Download The Failing Diabetic Heart: Focus on Diastolic Left Ventricular Dysfunction

The Failing Diabetic Heart: Focus on
Diastolic Left Ventricular Dysfunction
Loek van Heerebeek, MD, Aernout Somsen, MD, PhD,
and Walter J. Paulus, MD, PhD
Corresponding author
Walter J. Paulus, MD, PhD
Laboratory of Physiology, VU University Medical Center, Van der
Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
E-mail: [email protected]
Current Diabetes Reports 2009, 9:79–86
Current Medicine Group LLC ISSN 1534-4827
Copyright © 2009 by Current Medicine Group LLC
Diabetes mellitus (DM) is highly prevalent and is
an important risk factor for congestive heart failure
(HF). Increased left ventricular (LV) diastolic stiffness is recognized as the earliest manifestation of
DM-induced LV dysfunction, but its pathophysiology remains incompletely understood. Mechanisms
whereby DM increases LV diastolic stiffness differ
between HF with normal LV ejection fraction (EF)
(HFNEF) and HF with reduced LVEF (HFREF). In
diabetic HFREF, fibrosis and deposition of advanced
glycation end products (AGEs) are the most important contributors to high LV diastolic stiffness,
whereas in diabetic HFNEF, elevated resting tension of hypertrophied cardiomyocytes is the most
important contributor to high LV diastolic stiffness.
As HF mortality remains high in DM despite proven
efficacy of current treatments, better understanding
of the pathophysiology of high LV diastolic stiffness
could be beneficial for novel therapeutic strategies.
Introduction
The prevalence of diabetes mellitus (DM), especially type
2 DM, is steadily increasing and is expected to reach pandemic proportions in the next few decades [1]. DM is an
important risk factor for congestive heart failure (HF).
Mortality and hospitalization rates in diabetic patients
with HF remain particularly high, and HF patients with
DM have a worse prognosis than those without DM, especially when suffering with ischemic heart disease [2,3].
The prevalence of DM in HF approximates 20% to 35%
[2], and is higher in patients with HF and normal left ventricular (LV) ejection fraction (HFNEF) [4,5]. Currently,
HFNEF is diagnosed in about 50% of HF patients; chang-
ing population demographics will increase its prevalence
even more [6]. HFNEF and type 2 DM commonly coexist
and the two conditions relate to hypertension, obesity,
and older age [6]. In a recent study, type 2 DM and hypertension occurred in 57% and 82% of HFNEF patients,
whereas no HFNEF patients had type 1 DM. In contrast,
in HF patients with reduced ejection fraction (HFREF),
19% had type 2 DM and 8% had type 1 DM, whereas
11% were hypertensive [7•]. Furthermore, type 2 DM
commonly associates with the metabolic syndrome, which
represents a constellation of cardiovascular risk factors,
including obesity, hypertension, insulin resistance, dyslipidemia, microalbuminuria, and hypercoagulability. The
metabolic syndrome predicts subsequent development of
type 2 DM and is associated with cardiovascular mortality and LV diastolic dysfunction [8].
The increased incidence of HF in DM persists despite
correction for common confounders, such as hypertension
or coronary artery disease (CAD), because DM directly
affects cardiac structure and function, a condition called
diabetic cardiomyopathy [9]. Although initially classified
as a dilated cardiomyopathy, LV diastolic dysfunction was
later recognized as the earliest manifestation of diabetic
cardiomyopathy [10]. About 75% of normotensive, wellcontrolled type 2 diabetic patients without CAD show
evidence of LV diastolic dysfunction with tissue Doppler imaging [11]. The pathophysiology of LV diastolic
dysfunction in diabetic HF remains incompletely understood, which hinders the development of more effective
therapeutic strategies. This article therefore focuses on
the pathophysiology and possible therapeutic implications
of LV diastolic dysfunction in diabetic HF.
Mechanisms of LV Diastolic Dysfunction in DM
The following paragraphs discuss the mechanisms responsible for increased LV diastolic dysfunction in DM (Table 1).
Fibrosis
Diabetes changes the myocardial extracellular matrix,
as evident from enhanced interstitial and perivascular
fibrosis, increased expression of collagen type I, and
downregulation of collagen-degrading matrix metallopro-
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Table 1. Mechanisms responsible for increased LV diastolic stiffness in diabetic heart failure
Mechanisms
Myocardial fibrosis
Effects
Study
Increased collagen type I expression
[9,12]
Increased expression of profibrotic cytokines (TGF-β, IL-1β)
Decreased expression of MMPs
AGEs
Increased collagen production
[13,14]
Increased collagen and ECM cross-linking
Activation of AGE receptor–based signaling
Increased oxidative stress
Impaired calcium homeostasis
Endothelial dysfunction
Impaired NO bioavailability
Metabolic disturbances
FFA oxidation
[9,15,16]
Lipid accumulation and lipotoxicity
Uncoupling of mitochondrial oxidative phosphorylation
Impaired calcium
homeostasis
Endothelial dysfunction
Reduced activities of calcium handling proteins (SERCA2, ryanodine
receptor, Na2+-Ca2+ exchanger, sarcolemmal Ca2+ ATPase)
[9]
Increased expression of inflammatory markers (E-selectin, ICAM-1,
VCAM-1)
[17,18]
Microalbuminuria
Impaired NO bioavailability
Chronic inflammation
Increased oxidative stress
Myocardial oxidative stress
Enhanced ROS production
[19–22]
Impaired antioxidant defense systems
Glucose auto-oxidation; activation of polyol pathways
Enhanced formation of AGEs
Increased FFA and leptin
Impaired NO bioavailability
Toxic reactive substances (ie, peroxynitrite)
Impaired myocardial
NO bioavailability
Endothelial NOS uncoupling
[20,22,23]
Impaired S-nitrosylation–based signaling
Increased LV diastolic stiffness
Impaired myocardial
cGMP signaling
Increased cardiomyocyte
resting tension
Altered titin regulation
Impaired PKG activity
[24•,25,26•,27–29]
Cytoskeletal abnormalities
[30,31•,32•,33,34]
Increased stiff titin N2B expression
[31•,32•,33,34]
Titin hypophosphorylation
Disruption in titin-based signaling
AGE—advanced glycation end product; ECM—extracellular matrix; FFA—free fatty acid; ICAM-1—intercellular adhesion molecule 1;
IL-1β—interleukin-1β; LV—left ventricular; MMP—matrix metalloproteinase; NO—nitric oxide; NOS—nitric oxide synthase;
PKG—protein kinase G; ROS—reactive oxygen species; SERCA2—sarcoendoplasmatic reticulum Ca 2+ ATPase; TGF-β—transforming
growth factor-β; VCAM-1—vascular cell adhesion molecule 1.
teinases [12]. These pathologic mechanisms are mediated
by hyperglycemia, oxidative stress, and elevated aldoste-
rone and angiotensin II levels [12]. Echocardiograms of
diabetic patients show abnormal integrated backscatter
The Failing Diabetic Heart
(a marker of myocardial reflectivity), which confi rms
increased collagen deposition [12].
Advanced glycation end products
Advanced glycation end products (AGEs) are modifications of proteins or lipids that become nonenzymatically
glycated and oxidized after contact with aldose sugars,
with creation of nearly irreversible cross-links. Formation
and accumulation of AGEs is enhanced by hyperglycemia,
oxidative stress, aging, and hypertension [13,14]. Myocardial AGE deposition augments LV diastolic stiffness by
direct and indirect mechanisms, including formation of
collagen cross-links, stimulation of collagen production,
and activation of specific AGE receptors. AGE receptor activation induces profibrotic signaling and impairs
calcium homeostasis [13,14]. In addition, AGEs increase
oxidative stress and proinflammatory cytokine release
[13,14]. Increased serum AGE levels were identified as an
independent predictor of cardiac death and rehospitalization and are associated with LV diastolic stiffness, with
endothelial dysfunction, with impaired vascular compliance, and with reduced nitric oxide (NO) bioavailability,
in type 1 and 2 DM patients [13,14]. AGE deposition
results from poor glycemic control, which carries an
increased risk of HF. Each 1% increase in hemoglobin A1c
level was shown to be associated with an 8% increase in
HF prevalence [15].
Metabolic disturbances
Substrate metabolism is altered in DM with a shift from
glucose utilization to increased free fatty acid oxidation.
This leads to myocardial lipotoxicity, uncoupling of
mitochondrial oxidative phosphorylation, and disturbed
contraction/relaxation coupling [9]. Reduced high-energy
phosphate metabolism was shown to parallel LV diastolic
dysfunction in well-controlled, normotensive type 2 diabetic patients without CAD [16].
Impaired calcium homeostasis
Intracellular calcium (Ca 2+) importantly regulates cardiac
contractility and calcium influx. Depolarization-activated
voltage-dependent L-type Ca 2+ channels trigger excitation/contraction coupling, which is regulated by various
calcium-handling proteins [9]. In type 1 and 2 DM, disturbed cardiomyocyte (CM) calcium handling results from
reduced activity of calcium-handling proteins, such as sarcoplasmic reticulum adenosine triphosphatase (ATPase;
SERCA2a), ryanodine receptor, Na 2+-Ca 2+ exchanger, and
sarcolemmal Ca 2+ ATPase. Reduced activities of these calcium-handling proteins impair LV systolic and diastolic
function [9].
Endothelial dysfunction
Endothelial dysfunction predicts cardiovascular mortality,
correlates with functional capacity of chronic HF patients,
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and plays a central role in the pathophysiology of congestive HF, type 1 and 2 DM, hypertension, and chronic
renal failure [17,18]. In DM and HF, endothelial dysfunction results from inflammatory processes and leads to
impaired vasodilator responses, reduced NO bioavailability, and a prothrombotic state [17]. Increased markers of
endothelial inflammation, such as E-selectin, intercellular
adhesion molecule 1, and vascular cell adhesion molecule
1, were demonstrated in metabolic syndrome and obesity
and represent an independent risk factor for subsequent
development of type 2 DM [17].
Myocardial oxidative stress
Increased oxidative stress underlies endothelial dysfunction, as evident from elevated production of reactive
oxygen species (ROS; eg, superoxide, hydrogen peroxide,
and the hydroxyl radical) and from impaired activity of
antioxidant defense systems [19,20]. Hyperglycemia
induces oxidative stress via several mechanisms, which
include glucose auto-oxidation, formation of AGEs,
activation of the polyol pathway, and increased levels of
free fatty acid and leptin [19]. Prominent cardiovascular
sources of ROS production include xanthine oxidoreductase, NADPH oxidase, mitochondrial oxidases, and
uncoupled NO synthases [19,20]. Increased generation
of ROS contributes to cardiac injury, by direct oxidative
cellular damage and by diminished NO bioavailability
[20]. Superoxide directly reacts with and inactivates NO,
with subsequent production of peroxynitrite. Increased
peroxynitrite levels contribute to congestive HF and
cardiovascular diabetic complications [21]. In addition,
peroxynitrite oxidizes tetrahydrobiopterin, which is a
necessary cofactor regulating the function of the multicomponent endothelial NO synthase (eNOS). eNOS is
the most prominent vascular source of NO. In oxidative
environments, diminished tetrahydrobiopterin induces
eNOS uncoupling, which leads to production of superoxide instead of NO, thereby amplifying oxidative stress
and endothelial dysfunction. Evidence for uncoupling of
eNOS has been obtained in patients with DM, hypertension, and hypercholesterolemia [22].
Myocardial NO bioavailability
NO exerts favorable effects on LV diastolic distensibility,
and low myocardial NO bioavailability was previously
demonstrated to raise LV diastolic stiffness and reduce
LV preload reserve in HFREF patients [23]. Furthermore,
NO and superoxide regulate myocardial signal transduction via post-translational modification of effector proteins
through the process of S-nitrosylation [20]. S-nitrosylation
comprises the covalent attachment of NO to thiol side
chains of cysteine residues and serves as a major effector of
NO bioactivity, regulating various proteins, transcription
factors, and ion channels. When physiologically present,
superoxide facilitates S-nitrosylation, whereas oxidative
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stress disrupts these signaling cascades, leading to a state
of NO/superoxide redox-disequilibrium [20]. Interestingly,
cardiac NO signaling appears highly compartmentalized as
evident from the colocalization of NO sources and targets
within confined subcellular compartments, which appear
to be disrupted in HF [20]. Decreased myocardial NO bioavailability in diabetic HF could thus interfere with vital
intracellular NO redox-based signaling and contribute to
the observed diastolic LV dysfunction.
Myocardial cGMP signaling
Another important aspect of NO-based signaling involves
NO-mediated activation of soluble guanylate cyclase,
which generates cGMP. The second major pathway for
cGMP synthesis involves natriuretic peptide (NP)–mediated membrane guanylate cyclase stimulation [24•]. cGMP
is a key regulatory second messenger and modulates
cardiac inotropic and metabolic responses via activation
of its downstream effectors, including protein kinase G
(PKG). PKG stimulation results in decreased myofi lament
calcium sensitivity, attenuation of CM hypertrophy, and
protection against ischemia-reperfusion injury. Therefore,
PKG has anti-hypertrophic, anti-remodeling, and antiinflammatory actions [25]. Termination of cGMP action
and PKG signaling is induced through hydrolyzation by
phosphodiesterases (PDEs), of which 11 different primary
isoenzymes have been described [24•]. In the cardiovascular system, PDE type 5 (PDE5) is particularly important
as it becomes upregulated in pathologic conditions, such
as congestive HF, pulmonary arterial hypertension, and
right ventricular and LV hypertrophy [24•,25,26•].
Recent studies demonstrated that NO-cGMP and
NP-cGMP pathways are also compartmentalized and differentially regulated by PDEs, as PDE5 closely interacts
with NO-stimulated cGMP, but not with NP-stimulated
cGMP [24•]. PDE5 normally appears in a striated pattern
colocalizing with α-actinin at the sarcomeric Z-disc. This
striated pattern is important for effective β-adrenergic
signaling and is lost in failing myocardium [24•].
Downregulation of NO-cGMP-PKG signaling was
demonstrated in DM and contributed to diabetic vascular
complications [27]. Hyperglycemia reduced PKG expression and activity through PKC-dependent activation of
NAD(P)H oxidase-mediated ROS production [27]. PKG
activity can be indirectly measured using antibodies
against the specific PKG substrate vasodilator-stimulated
phosphoprotein (VASP), of which the phosphorylated
isoform serine-239 (P-VASP) is a specific marker for
PKG activity [28]. Decreased PKG activity was found
in hypertrophied LV myocardium [29]; recently, we
also demonstrated decreased P-VASP/VASP ratios and,
therefore, downregulated PKG activity in endomyocardial biopsies of HFNEF patients without CAD. Thus,
cGMP-PKG-PDE signaling is an important and complex
regulatory mechanism that underlies fundamental myo-
cardial contractile processes. This mechanism is adversely
affected by DM, and impaired cGMP-PKG-PDE signaling
could be an important contributor to the high LV diastolic
stiffness of the failing diabetic heart.
CM resting tension and titin
Increased CM resting tension (Fpassive) was previously
shown to significantly contribute to the high LV diastolic stiffness observed in HFNEF patients [30,31•]. In
vitro–determined CM Fpassive correlated with LV diastolic
stiffness, LV end-diastolic wall stress, and LV end-diastolic pressure [30,31•]. In these studies, Fpassive was
determined in skinned CM (ie, in CMs with all sarcoplasmic and sarcolemmal membrane structures removed
by prior submersion in a detergent). CMs were isolated
from LV endomyocardial biopsies. Interestingly, increased
CM Fpassive in HFNEF was lowered to control values after
administration of protein kinase A (PKA); a phosphorylation deficit of myofi lamentary or cytoskeletal proteins was
therefore inferred to account for the high Fpassive [30,31•].
The giant sarcomeric elastic protein titin contains PKA
phosphorylation sites and is an important determinant of
CM Fpassive and elasticity [32•]. Titin spans half a sarcomere
from the Z-disc to the M-line and functions as a sarcomeric stretch/stress sensor protein involved in mediation
and transmission of external force signals from the extracellular matrix to the CM cytoskeleton. Titin alters CM
Fpassive through isoform shifts from a stiff N2B isoform to a
more compliant N2BA isoform and through phosphorylation status. Phosphorylation of titin’s N2B region by PKA
reduces myofibrillar Fpassive in human myocardium and in
isolated rat CM [32•]. Recently, increased expression and
lower phosphorylation of the stiff N2B titin isoform were
demonstrated in CM isolated from HFNEF patients [31•].
Thus, both changes in titin isoform expression and phosphorylation contributed to the increased CM Fpassive and
LV diastolic stiffness in HFNEF.
Furthermore, administering PKG to CM isolated from
HFNEF patients lowered Fpassive to a level comparable
to the level observed after PKA administration [33]. No
additional fall was noted in CM Fpassive when PKA was
administered after PKG. This suggested that PKG and
PKA acted on the same phosphorylation site [33]. PKG
phosphorylation sites on titin were recently identified [34].
Combined with the previously discussed downregulation
of cGMP-PKG-PDE signaling, these results suggest that
PKG-mediated hypophosphorylation of titin could be a
major determinant of the high CM Fpassive and the high LV
diastolic stiffness observed in HFNEF patients.
Relative Importance of Mechanisms of LV
Diastolic Dysfunction in DM
Recently, we demonstrated that LV myocardial stiffness
was higher in diabetic HFREF (DM+HFREF) and diabetic
The Failing Diabetic Heart
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Figure 1. Diabetes mellitus (DM)–related pathways of myocardial damage and resulting clinical phenotypes of the failing diabetic heart in
the absence of coronary artery disease. DM impairs left ventricular (LV) function through advanced glycation end product (AGE) deposition-inflammation-fibrosis in patients with heart failure with reduced LV ejection fraction (HFREF). HFREF usually results from previous
myocarditis. In DM patients with glomerulosclerosis, AGE deposition-inflammation-fibrosis can occasionally be the only cause of HFREF, as
described in the original reports of diabetic cardiomyopathy (CMP) [35]. DM impairs LV function through myocyte hypertrophy–myocyte
stiffness in patients with heart failure with normal LV ejection fraction (HFNEF). In most patients, HFNEF results from concomitant arterial hypertension. However, sometimes DM is the only cause of HFNEF, and in these patients a novel HFNEF phenotype of diabetic CMP
becomes manifest.
HFNEF (DM+HFNEF) patients compared with nondiabetic
HFREF (DM-HFREF) and HFNEF (DM-HFNEF) patients [7•].
No significant differences were noted in HF treatment
among these patient groups. The mechanisms responsible
for the increased LV diastolic stiffness differed in DM+HFREF
and in DM+HFNEF, as evident from analysis of structure and
function of LV myocardium procured by transvascular LV
endomyocardial biopsy technique. In DM+HFREF patients,
interstitial fibrosis was significantly higher compared with
DM-HFREF, DM-HFNEF, and DM+HFNEF patients in whom
levels of interstitial fibrosis were comparable [7•]. In addition, myocardial AGE deposition was exclusively present
in the microvasculature and was again significantly higher
in DM+HFREF patients compared with DM-HFREF patients.
In DM+HFNEF patients, only a nonsignificant trend toward
increased microvascular AGE deposition was observed
[7•]. In DM+HFREF patients, AGE deposition was paralleled
by endothelial E-selectin expression, a marker of inflammatory endothelial activation [7•].
In DM+HFNEF, increased LV diastolic stiffness mainly
resulted from elevated Fpassive of hypertrophied CM [7•].
CM Fpassive was similar between DM+HFREF and DM-HFREF
patients. The increased CM Fpassive in DM+HFNEF patients
was corrected by PKA [7•]. Increased Fpassive in DM+HFNEF
patients was paralleled by opening of the CM Z-discs,
which appeared wider in DM+HFNEF than in DM-HFNEF [7•].
Z-disc widening had previously been observed in transgenic mice after nebulin or muscle LIM protein knockout
[32•] and was thought to result from altered elastic properties of cytoskeletal proteins, which pull at and open up
adjacent Z-discs.
From the foregoing results, DM appears to impair
myocardial function by two distinct pathways, each
resulting in a different HF phenotype: the fi rst pathway
consists of AGE deposition-inflammation-fibrosis and
results in an HFREF phenotype, whereas the second pathway consists of myocyte hypertrophy–myocyte stiffness
and results in an HFNEF phenotype (Fig. 1). In DM+HFREF
patients, the pathway of AGE deposition-inflammationfibrosis resulted not only in diastolic LV dysfunction but
also in systolic LV dysfunction, as evident from LV dilatation and depressed LV ejection fraction. Previous viral or
toxic myocarditis is the most likely cause for the dilated
cardiomyopathy in most DM+HFREF patients because fasting glucose, hemoglobin A1c, and DM duration were all
similar in the DM+HFREF and DM+HFNEF groups. Inflammatory myocardial damage is known to facilitate AGE
deposition. Furthermore, AGE deposition itself amplifies
myocardial inflammation [13,14], as evident from the
observed rise of myocardial E-selectin in the DM+HFREF
patients. In the presence of longstanding poor glycemia
control, these interactions between AGE deposition and
myocardial inflammation could eventually induce a diabetic cardiomyopathy without foregoing viral or toxic
myocarditis, as observed in the initial reports on diabetic
cardiomyopathy [35] and as suggested by the raised DM
prevalence in idiopathic dilated cardiomyopathy [36].
In DM+HFNEF, increased CM Fpassive and CM hypertrophy were the most important contributors to the high LV
diastolic stiffness. Most of the HFNEF patients suffered
from hypertensive heart disease. However, CM hypertrophy observed in the DM+HFNEF patients was unrelated
to higher LV pressure overload because LV peak systolic
pressure and LV peak systolic wall stress were similar in
the DM+HFNEF and DM-HFNEF groups. DM was the unique
cause of high LV stiffness in only a small subgroup of the
DM+HFNEF patients, who had no arterial hypertension. This
subgroup presents with a novel phenotype of diabetic cardiomyopathy, which differs from the original reports [35],
as these patients have preserved LV ejection fraction, no
LV cavity dilatation, and elevated diastolic LV stiffness.
Treatment of High LV Diastolic Stiffness
Pathophysiologic mechanisms underlying high LV diastolic stiffness in diabetic HF are multifactorial, involving
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myocardial and vascular dysfunction and extracellular
and intracellular disturbances. A selective treatment strategy to reduce high LV diastolic stiffness in diabetic HF is
therefore also composed of multiple compounds.
Angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers
Numerous HF trials demonstrated improved cardiovascular morbidity and mortality by angiotensin-converting
enzyme inhibitors (ACEIs) or angiotensin receptor blockers
(ARBs), and inhibitors of the renin-angiotensin-aldosterone system have become indispensable drugs for HF
treatment [37,38]. The beneficial effects of ACEIs or ARBs
in HF and DM are manifold and include improvement
of endothelial function, raised vascular and myocardial
NO bioavailability, enhanced insulin sensitivity, control
of arterial hypertension, prevention of unfavorable LV
remodeling, and less vascular inflammation or oxidative
stress. ACEIs and ARBs can also prevent end-organ damage in ischemic heart disease, renal disease, hypertension,
and DM, and possibly development of type 2 DM [37,38].
Numerous studies demonstrated that angiotensin II and
aldosterone stimulate myocardial fibroblast-mediated
collagen synthesis and decrease myocardial collagenase
activity. These actions result in progressive myocardial
fibrosis and high LV diastolic stiffness [39]. Chronic use
of ACEIs and ARBs improves echocardiographic parameters of LV diastolic function in patients with hypertensive
heart disease and type 2 DM [39,40]. Furthermore, aldosterone inhibitors, such as spironolactone and eplerenone,
also reduce myocardial fibrosis as a result of decreased
NAD(P)H oxidase–derived ROS generation and increased
NO bioavailability [41].
AGE cross-link breakers
In congestive HF, administration of the AGE breaking
compound 4,5-dimethyl-3-phenacylthiazolium chloride
(ALT-711), which cleaves AGE cross-links between proteins and preserves natural carbohydrate modification to
proteins, improved arterial compliance and LV diastolic
function and decreased pulse pressure, myocardial fibrosis, and LV mass [13,14]. Furthermore, patients with
systolic HF treated with ALT-711 demonstrated a trend
toward improved LV systolic function [13,14]. Adequate
glycemic control, ACEIs, ARBs, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or
statins also reduce AGE accumulation [13,14].
Statins
Statins importantly reduce cardiovascular risk in diabetic
patients, as evident from numerous primary and secondary
prevention studies [3]. Statins lower cholesterol biosynthesis via inhibition of the conversion of HMG-CoA to
mevalonic acid. In addition, statins exert numerous cholesterol-independent beneficial actions in cardiovascular
disease, referred to as the pleiotropic actions of statins.
These actions include reduction of inflammation, oxidative stress, and thrombogenicity. Statins thereby improve
coronary endothelial function with increased NO bioavailability and enhanced myocardial PKG activity [38,42].
This last effect could be especially beneficial for the high
LV diastolic stiffness of diabetic HFNEF patients.
Peroxisome proliferator-activated receptor agonists
Peroxisome proliferator-activated receptor (PPAR)-α and
PPAR-δ are members of the nuclear hormone receptor
superfamily of ligand-activated transcription factors, which
upon activation bind to DNA (PPAR-response element)
to regulate gene transcription [43,44]. PPAR-α (fibrates)
and PPAR-γ (thiazolidinediones) agonists were shown to
reduce cardiovascular events in high-risk populations with
metabolic syndrome, dyslipidemia, or DM and to improve
atherogenic dyslipidemia and metabolic control in DM
[43,44]. In addition, PPARs also exhibit anti-inflammatory
and antioxidative actions with improved endothelial function through restored insulin-dependent endothelial NO
release [43,44]. However, a higher prevalence of congestive HF was demonstrated in diabetic patients treated with
thiazolidinediones. The latter is probably explained by thiazolidinediones’ favorable effects on myocyte hypertrophy
and contractile performance being offset by increased renal
sodium reabsorption and plasma volume expansion.
Isosorbide-dinitrate
The A-Heft (African-American Heart Failure Trial)
demonstrated that therapy with a fi xed-dose combination of isosorbide dinitrate (NO donor) and hydralazine
(vasodilator and antioxidant) improved cardiovascular
morbidity and mortality in African-American patients
with advanced HF, when added to conventional HF
therapy [45]. Isosorbide-dinitrate/hydralazine therapy
improved both cardiovascular hemodynamics as well as
LV remodeling and this improvement probably resulted
from enhanced NO bioavailability [45].
Natriuretic peptides
NPs (ie, atrial natriuretic peptide, brain natriuretic peptide [BNP], and C-type natriuretic peptide) are released
from the myocardium in response to increased CM
stretch. They stimulate natriuresis, improve myocardial relaxation, reduce ventricular preload, and exert
sympathico-inhibitory effects [46]. BNP concentrations
are consistently raised in disorders associated with LV
diastolic dysfunction, such as aortic stenosis, hypertrophic cardiomyopathy, or restrictive cardiomyopathy
[46]. Nesiritide is a recombinant form of human Btype NP and also exhibits vasodilator, natriuretic, and
lusitropic activities. Nesiritide administration resulted
in reduced pulmonary wedge pressure in patients with
acute decompensated HF. However, the recent FUSION
The Failing Diabetic Heart
II (Follow-Up Serial Infusions of Nesiritide) trial, which
evaluated the clinical use of outpatient, intermittent
nesiritide infusions in advanced HFREF patients, failed
to observe cardiovascular end-point reductions when
compared with standard care outpatient management
[47]. Whether nesiritide administration could be benefi cial in HFNEF remains unknown.
PDE inhibitors
PDE5 inhibition with sildenafi l is currently used for treating pulmonary hypertension [26•,48]. In patients with
pulmonary hypertension, sildenafi l decreases pulmonary
vascular resistance, increases cardiac output, reverses
myocardial hypertrophy, and improves endotheliumdependent flow-mediated dilation [26•,48]. This beneficial
effect on endothelial dysfunction has also been observed
in diabetic men [49] and could therefore be used for treating high diastolic LV stiffness in diabetic HF.
Conclusions
Even in the absence of CAD, the failing diabetic heart has
elevated LV diastolic stiffness. Mechanisms responsible for
the elevated LV diastolic stiffness are multifactorial and
differ between DM+HFREF and DM+HFNEF patients. Inflammation, deposition of AGEs, and collagen are important
determinants of increased LV diastolic stiffness in DM+HFREF,
whereas increased Fpassive of hypertrophied CM is the main
determinant of increased LV diastolic stiffness in DM+HFNEF.
Downregulation of NO-mediated cGMP-PKG signaling,
probably induced by vascular inflammation and oxidative
stress, could account for the high Fpassive of hypertrophied
CM observed in DM+HFNEF patients.
Disclosures
No potential confl icts of interest relevant to this article
were reported.
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