Impact of diabetes on postinfarction heart failure and left ventricular remodeling.

Abstract

Diabetes mellitus, the metabolic syndrome, and the underlying insulin resistance are increasingly associated with diastolic dysfunction and reduced stress tolerance. The poor prognosis associated with heart failure in patients with diabetes after myocardial infarction is likely attributable to many factors, important among which is the metabolic impact from insulin resistance and hyperglycemia on the regulation of microvascular perfusion and energy generation in the cardiac myocyte. This review summarizes epidemiologic, pathophysiologic, diagnostic, and therapeutic data related to diabetes and heart failure in acute myocardial infarction and discusses novel perceptions and strategies that hold promise for the future and deserve further investigation.

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PREVENTION OF HEART FAILURE AFTER MYOCARDIAL INFARCTION (MARTIN ST JOHN SUTTON, SECTION EDITOR)
Impact of Diabetes on Postinfarction Heart Failure and Left
Ventricular Remodeling
Helene von Bibra & Martin St John Sutton
Published online: 13 August 2011
# The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract Diabetes mellitus, the metabolic syndrome, and
the underlying insulin resistance are increasingly associated
with diastolic dysfunction and reduced stress tolerance. The
poor prognosis associated with heart failure in patients with
diabetes after myocardial infarction is likely attributable to
many factors, important among which is the metabolic
impact from insulin resistance and hyperglycemia on the
regulation of microvascular perfusion and energy genera-
tion in the cardiac myocyte. This review summarizes
epidemiologic, pathophysiologic, diagnostic, and therapeu-
tic data related to diabetes and heart failure in acute
myocardial infarction and discusses novel perceptions and
strategies that hold promise for the future and deserve
further investigation.
Keywords Diastolic dysfunction.Tissue Doppler.
Metabolic syndrome.Type 2 diabetes.Insulin resistance.
Cardiovascular disease.Left ventricular remodeling.Intact
proinsulin.Low carbohydrate diet
Introduction
The striking increase in the worldwide prevalence of the
metabolic syndrome parallels the epidemics of obesity and
diabetes [1]. Type 2 diabetes mellitus and insulin resistance
are established risk factors for heart failure (HF) [2, 3].
Many patients with diabetes have diastolic dysfunction [4]
that is the antecedent in the increasing prevalence of HF
with preserved ejection fraction [5••]. Similarly, systolic HF
and coronary artery disease (CAD), including myocardial
infarction (MI), are interlinked in a reciprocal relationship.
Diabetes has been a consistently powerful risk factor for
development of post-MI HF, accounting for 66% of
mortality during the first year [6]. The combination of
diabetes and HF after MI requires preventive action because
it is usually not associated with the characteristic left
ventricular (LV) remodeling [7]. If LV remodeling does
develop, it requires appropriate treatment [8] that includes
revascularization and metabolically and hemodynamically
effective treatment strategies that limit infarct size, cardiac
dysfunction, and LV remodeling. This review summarizes
epidemiologic, pathophysiologic, diagnostic, and therapeu-
tic data related to diabetes/metabolic syndrome and HF and
LV remodeling post-MI.
Pathophysiological Impact of Diabetes on Heart Failure
and Remodeling
Several mechanisms promote metabolic consequences that
lead to cardiac dysfunction and HF in diabetes. The primary
etiology of the metabolic syndrome in type 2 diabetes is
chronic overnutrition resulting in insulin resistance,
abdominal obesity, hyperinsulinemia, and lipotoxicity.
Another important mechanism deduced mainly from exper-
imental work is myocardial energy demand/supply mis-
match from 1) increased oxygen demand in the diabetic
myocardium related to increased vascular stiffness; and 2)
decreased energy supply from myocardial underperfusion,
H. von Bibra (*)
Klinic for Endocrinology, Diabetes and Vascular Medicine,
Klinikum Bogenhausen, Städtische Klinikum München GmbH,
Englschalkingerstrasse 77,
81925 München, Germany
e-mail: vonbibra@gmx.de
M. St John Sutton
Department of Medicine, Cardiovascular Division,
University of Pennsylvania School of Medicine,
Philadelphia, PA 19106, USA
Curr Heart Fail Rep (2011) 8:242–251
DOI 10.1007/s11897-011-0070-8

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endothelial dysfunction, and reduced myocellular energy
production. This energy mismatch is associated with
increased stress in the infarct-related segments and neuro-
hormonal upregulation in the remote zones.
Increased Myocardial Energy Demand
Increased myocardial oxygen consumption (MVO2) has
been observed in human studies and in experimental
diabetes models [9, 10]. Similarly, increased myocardial
energy demand assessed by increased rate pressure product
has been demonstrated at rest and during stress in patients
with type 1 [11] and type 2 diabetes [12, 13]. This
observation has been ascribed to increased arterial wall
stiffness as an important determinant for increases in
systolic blood pressure and pulse pressure [14, 15].
Decreased Myocardial Energy Supply
Microvascular Perfusion Abnormalities
In patients with diabetes, the increased incidence of HF
post-MI is mainly due to a diminished microvascular
perfusion after reperfusion therapy [16], and a reduced
coronary flow reserve is consistently observed at cardiac
catheterization. The modulation of myocardial blood flow
at the level of microcirculation is achieved from blood
volume changes from the recruitment or derecruitment of
capillaries. The only diagnostic method that provides
insight into this aspect of perfusion, dedicated to meta-
bolic substrate exchange, is myocardial contrast echocar-
diography. The microbubbles residing strictly within the
lumen of the capillaries enable assessment of myocardial
capillary volume index, flow velocity, and myocardial
blood flow index [17, 18]. A consistent observation in
patients with diabetes without CAD is a decreased
capillary volume at stress by a diminished stress-induced
increase (17% vs 50% in control patients) [11–13]. Factors
contributing to this limited response are hyperglycemia,
hyperlipemia, oxidative stress, and endothelial dysfunc-
tion present in any postprandial phase [19, 20]. After a
physiologic mixed meal (400 kcal), a 50% reduction in
capillary blood volume was demonstrated in patients with
diet-treated type 2 diabetes, but not in control patients
[21]. Translating this effect into the setting of acute MI in
coronary care units highlights the additional risk of
undetected myocardial hypoperfusion in each postprandial
phase for diabetic patients. The regulation of capillary
recruitment is dynamic and improves with glycemic
control in the fasting and postprandial states as well as
with cardiovascular preventive medication, as demonstrated
in small human studies [13, 22, 23]. These data indicate that
capillary volume modulation plays an important but little
acknowledged role in the regulation of human myocardial
perfusion requiring prospective investigations.
Endothelial Dysfunction
Endothelial dysfunction is an early abnormality in CAD,
obesity, and the metabolic syndrome with insulin resistance
and an imbalance between the reduced bioactivity of nitric
oxide and endothelin-1. Additional inducing factors are
hyperglycemia, hypercholesterinemia, and hypertension.
Augmentation has been observed after the intake of oleic
acid (eg, olive oil), antioxidants (eg, vegetables, fruit, and
vitamins C and E), and the phenolic compounds in red
wine. Pharmaceutical improvement has been achieved with
insulin, statin, angiotensin-converting enzyme (ACE) inhib-
itors, and angiotensin-1 blockers or with thiazolidinediones
(TZDs). Abnormalities of flow-mediated vasodilation of the
brachial artery [24] are considered to be markers of
abnormal myocardial perfusion, but the mechanisms of
regulation may differ in these vascular territories.
Reduced Myocardial Energy Production
Patients with diabetes have reduced regional function in the
noninfarctzonedespiteasimilarejectionfractioncomparedto
control patients without diabetes, and have a two- to threefold
greater incidence of HF after acute MI [7, 25]. Multiple
studies have suggested that diabetes is associated with a
cardiomyopathy characterized by diastolic abnormalities [26,
27••] and higher chamber stiffness, independent of hyper-
tension and CAD [25, 28•]. Although increased chamber
stiffness usually is thought to result from structural myocar-
dial alterations such as hypertrophy, fibrosis, and modifica-
tions of the extracellular matrix, it is often due to myocardial
relaxation abnormalities secondary to energy restraints from
acute hypoxemia, ischemia, or metabolic stress [29].
In the normal heart, 70% of myocardial energy produc-
tion is derived from free fatty acid (FFA) oxidation. During
stress or hypoxia, this is shifted to more glucose oxidation
that requires less oxygen for adenosine triphosphate (ATP)
production. However, in insulin resistance, glucose uptake
and oxidation are suppressed and myocytes remain almost
completely dependent on the use of FFA oxidation.
Additionally, increased FFA levels together with insulin
resistance promote synthesis of uncoupling proteins, result-
ing in the production of heat instead of ATP, so that up to a
40% decrease in ATP production may result compared to
glucose oxidation [30]. This inability to switch fuels also
may lead to generation of reactive oxygen species (ROS)
and unfavorable alterations in calcium metabolism. These
adverse metabolic effects are induced by insulin resistance
and effectively contribute to HF also in patients with
diabetes by sustaining neurohormonal activation.
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Lipotoxicity and Glucotoxicity
Lipotoxicity
Strongly related to insulin resistance, obesity is a known
risk factor for HF [31]. Animal studies suggest that the
underlying mechanisms are overstorage of lipids and
lipotoxic injury to myocytes associated with high serum
levels of FFA and triglycerides that involve increased FFA
uptake, diminished mitochondrial oxidative capacity, gen-
eration of ROS, and increased apoptosis [32]. Of particular
importance, insulin resistance alters the distribution pattern
of postprandial energy storage after ingestion of a high-
carbohydrate mixed meal away from glycogen synthesis in
skeletal muscle cells to de novo hepatic production of
triglycerides (lipogenesis). This increase in plasma trigly-
cerides and decrease in high-density lipoprotein (HDL)
concentration [33••] implies that carbohydrate restriction
may improve serum lipid values. Compared to lean control
patients, increasing intracardiac lipid storage was demon-
strated in overweight individuals, individuals with addi-
tional impaired glucose tolerance, and individuals with
overt type 2 diabetes in a magnetic resonance imaging
(MRI) study [34]. Furthermore, in patients with diabetes,
cardiac steatosis correlates with diastolic dysfunction [35].
Glucotoxicity
Lipotoxicity is an important mechanism in the metabolic
syndrome. In patients with lipotoxicity, glucotoxicity plays an
intermittent role only during significant hyperglycemia in the
postprandial phase lasting for up to 2 h. However, in overt
diabetes, postmeal hyperglycemia is prolonged to at least 4 h,
so that glucotoxicity exacerbates the metabolic consequences
of chronic overnutrition during most of the day.
Glucotoxic effects involve three additional mechanisms
for dysfunction in the diabetic heart. These involve 1) ROS
that amplify hyperglycemia induced activation of protein
kinase C isoforms; 2) increased formation of glucose-
derived advanced glycation end products; and 3) increased
glucose flux through the aldose reductase pathways [32].
Admission glucose levels have a prognostic role in patients
with acute MI and in patients with HF [36, 37].
Oxidative Stress (Reactive Oxygen Species)
ROS also play a role in the disturbed glucose and lipid
metabolism in chronic overnutrition that may be generated
by both the hyperlipidemia and hyperglycemia pathways.
After a carbohydrate meal, ROS increases in overweight
patients with diabetes but not in lean control individuals
(von Bibra, unpublished data; [20]). In the context of
diastolic dysfunction, it is striking that many mechanisms
activated by an increased generation of ROS lead to
reduced availability of energy. The direct effects of ROS
on cardiomyocytes involve impaired mitochondrial energy
production [38••] and reduced cardiac efficiency [32].
Further effects imply altered insulin signaling, reduced
availability of nitric oxide, and mitochondrial damage that
can lead to abnormal cardiac structural and functional
remodeling [26, 39]. Indirect effects may involve down-
regulated perfusion by endothelial dysfunction [40].
Neurohormonal Alterations
Another primary mechanism linking HF, diabetes, and
insulin resistance is upregulation of the sympathetic
nervous system and the renin-angiotensin system during
reduced cardiac output that may lead to a vicious cycle via
increases in circulating FFA concentrations [41]. Different
mechanisms, affecting heart rate regulation and exercise
tolerance, are implicated in cardiac autonomic neuropathy.
Additionally, in HF and in LV remodeling, inflammatory
mediators are upregulated, the most prominent being tissue
necrosis factor-α (TNF-α). Insulin resistance is associated
with upregulation of the same inflammatory pathways that
can be attenuated by insulin sensitization treatment.
However, this has been largely unsuccessful in human
clinical trials because only individual components of the
inflammatory cascade have been targeted [38••].
Impact on Diagnostics
Because of the numerous interactive metabolic pathways
and their metabolic, hemodynamic, and functional con-
sequences, we will focus on causal mechanisms and insulin
resistance rather than symptoms or consequences. Because
insulin resistance is a nutritional disease, relevant diagnos-
tic methods for assessing postmeal metabolism and severity
of insulin resistance are discussed.
Insulin Resistance and Diabetes
Clinicians lack a grading system for type 2 diabetes.
Occasionally, the type of therapy (diet vs oral antidiabetics
vs insulin) has been used as a substitute. Type 2 diabetes is
the result of two developments: 1) chronic overnutrition
with resulting insulin resistance and 2) at least a relative
failure of pancreatic ß-cells to release sufficient insulin to
maintain glucose homeostasis. In this context, insulin
resistance is the basic mechanism, but its diagnosis is not
straightforward. Commonly, attempts are made using the
homeostasis model of insulin resistance [42]. This measure
may be misleading in the phase of failing ß-cell function
and during insulin-based therapy. Intact proinsulin is a
244 Curr Heart Fail Rep (2011) 8:242–251

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precursor molecule of insulin that is released into circula-
tion, is associated with increasing insulin resistance, and
has a similar adipogenetic activity to insulin but only 10%
to 20% of the glucose-lowering effect. Recently, determi-
nation of proinsulin has been used as a diagnostic tool
because an increasing proinsulin to insulin ratio predicts
insulin resistance and deterioration of glucose tolerance
[43]. Increasing intact proinsulin reflects increasing β-cell
dysfunction. Thus, both measures are useful biomarkers for
insulin resistance and β-cell dysfunction and for assessing
the impact of therapeutic intervention on β-cell function in
type 2 diabetes [44, 45]. Such a diagnostic tool would allow
staging of patients with diabetes for appropriate antidiabetic
therapy and establishing the risk of insulin resistance in
obese patients [46••].
Finally, in the setting of acute MI and revascularization,
blood glucose control in patients with diabetes should
routinely involve fasting and postmeal glucose measure-
ments (such as hyperglycemic peaks with the associated
sequelae of hyperinsulinemia, ROS generation, and endo-
thelial dysfunction) because only the latter reflects the
amount and type of ingested carbohydrates [20, 21, 47].
Diastolic Cardiac Function
The traditional assessment of diastolic and systolic LV
function by mitral inflow pattern and LV ejection fraction
has been largely superseded by parameters derived from
quantitative tissue Doppler imaging involving LV longitu-
dinal function during diastole and systole [48, 49] and
assessment of LV filling pressure [50, 51]. Assessment of
regional and global LV function in acute MI and LV
remodeling requires parameters that are feasible even in
overweight individuals at the bedside, are sensitive to energy
restraints, and, ideally, have prognostic value and the ability
to monitor therapeutic interventions. Early diastolic function
is more sensitive to changes in myocardial perfusion than
systolic function as shown in human and animal studies with
percutaneoustransluminal coronaryangioplasty, a model with
a precise onset and end of myocardial perfusion [52, 53].
Because the early diastolic filling period is short (approxi-
mately 100 ms), accurate measurement of early diastolic
velocity/function requires high temporal resolution of the
imaging technique (frame rate >100 frames/s), which is
provided by pulsed tissue Doppler and in high-quality color
Doppler systems, but not with MRI [27••]. Pulsed tissue
Doppler imaging has the additional advantage of online
velocity quantification based on fast Fourier transform
analysis and, importantly, has good feasibility even in
individuals who are difficult to image with 2-dimensional
echocardiography [54, 55]. Furthermore, the influence of
aging on diastolic function may be used to define diastolic
dysfunction [12, 27••], which is critical for the diagnosis of
diastolic HF and dysfunction [50, 51]. The advantages of
tissue Doppler–based velocity measurements should not
detract from advantages of other ultrasound techniques, such
as myocardial strain and strain rate analysis using speckle
tracking, which permits assessment of regional and global
myocardial function.
Microvascular and Endothelial Function
Myocardial contrast echocardiography, as described above,
is a technique yielding specific information on microvascular
myocardial perfusion at the bedside in the setting of acute MI,
after myocardial revascularization, and in endothelial dysre-
gulationfrominsulinresistance.Althoughstandardizedbythe
American and European Societies of Echocardiography [56,
57], myocardial contrast echocardiography has not yet found
acceptance into routine clinical practice. It needs the
commitment of clinicians to learn how to use this imaging
technology for diagnostic insight [18, 58••].
Myocardial metabolic remodeling as a consequence of
utilizing different substrates may be assessed by specialized
imaging techniques, such as single-photon emission com-
puted tomography, positron emission tomography, and
magnetic resonance spectroscopy [59]. Finally, endothelial
dysfunction and respective treatment effects may be
assessed by flow-mediated vasodilation [24].
Impact on Treatment Options
Nutrition
Adequate composition of food intake is the cornerstone of
managing nutritional disease, such as insulin resistance and
type 2 diabetes. The official recommendations in Europe
and the United States have consistently promoted food that
contained little fat (approximately 25%) and a substantial
amount of carbohydrates (45%–60%) [60, 61]. The result of
low fat and high carbohydrate consumption in the United
States is an increasingly obese population [62••]. The
results of the INTERHEART study [63] raised increasing
concerns about these recommendations and led to recon-
sideration of the physiologic principles of metabolism:
carbohydrate restriction improves glycemic control and
reduces insulin fluctuations, which both are primary targets
that do not need weight loss [64••, 65•] but improve all
features of the metabolic syndrome. Positive effects on
insulin resistance, serum triglyceride and HDL levels,
glucose control, and cardiovascular risk factors have been
consistently demonstrated without any adverse effects,
given the need to reduce antidiabetic medications stepwise
(by 50% to 80%) to avoid hypoglycemia. The beneficial
effects of low-carbohydrate diets have been confirmed in
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randomized long-term studies [66, 67]. Noteworthy, bene-
ficial effects of carbohydrate restriction on postmeal
endothelial dysfunction were demonstrated in individuals
with abdominal obesity and in those with atherogenic
dyslipidemia [68, 69].
Improved cardiac function by low-carbohydrate nutrition
in type 2 diabetes was shown in a pilot study or indirectly
via tight caloric restriction (400 kcal per day) in obese
individuals with diabetes [70, 71]. In severe obesity,
randomized long-term studies have confirmed improvement
in cardiac function after weight loss due to a low glycemic
index diet or bariatric surgery [72]. Large dietary studies
based on reduced caloric intake by increased vegetable
consumption have proven benefits for CAD risk [73].
Extendingtheirtraditionalrecommendations,theAmerican
Diabetes Association in 2008 stated that low–glycemic index
foods (ie, between 40 and 130 g/day of low-glycemic
carbohydrate or less than 26% of a nominal 2000 kcal diet)
that are rich in fiber and other macronutrients may improve
outcome [60].
There now is ample evidence that the nutritional therapy
in type 2 diabetes with insulin resistance should be
carbohydrate restriction. The available studies did not
reveal any associated harm. If such a straightforward
approach can alleviate a condition for which there is no
known effective drug, its potential should be vigorously
applied and explored.
Insulin Sensitizers
Because of the basic and adverse consequences of insulin
resistance in patients with diabetes, this review focuses on
insulin sensitizers such as biguanides, TZDs, and glucagon-
like peptide 1 (GLP-1).
Metformin has been associated with improved outcome
inboththe prospective United Kingdom ProspectiveDiabetes
StudyandinpatientswithdiabetesandHFinanobservational
Canadian study [74, 75]. More recently, it was shown to
improve LV diastolic function [76]. Unfortunately, the use of
metformin is contraindicated because of a perceived
increased risk of lactic acidosis in HF, although the
supporting evidence is lacking both for lactic acidosis and
for the policy of stopping metformin 48 h before and after
procedures in cardiac patients [77]. A recent meta-analysis
on the use of antidiabetic drugs in patients with HF
concluded that metformin was not associated with any
adverse events, but instead had a reduced mortality risk [78].
TZDs were designed to increase insulin sensitivity.
However, prospective studies are scarce because of the
warnings against the use of TZDs in patients with HF
symptoms [79]. More recent data suggest that these risks
are controllable and acceptable, being in the range of 5% to
15% for TZD-induced fluid retention that is part of the
insulin-sensitizing action in the renal collecting ducts, but
not necessarily a symptom of worsening myocardial
function [80]. In patients with diabetes without cardiac
disease, diastolic function was improved by pioglitazone in
an MRI study [81]. In patients with HF (New York Heart
Association class I–II), rosiglitazone improved glycemic
control and did not adversely affect LV ejection fraction
[82]. Observational data and a retrospective study reported
some reduction in the risk of death despite a smaller
increase in the risk of readmission for HF by the use of
TZDs [83, 84]. Recently, concerns have been raised
regarding the cardiovascular side effects of rosiglitazone,
which now is available in the United States with additional
restrictions but is not available any more in Europe.
First promising results were shown by GLP-1, which is
secreted in the intestine in response to oral ingestion of
glucose and stimulates insulin secretion, suppresses gluca-
gon secretion, delays gastric emptying, and increases
satiety. Because of its short half-life (1–2 min) due to
cleavage by the ubiquitous dipeptidyl peptidase-4 (DPP-4),
long-acting analogues of GLP-1 (exenatide, liraglutide) and
inhibitors of DPP-4 (sitagliptin, vildagliptin, saxagliptin,
linagliptin, and alogliptin) have been developed.
GLP-1 does not cause hypoglycemia and has promising
effects on the cardiovascular system. Nitric oxide–depen-
dent endothelial function is increased in healthy individuals
and in patients with diabetes [85, 86]. Both GLP-1 and its
analogue exenatide reduce ischemia/reperfusion injury in
experimental studies. There are small human studies
demonstrating beneficial effects of GLP-1 on LV ejection
fraction in ST-elevation anterior MI with LV dysfunction
after successful reperfusion [87]; in coronary artery
bypass grafting [88]; and in HF [89]. Also, the use of
DPP-4 inhibitors demonstrated beneficial effects on
postprandial glycemia, lipidemia, and oxidative stress in
patients with type 2 diabetes [90, 91] and, after a single
morning dose, on postprandial endothelial function [92].
DPP-4 inhibitors administered before an oral load of
glucose, 75 g, demonstrated improved LV performance
and mitigated stunning during dobutamine stress in
patients with CAD, but undefined as for coexisting
diabetes [93]. Further studies are needed to determine
whether synthetic GLP-1 mimetics and DPP-4 inhibitors
are able to reproduce the beneficial effects of GLP-1.
Some answers may be expected from ongoing studies on
cardiovascular outcomes in patients with diabetes with
GLP-1 analogues or DPP-4 inhibitors. These studies focus
on diabetic metabolism (efficacy of lowering blood
glucose in coronary care unit or of maintaining β-cell
function), on the limitation of infarct size in acute
coronary syndrome, or on global myocardial function in
combination with granulocyte-colony stimulating factor
and cardiovascular risk.
246Curr Heart Fail Rep (2011) 8:242–251