochondrial generation of superoxide.37,39,40

In turn, excess superoxide leads to DNA damage and activa-

tion of poly (ADP ribose) polymerase (PARP) as a reparative

enzyme.36 However, PARP also mediates the ribosylation and

inhibition of glyceraldehyde phosphate dehydrogenase

(GAPDH), diverting glucose from its glycolytic pathway and

into alternative biochemical pathways that are considered the

mediators of hyperglycemia induced cellular injury. These

include increases in advanced glycation end products

(AGEs), increased hexosamine and polyol flux, and activa-tion of classical isoforms of protein kinase C. Table 1

summarizes the effects of these alternative biochemical fates

of glucose on cardiac structure and function in states of

hyperglycemia.4151 Taken together, these data provide mech-

anistic evidence linking hyperglycemia to altered expression

and function of both the ryanodine receptor (RyR) and

sarco(endo)plasmic reticulum Ca2-ATPase (SERCA2) thatmay contribute to decreased systolic and diastolic function. In

addition, hyperglycemia contributes to altered cardiac struc-

ture through posttranslational modification of the extracellu-

lar matrix.

Cardiac Phenotypes in Experimental Modelsof Type 1 and Type 2 Diabetes Mellitus

The altered cardiac phenotypes associated with diabetic

cardiomyopathy have been investigated in a wide array of

experimental animal models.52,53 From a mechanistic per-

spective, the manifestations of diabetic cardiomyopathy

should be predictable based on the duration and the severityof the abnormalities in NEFAs, insulin, and glucose ho-

meostasis. However, the experimental conditions under

which the models are studied add significant complexity to

our understanding. In particular, the nature of the available

substrates and hormonal milieu may be limited in isolated

myocytes or isolated heart preparations and contribute to

functional abnormalities that are not recapitulated in intact

models. Table 2 summarizes the biochemical, structural, and

functional abnormalities reported in these models.

Models of Hyperglycemia

Without HyperinsulinemiaStreptozotocin (STZ) and alloxan are the 2 of the most

common islet cell toxins that are used to induce type I

diabetes in experimental animal models. The metabolic fea-

tures52,53 include the prompt development of profound hyper-

glycemia (25 to 30 mmol/L), modest hypertriglyceridemia

(200 to 400 mol/L), ketosis, and markedly reduced plasma

insulin levels (20 pmol/L). As such, the model is particu-

larly useful in examining the effects of hyperglycemia in the

absence hyperinsulinemia.

STZ- and alloxan-induced diabetes have been associated

with myocardial atrophy as opposed to hypertrophy.54,55 This

is associated with loss of contractile proteins, myocytedropout without reparative fibrosis,56 consistent with the

TABLE 1. Alternative Metabolic Fates of Glucose Leading to Cardiac Structural and Functional Abnormalities in Hyperglycemia

Mediators Mechanisms of Action Consequences

Increased AGE4144 Crosslink RyRs41; crosslink type III collagen42,44 Decreased SR calcium release and myocyte contractility;

increased ventricular stiffness; impaired ventricular filling

Increased hexosamine flux45,46 Sp1-O-GluN acylation of transcription factors decreasing

SERCA2a expression45Prolonged calcium transients; impaired relaxation

Increased polyol flux47,48 Decreased regeneration of reduced glutathione leadingto oxidative stress; increased DNA fragmentation47;

sorbitol-induced AGEs48

Increased myocyte apoptosis; increased ventricularstiffness

Increased protein kinase C activation4951 Increased cardiac hypertrophy; increased extra cellular

matrix; decreased SERCA 2a function51Impaired relaxation; increased ventricular stiffness

AGE indicates advanced glycation end products; SR, sarcoplasmic reticulum.




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absence of the mitogenic and prosurvival effects of insulin.

Decreases in cardiac mass have also been noted with cardiacspecific knockout of the insulin receptor57 associated with

ventricular dilatation and impaired left ventricular (LV)

systolic performance. There has been consistent evidence of

intramyocardial lipid accumulation reflecting a compensatory

shift in myocardial preference for fatty acids in the absence of

insulin mediated glucose uptake.54,56

Alterations in SERCA2 have been reported in association

with the hyperglycemia in STZ induced diabetes leading to

decreased SR calcium sequestration and intracellular calcium

overload.54,55 Decreases in contractile proteins such as

-actin and myosin ATPase activity54,55 have also been noted

in association with shifts in myosin heavy chain isoforms

from to ,53,54,58,59 contributing to decreased systolictension development.

The functional consequences of these cellular effects have

been studied in cardiomyocytes, isolated perfused hearts and

in vivo in rats with STZ induced diabetes. Abnormalities in

diastolic function (increased LV end-diastolic pressure and

operating chamber stiffness) can be observed in isolated heart

preparations within 7 days, with significant decreases in LV

systolic pressure, LV developed pressure, and LV dP/dt max

evident within 3 weeks56 and progressing to profound systolic

function over 1 year.6062 Notably, these impairments in

diastolic and systolic dysfunction occur in the absence of

significant changes in myocardial perfusion.56,60 These im-

portant observations indicate that diastolic abnormalities,

both impaired relaxation and increased stiffness, occur in the

absence of hypertrophy and precede by weeks the onset of

systolic dysfunction.60 Equally important is the observation

that administration of insulin in type 1 diabetic rats partially

corrects the systolic abnormalities in association with resto-

ration of contractile proteins, even though modest hypergly-

cemia persists.61,62

These studies suggest that experimental type 1 diabetes,

characterized principally by hyperglycemia is associated with

altered calcium handling, impaired diastolic function, altered

contractile proteins, and progressive systolic dysfunction as

the magnitude and duration of the hyperglycemia progress-es.54,55,58,59 These abnormalities occur in the absence of

myocyte hypertrophy or fibrosis. The findings are consistent

with a dominant influence of hyperglycemia and the absenceof the influence of insulin. Thus, hyperglycemia alone is

sufficient to account for the functional, but not necessarily the

structural, changes observed in diabetic cardiomyopathy.

Models of Hyperinsulinemia With orWithout Hyperglycemia

Models of type 2 diabetes are metabolically distinct from type

1 diabetes largely related to increased plasma insulin levels

associated with altered cellular insulin action. Increased

NEFAs and marked hyperinsulinemia are early accompani-

ments, whereas hyperglycemia is a later development attrib-

utable to exhaustion of pancreatic -cell reserves. However,the cardiac manifestations in experimental models of type 2

diabetes vary considerably based on the onset and severity of

these metabolic perturbations, as well as the complex inter-

actions of intramyocardial lipids, insulin, and glucose on the

cardiomyocyte structure and function.

Many of the commonly used experimental models of type

2 diabetes are associated with obesity caused by genetic

perturbations in the Ob gene and its product, leptin.6367

Leptin is a 16-kDa peptide produced by adipocytes that acts

via specific receptors on the hypothalamus to inhibit food

intake and increase energy expenditure. Notably, leptin re-

ceptors have been identified in the rat myocardium63,64 and

regulate fatty acid oxidation independent of effects on the

acetyl CoA-malonyl CoA axis.65 Leptin has also been shown

to stimulate myocyte hyperplasia in rats66 and humans67

through both PI3-K and ERK1/2-dependent mechanisms,

similar to insulin. The metabolic phenotype associated with

both leptin-deficient (ob/ob) and the leptin receptordefi-

cient (db/db) mice include obesity, insulin resistance,

compensatory hyperinsulinemia, hypertriglyceridemia, and

various degrees of hyperglycemia.

The cardiac phenotype of the ob/ob (leptin-deficient)

mice has been studied both early and later in its development

with varying results. There is evidence of LV hypertrophy

and intramyocardial lipid accumulation both early68

andlate,69 suggesting that hyperleptinemia is not necessary for the

TABLE 2. Metabolic and Cardiac Phenotypes in Experimental Models of Diabetic Cardiomyopathy

Model

Biochemical Morphological Functional

Hyperlipidemia Hyperinsulinemia Hyperglycemia

Cardiac

Mass Fibrosis

Intramyocardial

Lipids Systol ic Diastolic

Coronary

Flow

Type 1 diabetes

STZ/Alloxan 1 11 111 11 % 1 22 22 %

Type 2 diabetes

ob/ob 1 11 1 1 % 1 %, 2* % %

db/db 1 11 11 1 % %, 2* 11 %

ZF 11 11 1 11 1 11 2, %* 2 %

ZDF 11 11 111 1 % 11 2, % 2 %

OLETF 11 11 1 1 1 1 % 2 22

Humans 1 1 1 11 % % % 222 22

*Only cardiac power was reduced. 1 indicates increase; 2 decrease; 1 arrow, mild; 2 arrows, moderate; 3 arrows, severe; %, no difference.




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development of LV hypertrophy. At 3 months with normal

fasting glucose but impaired glucose tolerance, LV systolic,

diastolic, and developed pressures are normal, but there is

evidence of decreased cardiac power in isolated, working

heart preparations.68 Notably, the degree of functional impair-

ment varies depending on the concentrations of palmitate and

insulin in the perfusate.69 In contrast, LV systolic function is

preserved at both 3 months70 and 6 months71 when intact

ob/ob mice are studied in vivo by echocardiography,

whereas impaired diastolic function has been noted in some

studies.

The hyperleptinemic db/db (leptin receptordeficient)

mice have a similar metabolic phenotype, but more profound

hyperglycemia (30 to 50 mmol/L) manifest earlier in devel-

opment. The hyperglycemic db/db mice have no cardiac

hypertrophy at 3 months,72 despite combined hyperinsulin-

emia and hyperleptinemia, but develop LV hypertrophy

later.69 In isolated working hearts, db/db mice have normal

LV systolic and developed pressures but increased ventricular

stiffness and impaired cardiac power.72

However, systolicfunction is preserved in db/db mice at 6 months when

studied in vivo.69 The conflicting data as to the nature and

extent of cardiac functional abnormalities between working

heart and intact preparations can be reconciled by considering

differences in substrate availability between the preparations.

Hormone and substrate concentrations are limited in the

isolated, crystalloid perfused hearts,68,72 whereas alternative

substrates (lactate and pyruvate) and metabolic hormones are

available in physiological concentrations in the intact mod-

els.69 Under circumstances in which a full array of substrates

is available, LV systolic function is preserved. Notably, both

models are associated with the development of cardiac

hypertrophy independent of plasma leptin levels or action,suggesting that hyperleptinemia is not necessary for the

development of cardiac hypertrophy in type 2 diabetes.

Finally, in contrast to the cardiac phenotype in models of type

1 diabetes, systolic performance is largely preserved even in

the presence of profound hyperglycemia, provided that insu-

lin is present. Instead, myocardial hypertrophy is the most

commonly observed abnormality with increased chamber

stiffness seen in some cases.

A similar evolution in cardiac phenotype is evident in

genetically engineered rat models involving the absence of a

functional leptin receptor. The Zucker fatty (ZF) rat is

characterized metabolically by hyperleptinemia and conse-

quent obesity, hyperlipidemia, and marked hyperinsulinemia

with the late onset of hyperglycemia. As such, the model is

characteristic of obesity and insulin resistance early (3 to 6

months). In contrast, the Zucker diabetic fatty (ZDF) rat has

a similar genetic background but demonstrates earlier hyper-

glycemia, consistent with metabolic features of type 2

diabetes.

The morphological features of the ZF rat include increased

intramyocardial lipid and increased myocardial mass.7375

Hypertrophy is evident in individual myocytes75 and whole

hearts83 where there is an associated expansion in the extra-

cellular matrix.76 However, cardiac functional abnormalities

have been observed inconsistently in isolated heart prepara-tions with decreased cardiac power73 and systolic wall stress74

in some studies, whereas LV pressures and LV dP/dt77 and

the rate-pressure product78 are maintained in others. Diastolic

abnormalities have been noted early with prolonged isovolu-

mic relaxation,76 whereas chamber stiffness was reported to

be normal at 12 months.74

In contrast to the ZF rats, the ZDF rats do not demonstrate

consistent increases in cardiac mass.7981 At 2 months, there

is increased mass in the presence of marked hyperinsulinemiaat a time when glucose levels are normal.82 However, by 3

months, there is no increase in mass when plasma glucose

levels are high (27 mmol/L) and plasma insulin levels are

reduced.80 Fredersdorf et al83 established the importance of

the balance between hyperglycemia and hyperinsulinemia in

5-month old ZDF rats by controlling hyperglycemia with

exogenous insulin and demonstrating increased cardiac mass,

whereas ZDF rats that remained persistent hyperglycemic had

no increase in mass. In isolated heart preparations, the

magnitude of systolic dysfunction in ZDF rats tends to be

greater when accompanied by severe hyperglycemia.79,82

These effects are dependent on the substrate availability in

the perfusate.79 In contrast, studies in intact ZDF reveal intact

systolic function8385 myocardial hypertrophy,83 impaired

flow reserve,84 and diastolic relaxation.85

Thus, hyperinsulinemic ZF rats have myocardial hypertro-

phy and variable degrees of diastolic abnormalities, whereas

the diabetic ZDF rats have smaller increases in cardiac mass

and impairments in LV systolic function in isolated hearts but

not intact models. These findings are consistent with the

cellular effects of hyperinsulinemia to induce cardiac hyper-

trophy in contrast to the effects of hyperglycemia that

mitigate hypertrophy and affect systolic dysfunction to a

greater extent. Whether the observed abnormalities in diastol-

ic function are a consequence of hypertrophy or hyperglyce-

mia remains unresolved.

Models of Increased Intramyocardial LipidWithout Hyperinsulinemia or Hyperglycemia

The model of cardiac specific overexpression of PPAR in

mice is associated with cardiac contractile dysfunction that is

mediated by increased NEFA uptake and intracellular accu-

mulation.86,87 Although the cardiac phenotype is dramatic

both at baseline and in response to a superimposed cardiac

insult, the model does not possess characteristic features of

diabetes. However, this model is particularly useful in study-

ing the contribution of excess intracellular lipid accumulation

to cardiac contractile dysfunction, in the absence of hyper-glycemia and hyperinsulinemia.86 Recent data using trans-

genic murine models of cardiac specific overexpression of

fatty acid transport protein (FATP) demonstrated a cardiac

phenotype that features diastolic dysfunction.88 Taken together,

it is abundantly clear that increased circulating NEFAs, a

ubiquitous feature of both type 1 and 2 diabetes, contribute

fundamentally not only to the development of both insulin

resistance and compensatory hyperinsulinemia but also can

directly affect cardiac function.

Cardiovascular Manifestations in HumansWith Type 1 and Type 2 Diabetes

The most commonly observed cardiac abnormalities in clin-ical studies of asymptomatic diabetics included LV hypertro-




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