Abstract

Patients with diabetes exhibit an increased risk for cardiovascular complications, such as acute coronary syndromes, stroke, heart failure, or arrhythmias, as diabetes facilitates changes in the cardiovascular system of these patients. Atherosclerotic lesions have long been recognized as a cause for these events. However, recent findings support the idea that alterations in the circulating blood and the myocardium may be equally or even more important contributors to the development of life-threatening cardiovascular events in patients with diabetes. These alterations in the myocardium, vasculature, and blood characterize the vulnerable patient; the patient with diabetes at high risk for the development of cardiovascular complications. In this overview, we describe the changes that lead to vulnerability and summarize the current understanding of the pathophysiological mechanisms that contribute to the elevated risk for cardiovascular events in patients with diabetes.

Introduction

Patients with diabetes exhibit an increased propensity for cardiovascular complications, such as acute coronary syndromes, stroke, heart failure, or arrhythmias. For decades, arteriosclerotic lesions, as well as alterations in vascular blood flow, have been recognized as the main causes for the development of these cardiovascular events, but recent data suggest that additional pathophysiological mechanisms are equally or perhaps even more important for the onset and the clinical course of such complications. Thus, our current understanding is driven by the recognition that these potentially life-threatening events are caused not only by vascular changes but also by alterations in the nature of the circulating blood and the myocardium.1 As such, these three components—vulnerable vessel, vulnerable blood, and vulnerable myocardium—characterize what is today referred to as the vulnerable patient, who is defined as a patient with a high risk for the development of cardiovascular complications (Figure 1).1 The present overview will elaborate on these changes and summarize our current understanding of the pathophysiological mechanisms that are contributing to the elevated risk of patients with diabetes developing cardiovascular events.

Figure 1

The vulnerable patient with diabetes. Vulnerable vessel, vulnerable blood, and vulnerable myocardium characterize the vulnerable patient—a patient with a high risk for the development of cardiovascular complications.

Figure 1

The vulnerable patient with diabetes. Vulnerable vessel, vulnerable blood, and vulnerable myocardium characterize the vulnerable patient—a patient with a high risk for the development of cardiovascular complications.

Vulnerable vessel

For decades, atherogenesis, which is characterized by remodelling of arteries and results in subendothelial accumulation of fatty compounds (plaques), was viewed as a progressive disease of the vessel wall, leading to the reduction in the lumen diameter to a point such that a few activated platelets would be sufficient to occlude the vessel and result in an acute myocardial infarction. Data from pathologists questioned that concept by suggesting that most myocardial infarctions are caused by low-grade stenoses.2 In addition, two types of atherosclerotic lesions (atherosclerotic plaques) were identified; namely, stable plaques, which lead to high-grade obstruction, and unstable plaques (also known as vulnerable plaques), which both result in increased vulnerability and a high incidence of thrombi.3 Thus, the understanding of atherogenesis has evolved and, currently, the development of an atherosclerotic lesion is considered to be a multistage inflammatory process (Figure 2).4–6 The early stage is characterized by so-called endothelial dysfunction. Under the influence of specific risk factors, such as hyperglycaemia, as well as the direct interaction of adipose tissue-derived inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), the endothelium is activated.7 The resultant expression of adhesion molecules and the release of inflammatory mediators and chemokines facilitate the recruitment of inflammatory cells like monocytes and CD4-positive lymphocytes.8 These cells then enter the vessel wall and orchestrate the inflammatory response in the vessel wall through activation and interaction with molecules such as oxidized low-density lipoproteins (LDLs). Furthermore, the disturbance of endothelial function is associated with a reduction in the release of nitric oxide (NO), a mediator of protective effects (reduced vessel constriction, lower LDL levels, and reduced platelet aggregation) in the vessel wall. Interestingly, hyperglycaemia is associated with an imbalance between NO and peroxynitrite levels as well as a decrease in NO production.7 The impaired release of NO can be used clinically to assess endothelial dysfunction in patients. It has been shown that patients with impaired glucose tolerance and those with manifest diabetes present with impaired flow-mediated, endothelium-dependent vasodilation, suggesting the presence of endothelial dysfunction in these patients.9,10 In fact, endothelium-dependent vasodilation has been shown to predict future cardiovascular events, underscoring the importance of this early stage for further lesion development.11

Figure 2

Vulnerable vessel. Hyperglycaemia, adipose tissue-derived inflammation, as well as various cardiovascular risk factors influence all phases of atherogenesis in patients with diabetes, thus contributing to the development of complicated lesions that are prone to rupture and cause an acute coronary event. VSMC, vascular smooth muscle cells.

Figure 2

Vulnerable vessel. Hyperglycaemia, adipose tissue-derived inflammation, as well as various cardiovascular risk factors influence all phases of atherogenesis in patients with diabetes, thus contributing to the development of complicated lesions that are prone to rupture and cause an acute coronary event. VSMC, vascular smooth muscle cells.

Once inflammatory cells enter the vessel wall, monocytes differentiate to macrophages and foam cells, while T cells, which are mainly CD4-positive cells, transform towards Th1 cells, leading to the release of additional proinflammatory mediators, such as TNF-α, IL-2, and interferon-gamma (IFN-γ).6 At this stage, called fatty streak formation, vascular smooth muscle cells proliferate and migrate from the media into the developing lesion to further promote lesion development. Experimental data suggest that glucose increases smooth muscle cell proliferation and migration, the latter most likely through induction of osteopontin expression.12 Moreover, platelet hyperactivity that is associated with diabetes is thought to also contribute to lesion extension at this stage.4 In the next phase, advanced and potentially complicated lesions develop. Through apoptosis and cell death, as well as through an increase in proteolytic activity and lipid accumulation, the so-called necrotic lipid core of the plaque is formed. This necrotic core is covered by a protective fibrous cap consisting of vascular smooth muscle cells and extracellular matrix—mostly collagen and elastin. Stable plaques can convert to unstable plaques, which are characterized by a large necrotic lipid core, infiltration of inflammatory cells, and a thin and vulnerable fibrous cap.13 Advanced plaques from patients with diabetes exhibit the characteristic features of vulnerable plaques by containing many macrophages and T cells, a large necrotic lipid core, pronounced neovascularization in the adventitia, and a high incidence of thrombi.14 Moreover, the advanced plaques of patients with diabetes demonstrate higher expression of pro-coagulatory molecules, such as tissue factor (TF), as well as high levels of matrix-degrading enzymes, such as matrix metalloproteinases.15 Therefore, plaques from patients with diabetes exhibit a high susceptibility for rupture and are more likely to induce thromboembolic events.

The understanding of plaque rupture as the main cause of acute myocardial infarctions has been furthered by post-mortem observations that have shown that culprit lesions from patients with acute myocardial infarctions demonstrate ruptured fibrous caps with subsequent activation of the coagulation cascade and formation of an occluding or non-occluding thrombus.16 Recent data employing novel techniques, such as intravascular ultrasound with virtual histology (IVUS-VH), confirmed these pathophysiological findings by showing that a longer duration of diabetes was associated with thin-cap fibroatheroma (TCFA), a plaque phenotype associated with the risk of rupture and coronary events, as defined by IVUS-VH.17 Moreover, TCFA was more common in the most diseased segments of patients with diabetes compared with those without diabetes. Multivariate adjustment demonstrated the presence of diabetes as an independent predictor of TCFA defined by IVUS-VH,18 bolstering the concept that vulnerable plaques with subsequent plaque rupture are more common in patients with diabetes than in those without diabetes.

The concept of plaque rupture as the main and sole cause of an acute myocardial infarction has been challenged by data that suggest that additional ruptured plaques that are distinct from the culprit lesion can be found in patients with an acute coronary syndrome.19 These results suggest that plaque rupture alone may not be sufficient to cause acute coronary syndrome. This finding has shifted our understanding of the cause of coronary events from being due solely to vulnerable plaque to considering the role of the vulnerable patient, including vulnerable blood and vulnerable myocardium.

Vulnerable blood

Vulnerable blood describes components of the blood, such as inflammatory mediators, altered platelet function, hypercoagulability, and hypofibrinolysis, as well as microparticles (MPs) that may contribute to cardiovascular events (Figure 3).1

Figure 3

Vulnerable blood. Components of the prothrombotic risk cluster in diabetes mellitus—including platelet dysfunction, denser fibrin clot structure and hypofibrinolysis, increase in microparticles, and inflammation—are leading to alterations summarized as vulnerable blood. Platelet dysfunction in diabetes is induced by metabolic changes, oxidative stress, and endothelial dysfunction. The development of a compact and dense fibrin clot structure that is more difficult to lyse and is associated with an increased cardiovascular risk is induced by hyperglycaemia and elevation of components of the coagulation cascade. In addition, microparticles are also increased. Furthermore, the underlying inflammation milieu in diabetes does increase all processes enhancing the prothrombotic risk cluster. FVIII, factor VIII; IFN-γ, interferon gamma; IL-6, interleukin 6; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; vWF, von Willebrand factor.

Figure 3

Vulnerable blood. Components of the prothrombotic risk cluster in diabetes mellitus—including platelet dysfunction, denser fibrin clot structure and hypofibrinolysis, increase in microparticles, and inflammation—are leading to alterations summarized as vulnerable blood. Platelet dysfunction in diabetes is induced by metabolic changes, oxidative stress, and endothelial dysfunction. The development of a compact and dense fibrin clot structure that is more difficult to lyse and is associated with an increased cardiovascular risk is induced by hyperglycaemia and elevation of components of the coagulation cascade. In addition, microparticles are also increased. Furthermore, the underlying inflammation milieu in diabetes does increase all processes enhancing the prothrombotic risk cluster. FVIII, factor VIII; IFN-γ, interferon gamma; IL-6, interleukin 6; PAI-1, plasminogen activator inhibitor 1; TF, tissue factor; vWF, von Willebrand factor.

Inflammation in atherothrombosis

Several studies demonstrated that diabetic patients without prior cardiovascular disease have the same rate of myocardial infarction as non-diabetic patients who have had previous events,20–22 thereby highlighting the high risk of the diabetic population. The so-called ‘common soil’ hypothesis, originally put forward by Stern,23 suggested that diabetes and cardiovascular disease are created by a low-grade inflammatory milieu, which is causative for insulin resistance and vascular plaque formation.24,25 Inflammation can alter all processes that underlie the development of atherothrombosis in the vessel wall as described previously. However, the interaction between inflammation and coagulation is not limited to the site of vessel injury but can similarly be detected in the adipose tissue of obese patients. Visceral adipose tissue is a major source for inflammatory activity resulting from activated T-lymphocytes26 and macrophages,27,28 which, in conjunction with adipocytes, produce inflammatory cytokines, including IFN-γ,29 monocyte chemotactic protein-1, TNF-α, IL-6, and plasminogen activator inhibitor (PAI)-1, a fibrinolytic inhibitor.30 These inflammatory stimuli induce the expression of fibrinogen which, together with elevated PAI-1 levels, forms a systemic prothrombotic milieu.31–41 The interaction between inflammation, platelet dysfunction, and hypercoagulability/hypofibrinolysis is discussed in more detail in the next section.

Altered platelet function

Activation and aggregation of platelets—critical initial steps following plaque rupture—are accelerated under diabetic conditions. Platelets respond more frequently to sub-threshold stimuli under hyperglycaemic conditions, which increase their turnover and result in an accelerated thrombopoiesis of fresh and hyper-reactive platelets in diabetes.42 This platelet dysfunction is related to several mechanisms, including metabolic changes, oxidative stress, and endothelial dysfunction.43

Hyperglycaemia induces thromboxane synthesis,44 which mimics the state of activated platelets exposed to high shear stress conditions.45 Furthermore, hyperglycaemia causes increased superoxide production, which decreases NO release and impairs calcium homeostasis as a consequence of oxidative stress.46–48 In addition, hyperglycaemia leads to non-enzymatic glycosylation of platelet membrane proteins, which may change protein structure and conformation, thereby altering platelet function. Insulin binding to its receptor reduces platelet reactivity by inhibiting P2Y12 signalling,49 whereas insulin resistance promotes platelet aggregation and pro-coagulant activity.50

Hypercoagulability and hypofibrinolysis

A variety of studies report alterations of the coagulation system in patients with diabetes mellitus. TF is the key initiator of the coagulation cascade as it binds to factor VIIa, leading to the activation of factors IX and X and resulting in thrombus formation.51 TF levels are elevated under diabetic conditions as a consequence of the inflammatory milieu, hyperglycaemia, and oxidative stress.52–55 von Willebrand factor (vWF) is selectively expressed in platelets and endothelial cells and promotes the adhesion of thrombocytes to the vascular wall in zones of endothelial damage where it serves as a carrier protein for factor VIII. Both coagulation factors are up-regulated under inflammatory conditions, with elevated circulating levels that are associated with diabetes and cardiovascular disease.56–60 In addition, elevated levels of fibrinogen further contribute to the pro-coagulatory milieu in patients with diabetes.61–63 Non-enzymatic glycation of fibrinogen under hyperglycaemic conditions leads to the formation of a tight and rigid fibrin network,64–67 which was previously shown to be associated with an increased risk for myocardial infarction.68,69 These changes impair the fibrinolytic function of plasmin on the clot surface and slow thrombus lysis.64 Furthermore, PAI-1, the inhibitor of fibrinolysis, is elevated in patients with diabetes mellitus and independently associated with cardiovascular risk.38,70,71 PAI-1 expression is induced by a variety of stimuli, including inflammatory cytokines, insulin, very low LDL, and free-fatty acids, all of which extensively present in diabetes mellitus.72–79 In addition, increased levels of tissue plasminogen activator (t-PA) have been observed in patients with diabetes.80,81 Given that t-PA activates plasminogen and is thus responsible for the fibrinolysis of fibrin clots, elevated t-PA levels could have a beneficial effect. However, several studies have demonstrated an association between elevated t-PA levels and cardiovascular disease.82–85

Microparticles

MPs are vesicles that are released from various cell types, including platelets, endothelial cells, and leucocytes, following activation or apoptosis. MPs vary in size (0.2–1 µm) and, depending on their origin, in membrane composition of phospholipids and proteins. Once they are released into the circulation, they bind and fuse with their target cells through receptor–ligand interaction and act as biological vectors, which modulate inflammatory and coagulation reactions.86,87

Platelet-derived MPs, the first species identified, carry both phospholipids and TF (considered to be the main initiators of blood coagulation) on their outer membrane. TF has also been identified as a component of MPs from monocytes/macrophages, leucocytes, and endothelial cells.88 In addition, it has been demonstrated that MPs can also harbour and transport microRNA, a class of small non-coding RNA that binds to messenger RNA, to act as endogenous post-translational gene regulators and thereby influence protein expression of the target cells.89,90 Interestingly, elevated circulating levels of various MPs are found in patients with diabetes mellitus.91,92 Analyses of MPs from patients with diabetes revealed elevated numbers of TF-bearing MPs compared with healthy controls. More specifically, patients with diabetes exhibited higher percentages of TF-positive MPs from T-helper cells, granulocytes, and platelets; these correlated with parameters of the metabolic syndrome,93 suggesting a role for MPs in the genesis of the prothrombotic profile in diabetes.

Vulnerable myocardium

Vulnerable myocardium is a term used to describe that the myocardium can contribute to both the development of acute coronary syndrome and of heart failure (Figure 4). In the setting of acute coronary syndrome, occlusion of the left anterior descending artery in one patient may cause a silent myocardial infarction, whereas occlusion of a small arterial side branch in another patient may lead to sudden cardiac death. These differences suggest that various components within the myocardium may contribute to the clinical course of this potentially life-threatening event. The different components of the vulnerable myocardium are relatively unexplored, but some markers that characterize myocardial vulnerability have been defined. Current thinking suggests that there are markers associated with atherosclerosis-derived ischaemia, such as electrocardiogram abnormalities, perfusion and viability disorders, as well as wall-motion abnormalities. These markers can be distinguished from those independent of atherosclerosis-derived ischaemia, such as sympathetic hyperactivity, left ventricular hypertrophy, or other electrophysiological disorders.94 In patients with diabetes, these components appear to be of crucial importance in the context of cardiac events.

Figure 4

Vulnerable myocardium. Alterations in cardiac metabolism with cellular insulin resistance and a shift in substrate utilization form glucose to fatty acid oxidation leading to increased oxygen demand and reactive oxygen production as a cause for cardiomyocyte apoptosis and fibrosis. This is paralleled by AGE deposition, endothelial dysfunction, and microangiopathy, which, in conjunction with neuropathy and repolarization disorders, cause a state of vulnerability to external stressors, including ischaemia and electrolyte imbalance. AGE, advanced glycation end-products; Ca, calcium; NO, nitric oxide; ROS, reactive oxygen species.

Figure 4

Vulnerable myocardium. Alterations in cardiac metabolism with cellular insulin resistance and a shift in substrate utilization form glucose to fatty acid oxidation leading to increased oxygen demand and reactive oxygen production as a cause for cardiomyocyte apoptosis and fibrosis. This is paralleled by AGE deposition, endothelial dysfunction, and microangiopathy, which, in conjunction with neuropathy and repolarization disorders, cause a state of vulnerability to external stressors, including ischaemia and electrolyte imbalance. AGE, advanced glycation end-products; Ca, calcium; NO, nitric oxide; ROS, reactive oxygen species.

Chronic heart failure affects one in five patients with diabetes, leading to greater than four times the risk observed in the general population.95–97 This increased risk can be at least partially attributed to a clustering of cardiovascular risk factors, including obesity and hypertension, leading to coronary artery disease and subsequent ischaemic cardiomyopathy. In addition, a significant subset of patients with diabetes acquires pathophysiologically distinct impairment of cardiac function (i.e. diabetic cardiomyopathy) during the course of the disease. The pathophysiology of this alteration in myocardial function is not completely understood, but it can be attributed to metabolic derangements of the cardiomyocytes, which are similarly found in lean type I and obese type II diabetic individuals.98 Diabetes induces a variety of functional, structural, and metabolic abnormalities of the heart that cause cardiac hypertrophy, myocardial stiffness, and impaired diastolic function, which ultimately result in global heart failure.99 The incidence of heart failure is associated with the effectiveness of glucose control, suggesting that hyperglycaemia is either a disease-driving risk factor or a surrogate marker for insulin resistance.98,100,101 Insulin resistance of the cardiomyocyte causes a shift in energetic substrate utilization from glucose to fatty acid oxidation.102 This metabolic shift impairs the energetic flexibility of the cardiomyocyte and increases its oxygen demand.103 Fatty acid oxidation thereby requires more oxygen to produce an equivalent amount of adenosine triphosphate (ATP) as reached by glucose oxidation. The oxygen demand of the diabetic heart is further increased by mitochondrial uncoupling reactions, which contribute to an inefficient energy production.104 Consequently, the hearts of patients with diabetes rely more heavily on sufficient oxygen supply when compared with those of patients without diabetes, and they are more vulnerable to ischaemia, resulting in larger myocardial infarct sizes when challenged with comparable ischaemic stimuli compared with patients without diabetes.105 This is endangered in the presence of microvascular disease, which often coincides in patients with diabetes.106 Diabetic microangiopathy is the consequence of endothelial dysfunction and deposition of advanced glycation end-product (AGE), leading to impaired vascular capacity to increase blood flow under extensive tissue demand, which also gets further reduced under hypoglycaemic conditions.107,108 Endothelial dysfunction is attributable to decreased endothelial NO release as a consequence of oxidative stress.109,110 Reactive oxygen species are formed by the mitochondria in response to increased metabolic flux and fatty acid oxidation, in addition to AGE formation.111 Furthermore, AGEs are created by non-enzymatic glycosylation of structural and functional proteins under hyperglycaemic conditions, which directly alters protein integrity and activates inflammatory pathways via binding to the pattern recognition AGE receptor.112

Oxidative stress is directly linked with cardiomyocyte death and cellular apoptosis.113 This causes remodelling reactions with deposition of extracellular and intracellular matrix proteins and interstitial fibrosis.114 The resulting ventricular stiffness and cardiac hypertrophy impairs diastolic relaxation as detected by abnormal mitral valve inflow patterns as an early sign of diabetic cardiomyopathy.115 Ventricular relaxation further depends on a rapid diastolic cycling of cytosolic calcium to the endoplasmic reticulum.116,117 This process is impaired in the diabetic myocardium owing to decreased expression of relevant calcium transporters, including sarco/endoplasmic reticulum calcium ATPase (SERCA2), impaired cellular energy homeostasis, and functional abnormalities of contractile microfilaments.108,118 The consecutive diastolic calcium overload prolongs cardiac repolarization and the QT interval.119 This makes the heart vulnerable to early repolarization events as potential triggers for ventricular tachycardia. Accordingly, patients with diabetes display prolonged QT intervals, which independently predict sudden cardiac death and mortality.120,121 A variety of conditions coincide with diabetes mellitus that can contribute to rhythm instability and QT prolongation, including cardiac hypertrophy, myocardial infarction, and hypoglycaemia.121 Hypoglycaemia causes sympathoadrenergic activation, electrolyte disturbance, and pro-coagulatory, inflammatory reactions, which have been associated with increased clinical events.121 Moreover, impairment of the myocardial autonomic nervous regulation further increases the vulnerability of the heart.122 This is part of diabetic polyneuropathy, which is similarly dependent on hyperglycaemia-induced oxidative stress, AGE formation, and microangiopathy.123 As diabetic neuropathy primarily affects long nerve fibres, the vagus nerve, which is the longest autonomic nerve of the body, is affected early.122 This causes parasympathetic myocardial denervation with an accelerated sympathetic tone, leading to sinus tachycardia and impaired heart rate variability as well as inefficient energy demand. The clinical relevance of disturbance of the autonomic nerve system becomes apparent by a two- to three-fold increase in risk for sudden cardiac death in the presence of cardiac autonomic neuropathy.122 Damage of sensual nerve fibres can detach the heart from pain perception and lead to silent myocardial ischaemia and infarction with consequential inappropriate therapeutic actions in a state of unawareness.124

The vulnerable myocardium is, therefore, characterized by an altered metabolic state in conjunction with neural and vascular impairment, which increases its susceptibility to external stressors, including ischaemia, hypoglycaemia, and electrolyte imbalance. This leads to increased risk and worse outcomes for clinical events, including myocardial infarction and rhythm disorders, which all contribute to the impaired prognosis of the diabetic population.125

Summary

The recognition that cardiovascular risk in patients with diabetes is determined not only by the vulnerable vessel but also by components of the vulnerable blood and the vulnerable myocardium has major implications for future research and therapeutic developments. To achieve a more precise and accurate risk stratification in patients with diabetes in the future, novel risk markers should be identified, taking into account all three components of the vulnerable patient. As previously suggested, the ideal way to screen and assess a patient's vulnerability should include an inexpensive, relatively non-invasive, widely available, and readily applicable method in an asymptomatic population that is capable of adding predictive value to the established risk factors.94 Given the increasing healthcare burden of diabetes, both small trials and analyses from large cohort studies should focus on the development of screening tools to identify high-risk individuals. Moreover, therapeutic strategies to reduce cardiovascular risk in patients with diabetes should consider new treatment options for all three components of the vulnerable patient, paving the way for a more integrated approach to preventing cardiovascular events in this high-risk population.

Funding

This article is supported by grants from the Deutsche Forschungsgemeinschaft (MA 2047/ 4-1 to N.M., HE 5666/1-1 to K.H., LE1350/3-1) from the European Foundation for the Study of Diabetes to N.M. and M.L., and the Novartis-Stiftung für therapeutische Forschung to N.M., as well as from the Stiftung der Herzkranke Diabetiker to K.H. Editorial assistance was provided by Scientific Connexions (Newtown, PA, USA), funded by Bristol-Myers Squibb (Princeton, NJ, USA) and AstraZeneca (Wilmington, DE, USA).

Conflict of interest: N.M. served as a speaker for AstraZeneca, Berlin Chemie, Bristol-Myers Squibb, NovoNordisk, Merck Sharp and Dohme, Boehringer Ingelheim, Roche, and GlaxoSmithKline and as an advisor to GlaxoSmithKline, Merck Sharp and Dohme, Boehringer Ingelheim, Bristol-Myers Squibb, NovoNordisk, Roche, and AstraZeneca. M.L. served as a speaker for NovoNordisk, Merck Sharp and Dohme, Boehringer Ingelheim, Roche, and Sanofi-Aventis, and received grant support from Merck Sharp and Dohme.

References

1
Naghavi
M
Libby
P
Falk
E
Casscells
SW
Litovsky
S
Rumberger
J
Badimon
JJ
Stefanadis
C
Moreno
P
Pasterkamp
G
Fayad
Z
Stone
PH
Waxman
S
Raggi
P
Madjid
M
Zarrabi
A
Burke
A
Yuan
C
Fitzgerald
PJ
Siscovick
DS
de Korte
CL
Aikawa
M
Juhani Airaksinen
KE
Assmann
G
Becker
CR
Chesebro
JH
Farb
A
Galis
ZS
Jackson
C
Jang
IK
Koenig
W
Lodder
RA
March
K
Demirovic
J
Navab
M
Priori
SG
Rekhter
MD
Bahr
R
Grundy
SM
Mehran
R
Colombo
A
Boerwinkle
E
Ballantyne
C
Insull
W
Jr
Schwartz
RS
Vogel
R
Serruys
PW
Hansson
GK
Faxon
DP
Kaul
S
Drexler
H
Greenland
P
Muller
JE
Virmani
R
Ridker
PM
Zipes
DP
Shah
PK
Willerson
JT
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I
Circulation
 , 
2003
, vol. 
108
 (pg. 
1664
-
1672
)
2
Falk
E
Shah
PK
Fuster
V
Coronary plaque disruption
Circulation
 , 
1995
, vol. 
92
 (pg. 
657
-
671
)
3
Davies
MJ
Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White lecture 1995
Circulation
 , 
1996
, vol. 
94
 (pg. 
2013
-
2020
)
4
Ross
R
Atherosclerosis—an inflammatory disease
N Engl J Med
 , 
1999
, vol. 
340
 (pg. 
115
-
126
)
5
Libby
P
Molecular bases of the acute coronary syndromes
Circulation
 , 
1995
, vol. 
91
 (pg. 
2844
-
2850
)
6
Hansson
GK
Inflammation, atherosclerosis, and coronary artery disease
N Engl J Med
 , 
2005
, vol. 
352
 (pg. 
1685
-
1695
)
7
Xu
J
Zou
MH
Molecular insights and therapeutic targets for diabetic endothelial dysfunction
Circulation
 , 
2009
, vol. 
120
 (pg. 
1266
-
1286
)
8
Morigi
M
Angioletti
S
Imberti
B
Donadelli
R
Micheletti
G
Figliuzzi
M
Remuzzi
A
Zoja
C
Remuzzi
G
Leukocyte–endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a nf-kb-dependent fashion
J Clin Invest
 , 
1998
, vol. 
101
 (pg. 
1905
-
1915
)
9
Balletshofer
B
Rittig
K
Stock
J
Lehn-Stefan
A
Overkamp
D
Dietz
K
Häring
H
Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness
Atherosclerosis
 , 
2003
, vol. 
171
 (pg. 
303
-
309
)
10
Balletshofer
BM
Rittig
K
Enderle
MD
Volk
A
Maerker
E
Jacob
S
Matthaei
S
Rett
K
Haring
HU
Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance
Circulation
 , 
2000
, vol. 
101
 (pg. 
1780
-
1784
)
11
Schachinger
V
Zeiher
AM
Prognostic implications of endothelial dysfunction: does it mean anything?
Coron Artery Dis
 , 
2001
, vol. 
12
 (pg. 
435
-
443
)
12
Maile
LA
Capps
BE
Ling
Y
Xi
G
Clemmons
DR
Hyperglycemia alters the responsiveness of smooth muscle cells to insulin-like growth factor-I
Endocrinology
 , 
2007
, vol. 
148
 (pg. 
2435
-
2443
)
13
Hansson
GK
Jonasson
L
Lojsthed
B
Stemme
S
Kocher
O
Gabbiani
G
Localization of T lymphocytes and macrophages in fibrous and complicated human atherosclerotic plaques
Atherosclerosis
 , 
1988
, vol. 
72
 (pg. 
135
-
141
)
14
Moreno
PR
Purushothaman
KR
Fuster
V
Echeverri
D
Truszczynska
H
Sharma
SK
Badimon
JJ
O'Connor
WN
Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: Implications for plaque vulnerability
Circulation
 , 
2004
, vol. 
110
 (pg. 
2032
-
2038
)
15
Moreno
PR
Murcia
AM
Palacios
IFL
Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus
Circulation
 , 
2000
, vol. 
102
 (pg. 
2180
-
2184
)
16
Falk
E
Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi
Br Heart J
 , 
1983
, vol. 
50
 (pg. 
127
-
134
)
17
Lindsey
JB
House
JA
Kennedy
KF
Marso
SP
Diabetes duration is associated with increased thin-cap fibroatheroma detected by intravascular ultrasound with virtual histology
Circ Cardiovasc Interv
 , 
2009
, vol. 
2
 (pg. 
543
-
548
)
18
Marso
SP
House
JA
Klauss
V
Lerman
A
Margolis
P
Leon
MB
Diabetes mellitus is associated with plaque classified as thin cap fibroatheroma: an intravascular ultrasound study
Diab Vasc Dis Res
 , 
2010
, vol. 
7
 (pg. 
14
-
19
)
19
Rioufol
G
Finet
G
Ginon
I
Andre-Fouet
X
Rossi
R
Vialle
E
Desjoyaux
E
Convert
G
Huret
JF
Tabib
A
Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study
Circulation
 , 
2002
, vol. 
106
 (pg. 
804
-
808
)
20
Haffner
SM
Lehto
S
Ronnemaa
T
Pyorala
K
Laakso
M
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction
N Engl J Med
 , 
1998
, vol. 
339
 (pg. 
229
-
234
)
21
Malmberg
K
Yusuf
S
Gerstein
HC
Brown
J
Zhao
F
Hunt
D
Piegas
L
Calvin
J
Keltai
M
Budaj
A
Investigators
OR
Impact of diabetes on long-term prognosis in patients with unstable angina and non-q-wave myocardial infarction results of the OASIS (organization to assess strategies for ischemic syndromes) registry
Circulation
 , 
2000
, vol. 
102
 (pg. 
1014
-
1019
)
22
Donahoe
SM
Stewart
GC
McCabe
CH
Mohanavelu
S
Murphy
SA
Cannon
CP
Antman
EM
Diabetes and mortality following acute coronary syndromes
JAMA
 , 
2007
, vol. 
298
 (pg. 
765
-
775
)
23
Stern
MP
Diabetes and cardiovascular disease. The ‘common soil’ hypothesis
Diabetes
 , 
1995
, vol. 
44
 (pg. 
369
-
374
)
24
Duncan
BB
Schmidt
MI
Pankow
JS
Ballantyne
CM
Couper
D
Vigo
A
Hoogeveen
R
Folsom
AR
Heiss
G
Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study
Diabetes
 , 
2003
, vol. 
52
 (pg. 
1799
-
1805
)
25
Festa
A
D'Agostino
R
Jr
Tracy
RP
Haffner
SM
Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study
Diabetes
 , 
2002
, vol. 
51
 (pg. 
1131
-
1137
)
26
Kintscher
U
Hartge
M
Hess
K
Foryst-Ludwig
A
Clemenz
M
Wabitsch
M
Fischer-Posovszky
P
Barth
TF
Dragun
D
Skurk
T
Hauner
H
Bluher
M
Unger
T
Wolf
AM
Knippschild
U
Hombach
V
Marx
N
T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
1304
-
1310
)
27
Weisberg
SP
McCann
D
Desai
M
Rosenbaum
M
Leibel
RL
Ferrante
AW
Jr
Obesity is associated with macrophage accumulation in adipose tissue
J Clin Invest
 , 
2003
, vol. 
112
 (pg. 
1796
-
1808
)
28
Xu
H
Barnes
GT
Yang
Q
Tan
G
Yang
D
Chou
CJ
Sole
J
Nichols
A
Ross
JS
Tartaglia
LA
Chen
H
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
J Clin Invest
 , 
2003
, vol. 
112
 (pg. 
1821
-
1830
)
29
Rocha
VZ
Folco
EJ
Sukhova
G
Shimizu
K
Gotsman
I
Vernon
AH
Libby
P
Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity
Circ Res
 , 
2008
, vol. 
103
 (pg. 
467
-
476
)
30
Suganami
T
Nishida
J
Ogawa
Y
A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha
Arterioscler Thromb Vasc Biol
 , 
2005
, vol. 
25
 (pg. 
2062
-
2068
)
31
Rosenson
RS
Koenig
W
Utility of inflammatory markers in the management of coronary artery disease
Am J Cardiol
 , 
2003
, vol. 
92
 (pg. 
10i
-
18i
)
32
Ajjan
R
Grant
PJ
Futers
TS
Brown
JM
Cymbalista
CM
Boothby
M
Carter
AM
Complement c3 and c-reactive protein levels in patients with stable coronary artery disease
Thromb Haemost
 , 
2005
, vol. 
94
 (pg. 
1048
-
1053
)
33
Ajjan
RA
Standeven
KF
Khanbhai
M
Phoenix
F
Gersh
KC
Weisel
JW
Kearney
MT
Ariëns
RA
Grant
PJ
Effects of aspirin on clot structure and fibrinolysis using a novel in vitro cellular system
Arterioscler Thromb Vasc Biol
 , 
2009
, vol. 
29
 (pg. 
712
-
717
)
34
Pradhan
AD
Manson
JE
Rifai
N
Buring
JE
Ridker
PM
C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus
JAMA
 , 
2001
, vol. 
286
 (pg. 
327
-
334
)
35
Barzilay
JI
Abraham
L
Heckbert
SR
Cushman
M
Kuller
LH
Resnick
HE
Tracy
RP
The relation of markers of inflammation to the development of glucose disorders in the elderly: the cardiovascular health study
Diabetes
 , 
2001
, vol. 
50
 (pg. 
2384
-
2389
)
36
Freeman
DJ
Norrie
J
Caslake
MJ
Gaw
A
Ford
I
Lowe
GD
O'Reilly
DS
Packard
CJ
Sattar
N
West of scotland coronary prevention study. C-reactive protein is an independent predictor of risk for the development of diabetes in the west of Scotland coronary prevention study
Diabetes
 , 
2002
, vol. 
51
 (pg. 
1596
-
1600
)
37
Spranger
J
Kroke
A
Möhlig
M
Hoffmann
K
Bergmann
MM
Ristow
M
Boeing
H
Pfeiffer
A
Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based european prospective investigation into cancer and nutrition (EPIC)-Potsdam study
Diabetes
 , 
2003
, vol. 
52
 (pg. 
812
-
817
)
38
Juhan-Vague
I
Roul
C
Alessi
MC
Ardissone
JP
Heim
M
Vague
P
Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients—relationship with plasma insulin
Thromb Haemost
 , 
1989
, vol. 
61
 (pg. 
370
-
373
)
39
Collier
A
Rumley
A
Rumley
A
Paterson
JR
Leach
JP
Lowe
GD
Small
M
Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria
Diabetes
 , 
1992
, vol. 
41
 (pg. 
909
-
913
)
40
McGill
JB
Schneider
DJ
Arfken
CL
Lucore
CL
Sobel
BE
Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients
Diabetes
 , 
1994
, vol. 
43
 (pg. 
104
-
109
)
41
Aso
Y
Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis
Front Biosci
 , 
2007
, vol. 
12
 (pg. 
2957
-
2966
)
42
Watala
C
Blood platelet reactivity and its pharmacological modulation in (people with) diabetes mellitus
Curr Pharm Des
 , 
2005
, vol. 
11
 (pg. 
2331
-
2365
)
43
Colwell
JA
Nesto
RW
The platelet in diabetes: focus on prevention of ischemic events
Diabetes Care
 , 
2003
, vol. 
26
 (pg. 
2181
-
2188
)
44
Davì
G
Catalano
I
Averna
M
Notarbartolo
A
Strano
A
Ciabattoni
G
Patrono
C
Thromboxane biosynthesis and platelet function in type II diabetes mellitus
N Engl J Med
 , 
1990
, vol. 
322
 (pg. 
1769
-
1774
)
45
Gresele
P
Guglielmini
G
De Angelis
M
Ciferri
S
Ciofetta
M
Falcinelli
E
Lalli
C
Ciabattoni
G
Davì
G
Bolli
GB
Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus
J Am Coll Cardiol
 , 
2003
, vol. 
41
 (pg. 
1013
-
1020
)
46
Ferroni
P
Basili
S
Falco
A
Davì
G
Platelet activation in type 2 diabetes mellitus
J Thromb Haemost
 , 
2004
, vol. 
2
 (pg. 
1282
-
1291
)
47
Assert
R
Scherk
G
Bumbure
A
Pirags
V
Schatz
H
Pfeiffer
AF
Regulation of protein kinase c by short term hyperglycaemia in human platelets in vivo and in vitro
Diabetologia
 , 
2001
, vol. 
44
 (pg. 
188
-
195
)
48
Li
Y
Woo
V
Bose
R
Platelet hyperactivity and abnormal Ca2+ homeostasis in diabetes mellitus
Am J Physiol Heart Circ Physiol
 , 
2001
, vol. 
280
 (pg. 
H1480
-
H1489
)
49
Falcon
C
Pfliegler
G
Deckmyn
H
Vermylen
J
The platelet insulin receptor: detection, partial characterization, and search for a function
Biochem Biophys Res Commun
 , 
1988
, vol. 
157
 (pg. 
1190
-
1196
)
50
Ferreira
IA
Mocking
AI
Feijge
MA
Gorter
G
van Haeften
TW
Heemskerk
JW
Akkerman
JW
Platelet inhibition by insulin is absent in type 2 diabetes mellitus
Arterioscler Thromb Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
417
-
422
)
51
Owens
AP
Mackman
N
Tissue factor and thrombosis: the clot starts here
Thromb Haemost
 , 
2010
, vol. 
104
 (pg. 
432
-
439
)
52
Boden
G
Vaidyula
VR
Homko
C
Cheung
P
Rao
AK
Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose
J Clin Endocrinol Metab
 , 
2007
, vol. 
92
 (pg. 
4352
-
4358
)
53
Min
C
Kang
E
Yu
S
Shinn
SH
Kim
YS
Advanced glycation end products induce apoptosis and procoagulant activity in cultured human umbilical vein endothelial cells
Diabetes Res Clin Pract
 , 
1999
, vol. 
46
 (pg. 
197
-
202
)
54
Breitenstein
A
Tanner
FC
Lüscher
TF
Tissue factor and cardiovascular disease
Circ J
 , 
2010
, vol. 
74
 (pg. 
3
-
12
)
55
Samad
F
Pandey
M
Loskutoff
DJ
Tissue factor gene expression in the adipose tissues of obese mice
Proc Natl Acad Sci USA
 , 
1998
, vol. 
95
 (pg. 
7591
-
7596
)
56
Saito
I
Folsom
AR
Brancati
FL
Duncan
BB
Chambless
LE
McGovern
PG
Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the atherosclerosis risk in communities (ARIC) study
Ann Intern Med
 , 
2000
, vol. 
133
 (pg. 
81
-
91
)
57
Frankel
DS
Meigs
JB
Massaro
JM
Wilson
PW
O'Donnell
CJ
D'Agostino
RB
Tofler
GH
Von willebrand factor, type 2 diabetes mellitus, and risk of cardiovascular disease: the Framingham offspring study
Circulation
 , 
2008
, vol. 
118
 (pg. 
2533
-
2539
)
58
Kistorp
C
Chong
AY
Gustafsson
F
Galatius
S
Raymond
I
Faber
J
Lip
GY
Hildebrandt
P
Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes
Eur J Heart Fail
 , 
2008
, vol. 
10
 (pg. 
380
-
387
)
59
Bernardo
A
Ball
C
Nolasco
L
Moake
JF
Dong
JF
Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von willebrand factor multimers under flow
Blood
 , 
2004
, vol. 
104
 (pg. 
100
-
106
)
60
Danesh
J
Wheeler
JG
Hirschfield
GM
Eda
S
Eiriksdottir
G
Rumley
A
Lowe
GD
Pepys
MB
Gudnason
V
C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease
N Engl J Med
 , 
2004
, vol. 
350
 (pg. 
1387
-
1397
)
61
Aso
Y
Okumura
K
Yoshida
N
Tayama
K
Kanda
T
Kobayashi
I
Takemura
Y
Inukai
T
Plasma interleukin-6 is associated with coagulation in poorly controlled patients with type 2 diabetes
Diabet Med
 , 
2003
, vol. 
20
 (pg. 
930
-
934
)
62
Muller
S
Martin
S
Koenig
W
Hanifi-Moghaddam
P
Rathmann
W
Haastert
B
Giani
G
Illig
T
Thorand
B
Kolb
H
Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors
Diabetologia
 , 
2002
, vol. 
45
 (pg. 
805
-
812
)
63
Dunn
EJ
Ariëns
RA
Fibrinogen and fibrin clot structure in diabetes
Herz
 , 
2004
, vol. 
29
 (pg. 
470
-
479
)
64
Lütjens
A
te Velde
AA
vd Veen
EA
vd Meer
J
Glycosylation of human fibrinogen in vivo
Diabetologia
 , 
1985
, vol. 
28
 (pg. 
87
-
89
)
65
Nair
CH
Azhar
A
Wilson
JD
Dhall
DP
Studies on fibrin network structure in human plasma. Part II—clinical application: diabetes and antidiabetic drugs
Thromb Res
 , 
1991
, vol. 
64
 (pg. 
477
-
485
)
66
Jörneskog
G
Egberg
N
Fagrell
B
Fatah
K
Hessel
B
Johnsson
H
Brismar
K
Blombäck
M
Altered properties of the fibrin gel structure in patients with IDDM
Diabetologia
 , 
1996
, vol. 
39
 (pg. 
1519
-
1523
)
67
Dunn
EJ
Ariëns
RA
Grant
PJ
The influence of type 2 diabetes on fibrin structure and function
Diabetologia
 , 
2005
, vol. 
48
 (pg. 
1198
-
1206
)
68
Fatah
K
Silveira
A
Tornvall
P
Karpe
F
Blomback
M
Hamsten
A
Proneness to formation of tight and rigid fibrin gel structures in men with myocardial infarction at a young age
Thromb Haemost
 , 
1996
, vol. 
76
 (pg. 
535
-
540
)
69
Collet
JP
Allali
Y
Lesty
C
Tanguy
ML
Silvain
J
Ankri
A
Blanchet
B
Dumaine
R
Gianetti
J
Payot
L
Weisel
JW
Montalescot
G
Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis
Arterioscler Thromb Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
2567
-
2573
)
70
Schneider
DJ
Nordt
TK
Sobel
BE
Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients
Diabetes
 , 
1993
, vol. 
42
 (pg. 
1
-
7
)
71
Brazionis
L
Rowley
K
Jenkins
A
Itsiopoulos
C
O'Dea
K
Plasminogen activator inhibitor-1 activity in type 2 diabetes: a different relationship with coronary heart disease and diabetic retinopathy
Arterioscler Thromb Vasc Biol
 , 
2008
, vol. 
28
 (pg. 
786
-
791
)
72
Bastard
JP
Piéroni
L
Hainque
B
Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance
Diabetes Metab Res Rev
 , 
2000
, vol. 
16
 (pg. 
192
-
201
)
73
Faber
DR
de Groot
PG
Visseren
FL
Role of adipose tissue in haemostasis, coagulation and fibrinolysis
Obes Rev
 , 
2009
, vol. 
10
 (pg. 
554
-
563
)
74
Sawdey
MS
Loskutoff
DJ
Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta
J Clin Invest
 , 
1991
, vol. 
88
 (pg. 
1346
-
1353
)
75
Schneider
DJ
Sobel
BE
Synergistic augmentation of expression of plasminogen activator inhibitor type-1 induced by insulin, very-low-density lipoproteins, and fatty acids
Coron Artery Dis
 , 
1996
, vol. 
7
 (pg. 
813
-
817
)
76
Eriksson
P
Reynisdottir
S
Lönnqvist
F
Stemme
V
Hamsten
A
Arner
P
Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals
Diabetologia
 , 
1998
, vol. 
41
 (pg. 
65
-
71
)
77
Kishore
P
Li
W
Tonelli
J
Lee
DE
Koppaka
S
Zhang
K
Lin
Y
Kehlenbrink
S
Scherer
PE
Hawkins
M
Adipocyte-derived factors potentiate nutrient-induced production of plasminogen activator inhibitor-1 by macrophages
Sci Transl Med
 , 
2010
, vol. 
2
 pg. 
20ra15
 
78
Loskutoff
DJ
Samad
F
The adipocyte and hemostatic balance in obesity: studies of PAI-1
Arterioscler Thromb Vasc Biol
 , 
1998
, vol. 
18
 (pg. 
1
-
6
)
79
Fain
JN
Madan
AK
Insulin enhances vascular endothelial growth factor, interleukin-8, and plasminogen activator inhibitor 1 but not interleukin-6 release by human adipocytes
Metabolism
 , 
2005
, vol. 
54
 (pg. 
220
-
226
)
80
Takanashi
K
Inukai
T
Insulin resistance and changes in the blood coagulation-fibrinolysis system after a glucose clamp technique in patients with type 2 diabetes mellitus
J Med
 , 
2000
, vol. 
31
 (pg. 
45
-
62
)
81
Eliasson
MC
Jansson
JH
Lindahl
B
Stegmayr
B
High levels of tissue plasminogen activator (TPA) antigen precede the development of type 2 diabetes in a longitudinal population study. The northern Sweden MONICA study
Cardiovasc Diabetol
 , 
2003
, vol. 
2
 pg. 
19
 
82
Tousoulis
D
Antoniades
C
Bosinakou
E
Kotsopoulou
M
Tsoufis
C
Marinou
K
Charakida
M
Stefanadi
E
Vavuranakis
M
Latsios
G
Stefanadis
C
Differences in inflammatory and thrombotic markers between unstable angina and acute myocardial infarction
Int J Cardiol
 , 
2007
, vol. 
115
 (pg. 
203
-
207
)
83
Nordenhem
A
Leander
K
Hallqvist
J
de Faire
U
Sten-Linder
M
Wiman
B
The complex between tPA and PAI-1: risk factor for myocardial infarction as studied in the sheep project
Thromb Res
 , 
2005
, vol. 
116
 (pg. 
223
-
232
)
84
Mannucci
PM
Bernardinelli
L
Foco
L
Galli
M
Ribichini
F
Tubaro
M
Peyvandi
F
Tissue plasminogen activator antigen is strongly associated with myocardial infarction in young women
J Thromb Haemost
 , 
2005
, vol. 
3
 (pg. 
280
-
286
)
85
Ridker
PM
Vaughan
DE
Stampfer
MJ
Manson
JE
Hennekens
CH
Endogenous tissue-type plasminogen activator and risk of myocardial infarction
Lancet
 , 
1993
, vol. 
341
 (pg. 
1165
-
1168
)
86
Diamant
M
Tushuizen
ME
Sturk
A
Nieuwland
R
Cellular microparticles: new players in the field of vascular disease?
Eur J Clin Invest
 , 
2004
, vol. 
34
 (pg. 
392
-
401
)
87
Diehl
P
Fricke
A
Sander
L
Stamm
J
Bassler
N
Htun
N
Ziemann
M
Helbing
T
El-Osta
A
Jowett
JB
Peter
K
Microparticles: major transport vehicles for distinct microRNAs in circulation
Cardiovasc Res
 , 
2012
, vol. 
93
 (pg. 
633
-
644
)
88
Puddu
P
Puddu
GM
Cravero
E
Muscari
S
Muscari
A
The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases
Can J Cardiol
 , 
2010
, vol. 
26
 (pg. 
140
-
145
)
89
Ratajczak
J
Miekus
K
Kucia
M
Zhang
J
Reca
R
Dvorak
P
Ratajczak
MZ
Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery
Leukemia
 , 
2006
, vol. 
20
 (pg. 
847
-
856
)
90
Cai
X
Hagedorn
CH
Cullen
BR
Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs
RNA
 , 
2004
, vol. 
10
 (pg. 
1957
-
1966
)
91
Tripodi
A
Branchi
A
Chantarangkul
V
Clerici
M
Merati
G
Artoni
A
Mannucci
PM
Hypercoagulability in patients with type 2 diabetes mellitus detected by a thrombin generation assay
J Thromb Thrombolysis
 , 
2011
, vol. 
31
 (pg. 
165
-
172
)
92
Feng
B
Chen
Y
Luo
Y
Chen
M
Li
X
Ni
Y
Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus
Atherosclerosis
 , 
2010
, vol. 
208
 (pg. 
264
-
269
)
93
Diamant
M
Nieuwland
R
Pablo
R
Sturk
A
Smit
JW
Radder
JK
Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus
Circulation
 , 
2002
, vol. 
106
 (pg. 
2442
-
2447
)
94
Naghavi
M
Libby
P
Falk
E
Casscells
SW
Litovsky
S
Rumberger
J
Badimon
JJ
Stefanadis
C
Moreno
P
Pasterkamp
G
Fayad
Z
Stone
PH
Waxman
S
Raggi
P
Madjid
M
Zarrabi
A
Burke
A
Yuan
C
Fitzgerald
PJ
Siscovick
DS
de Korte
CL
Aikawa
M
Airaksinen
KE
Assmann
G
Becker
CR
Chesebro
JH
Farb
A
Galis
ZS
Jackson
C
Jang
IK
Koenig
W
Lodder
RA
March
K
Demirovic
J
Navab
M
Priori
SG
Rekhter
MD
Bahr
R
Grundy
SM
Mehran
R
Colombo
A
Boerwinkle
E
Ballantyne
C
Insull
W
Jr
Schwartz
RS
Vogel
R
Serruys
PW
Hansson
GK
Faxon
DP
Kaul
S
Drexler
H
Greenland
P
Muller
JE
Virmani
R
Ridker
PM
Zipes
DP
Shah
PK
Willerson
JT
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II
Circulation
 , 
2003
, vol. 
108
 (pg. 
1772
-
1778
)
95
Rubler
S
Dlugash
J
Yuceoglu
YZ
Kumral
T
Branwood
AW
Grishman
A
New type of cardiomyopathy associated with diabetic glomerulosclerosis
Am J Cardiol
 , 
1972
, vol. 
30
 (pg. 
595
-
602
)
96
Bertoni
AG
Duren-Winfield
V
Ambrosius
WT
McArdle
J
Sueta
CA
Massing
MW
Peacock
S
Davis
J
Croft
JB
Goff
DC
Jr
Quality of heart failure care in managed medicare and medicaid patients in North Carolina
Am J Cardiol
 , 
2004
, vol. 
93
 (pg. 
714
-
718
)
97
Kannel
WB
Hjortland
M
Castelli
WP
Role of diabetes in congestive heart failure: the Framingham study
Am J Cardiol
 , 
1974
, vol. 
34
 (pg. 
29
-
34
)
98
Lind
M
Bounias
I
Olsson
M
Gudbjornsdottir
S
Svensson
AM
Rosengren
A
Glycaemic control and incidence of heart failure in 20,985 patients with type 1 diabetes: An observational study
Lancet
 , 
2011
, vol. 
378
 (pg. 
140
-
146
)
99
Devereux
RB
Roman
MJ
Paranicas
M
O'Grady
MJ
Lee
ET
Welty
TK
Fabsitz
RR
Robbins
D
Rhoades
ER
Howard
BV
Impact of diabetes on cardiac structure and function: the strong heart study
Circulation
 , 
2000
, vol. 
101
 (pg. 
2271
-
2276
)
100
Iribarren
C
Karter
AJ
Go
AS
Ferrara
A
Liu
JY
Sidney
S
Selby
JV
Glycemic control and heart failure among adult patients with diabetes
Circulation
 , 
2001
, vol. 
103
 (pg. 
2668
-
2673
)
101
Stratton
IM
Adler
AI
Neil
HA
Matthews
DR
Manley
SE
Cull
CA
Hadden
D
Turner
RC
Holman
RR
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study
BMJ
 , 
2000
, vol. 
321
 (pg. 
405
-
412
)
102
Rijzewijk
LJ
van der Meer
RW
Lamb
HJ
de Jong
HW
Lubberink
M
Romijn
JA
Bax
JJ
de Roos
A
Twisk
JW
Heine
RJ
Lammertsma
AA
Smit
JW
Diamant
M
Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging
J Am Coll Cardiol
 , 
2009
, vol. 
54
 (pg. 
1524
-
1532
)
103
Stanley
WC
Lopaschuk
GD
McCormack
JG
Regulation of energy substrate metabolism in the diabetic heart
Cardiovasc Res
 , 
1997
, vol. 
34
 (pg. 
25
-
33
)
104
Boudina
S
Abel
ED
Diabetic cardiomyopathy revisited
Circulation
 , 
2007
, vol. 
115
 (pg. 
3213
-
3223
)
105
Paulson
DJ
The diabetic heart is more sensitive to ischemic injury
Cardiovasc Res
 , 
1997
, vol. 
34
 (pg. 
104
-
112
)
106
Cheung
N
Wang
JJ
Rogers
SL
Brancati
F
Klein
R
Sharrett
AR
Wong
TY
Diabetic retinopathy and risk of heart failure
J Am Coll Cardiol
 , 
2008
, vol. 
51
 (pg. 
1573
-
1578
)
107
Rana
O
Byrne
CD
Kerr
D
Coppini
DV
Zouwail
S
Senior
R
Begley
J
Walker
JJ
Greaves
K
Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans
Circulation
 , 
2011
, vol. 
124
 (pg. 
1548
-
1556
)
108
Falcao-Pires
I
Hamdani
N
Borbely
A
Gavina
C
Schalkwijk
CG
van der Velden
J
van Heerebeek
L
Stienen
GJ
Niessen
HW
Leite-Moreira
AF
Paulus
WJ
Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness
Circulation
 , 
2011
, vol. 
124
 (pg. 
1151
-
1159
)
109
Evans
JL
Goldfine
ID
Maddux
BA
Grodsky
GM
Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes
Endocr Rev
 , 
2002
, vol. 
23
 (pg. 
599
-
622
)
110
Mariappan
N
Elks
CM
Sriramula
S
Guggilam
A
Liu
Z
Borkhsenious
O
Francis
J
Nf-kappab-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type ii diabetes
Cardiovasc Res
 , 
2010
, vol. 
85
 (pg. 
473
-
483
)
111
Giacco
F
Brownlee
M
Oxidative stress and diabetic complications
Circ Res
 , 
2010
, vol. 
107
 (pg. 
1058
-
1070
)
112
Bierhaus
A
Nawroth
PP
Multiple levels of regulation determine the role of the receptor for age (rage) as common soil in inflammation, immune responses and diabetes mellitus and its complications
Diabetologia
 , 
2009
, vol. 
52
 (pg. 
2251
-
2263
)
113
Hori
M
Nishida
K
Oxidative stress and left ventricular remodelling after myocardial infarction
Cardiovasc Res
 , 
2009
, vol. 
81
 (pg. 
457
-
464
)
114
Tsutsui
H
Kinugawa
S
Matsushima
S
Mitochondrial oxidative stress and dysfunction in myocardial remodelling
Cardiovasc Res
 , 
2009
, vol. 
81
 (pg. 
449
-
456
)
115
Aljaroudi
W
Alraies
MC
Halley
C
Rodriguez
L
Grimm
RA
Thomas
JD
Jaber
WA
Impact of progression of diastolic dysfunction on mortality in patients with normal ejection fraction
Circulation
 , 
2012
, vol. 
125
 (pg. 
782
-
788
)
116
Janczewski
AM
Lakatta
EG
Modulation of sarcoplasmic reticulum Ca2+ cycling in systolic and diastolic heart failure associated with aging
Heart Fail Rev
 , 
2010
, vol. 
15
 (pg. 
431
-
445
)
117
Lompre
AM
Hajjar
RJ
Harding
SE
Kranias
EG
Lohse
MJ
Marks
AR
Ca2+ cycling and new therapeutic approaches for heart failure
Circulation
 , 
2010
, vol. 
121
 (pg. 
822
-
830
)
118
van Heerebeek
L
Somsen
A
Paulus
WJ
The failing diabetic heart: focus on diastolic left ventricular dysfunction
Curr Diab Rep
 , 
2009
, vol. 
9
 (pg. 
79
-
86
)
119
Takeda
N
Cardiac disturbances in diabetes mellitus
Pathophysiology
 , 
2010
, vol. 
17
 (pg. 
83
-
88
)
120
Veglio
M
Chinaglia
A
Cavallo-Perin
P
QT interval, cardiovascular risk factors and risk of death in diabetes
J Endocrinol Invest
 , 
2004
, vol. 
27
 (pg. 
175
-
181
)
121
Desouza
CV
Bolli
GB
Fonseca
V
Hypoglycemia, diabetes, and cardiovascular events
Diabetes Care
 , 
2010
, vol. 
33
 (pg. 
1389
-
1394
)
122
Pop-Busui
R
Cardiac autonomic neuropathy in diabetes: a clinical perspective
Diabetes Care
 , 
2010
, vol. 
33
 (pg. 
434
-
441
)
123
Fernyhough
P
Roy Chowdhury
SK
Schmidt
RE
Mitochondrial stress and the pathogenesis of diabetic neuropathy
Expert Rev Endocrinol Metab
 , 
2010
, vol. 
5
 (pg. 
39
-
49
)
124
Burgess
DC
Hunt
D
Li
L
Zannino
D
Williamson
E
Davis
TM
Laakso
M
Kesaniemi
YA
Zhang
J
Sy
RW
Lehto
S
Mann
S
Keech
AC
Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the fenofibrate intervention and event lowering in diabetes (FIELD) study
Eur Heart J
 , 
2010
, vol. 
31
 (pg. 
92
-
99
)
125
Mak
KH
Moliterno
DJ
Granger
CB
Miller
DP
White
HD
Wilcox
RG
Califf
RM
Topol
EJ
Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I investigators. Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries
J Am Coll Cardiol
 , 
1997
, vol. 
30
 (pg. 
171
-
179
)