Reviews/Commentaries/ADA Statements

Type 1 Diabetes and Coronary Artery Disease

  1. Trevor J. Orchard, MBBCH, MMEDSCI1,
  2. Tina Costacou, PHD1,
  3. Adam Kretowski, MD23 and
  4. Richard W. Nesto, MD4
  1. 1Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania
  2. 2Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, Colorado
  3. 3Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  4. 4Department of Cardiovascular Medicine, Lahey Clinic Medical Center, Burlington, Massachusetts
  1. Address correspondence and reprint requests to Trevor J. Orchard, MBBCh, MMedSci, Diabetes and Lipid Research Bldg., 3512 Fifth Ave., Pittsburgh, PA 15213. E-mail: tjo{at}pitt.edu
Diabetes Care 2006 Nov; 29(11): 2528-2538. https://doi.org/10.2337/dc06-1161

Although the increased risk of premature heart disease in type 1 diabetes has been recognized for some time, the underlying pathogenesis is still poorly understood. The most likely factor, a priori, to account for this increased risk is hyperglycemia. However, despite recent evidence from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study that prior intensive glycemic control reduces cardiovascular disease (CVD), the epidemiologic association between glycemia and coronary heart disease (CHD) is surprisingly weak. This paradox is a focus of the current review, which also evaluates other major determinants of coronary artery disease (CAD) in type 1 diabetes, including the roles of insulin resistance, cytokines, inflammatory biomarkers, and, briefly, genetic factors. Finally, the clinical implications of this information are discussed.

THE MAGNITUDE OF THE PROBLEM—

A high occurrence of, and mortality from, CHD in type 1 diabetes has been documented since the late 1970s (1,2). A 1984 registry reported a 10-fold or greater CHD mortality compared with that expected from U.S. national data (3). This very high relative risk, partly reflecting the extremely low CHD death rate in the general young-adult population, was subsequently confirmed by Joslin investigators (4), who reported that those with type 1 diabetes by 55 years of age experienced a sixfold greater cumulative CHD mortality compared with the rate expected using Framingham Study data. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) also reported a standardized mortality ratio (SMR) from ischemic heart disease of 9.1 (for men) and 13.5 (for women) for those with a diabetes diagnosis before 30 years of age (5).

Two recent prospective epidemiologic studies, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (6) and Eurodiab (7), a multicenter, clinic-based study in Europe, confirmed these earlier reports and reported an incidence of total coronary events (including electrocardiogram [ECG] changes) of 16% over 10 years and 9% over 7 years, respectively, of follow-up in type 1 diabetic patients. As the mean age at baseline was ∼30 years, these incidence rates reflect the experience of those aged in their late 30s. In EDC, total CAD incidence (including angina and ischemic ECG changes) was >2% per year for those aged ≥35 years. A more recent report (8), using 12-year follow-up data, suggested annual major CAD event (myocardial infarction [MI], fatal CAD, or revascularization) rates of 0.98% for those with diabetes durations of 20–30 years (aged, on average, 28–38 years). These event rates are the same for both sexes, indicating a loss of the protection from CHD mortality that females without diabetes experience.

The Diabetes Epidemiology Research International study will provide an international perspective, comparing cause-specific mortality rates using standard methodologies from representative cohorts of childhood-onset type 1 diabetes in the U.S. (Allegheny County) with national registries of similar individuals in Japan and Finland. CVD was a relatively rare cause of death in the early years of follow-up of these young subjects (9). However, a recent pooled analysis of the Allegheny County and the Pittsburgh EDC cohorts (mean age at follow-up 31 years) demonstrated that CAD was the new leading cause of mortality (10).

The recent follow-up of the Diabetes U.K. (11) cohort of 23,751 subjects diagnosed at <30 years of age with insulin-treated diabetes also shows similar mortality rates for men and women and enables robust sex-specific estimates of SMRs. In those aged 20–29 years, SMRs for ischemic heart disease mortality of 11.8 in men and 44.8 in women were reported, while for those aged 30–39 years, SMRs were 8.0 and 41.6, respectively. Other forms of CVD such as hypertension, valvular disease, cardiomyopathy, heart failure, and stroke were also increased. Whether there has been any recent decline in mortality or morbidity from CHD in type 1 diabetes, as has been reported for renal disease (12,13), is unclear. The Pittsburgh EDC (8) reported no difference in the cumulative incidence of CAD by 20, 25, or 30 years’ duration according to year of diagnosis (1950–1980). In contrast, major declines were seen for mortality and renal failure. The benefits of improved diabetes care, therefore, do not (at least as yet) appear to have reduced CAD mortality.

In addition to the above-mentioned studies, which directly deal with CAD events and are summarized in the online appendix Table 1 (available at http://care.diabetesjournals.org), data concerning a variety of other related measures have also been reported (online appendix Table 2). Eleven years after the close of the trial, the former DCCT intensive therapy group showed a lower rate of progression of intima-media thickening (IMT) (14), although glycemic control was similar in both groups after study close. This observation provides the foundation for the “imprinting” theory of glycemic control, i.e., that early vascular changes can lead to fundamental, perhaps structural, alterations that have long-lasting effects.

The excess coronary artery calcification (CAC) in type 1 diabetes seen in studies from Denver (15) and London (16), compared with general nondiabetic control populations, provide further support to the thesis of accelerated atherosclerosis in the coronary arteries. A major concern, however, is whether the calcium reflects atherosclerosis or medial wall calcification (i.e., Mockenberg’s sclerosis) commonly seen in type 1 diabetes. The Pittsburgh EDC study provides some reassurance that CAC reflects atherosclerosis, as there was a strong correlation between CAC and both clinical disease and cardiovascular risk factors (17). These three research groups have formed a collaboration to examine the role of electron beam computed tomography in type 1 diabetes. Online appendix Table 3 gives the pooled prevalence of any CAC in the pooled dataset as background for interpreting CAC scores in the type 1 diabetic population. Overall, the risk of having any CAC appears to be increased by ∼50%.

Finally, a number of angiographic and autopsy studies further suggest more extensive disease in type 1 diabetic than in nondiabetic cohorts (18–20), as does a study from Oslo (21) that demonstrated, using intravascular ultrasound, that all 29 type 1 diabetic subjects studied had significant coronary intimal thickening. Coincident with changes in IMT are changes in arterial compliance and distensibility. Endothelial dysfunction has been seen in teenage subjects within the first decade of type 1 diabetes onset (22,23). Thus, these studies confirm that changes in vascular structure and function occur early in the course of type 1 diabetes.

RISK FACTORS FOR CAD IN TYPE 1 DIABETES—

When considering CAD risk factors in type 1 diabetes, three major questions arise. First, do the standard CAD risk factors operate as in the nondiabetic population? Second, are there additional specific CAD risk factors in type 1 diabetes? Third, does either (or both) of the above explain the excess risk for CAD?

Online appendix Table 4 summarizes the results that address the first question. In the 10-year follow-up report from EDC, lipids (both HDL and non-HDL cholesterol), hypertension, smoking, and a marker of inflammation, i.e., total white blood cell count, predicted total CAD events with some variation according to the type of CAD event (e.g., depressive symptomatology predicted angina, whereas nephropathy and a proxy measure of insulin sensitivity [estimated glucose disposal rate, eGDR] predicted hard events). eGDR is a regression equation with terms for waist-to-hip ratio, hypertension, and HbA1 and was derived from an hyperinsulinemic-euglycemic clamp substudy of 24 EDC participants. The R2 for eGDR versus measured GDR was 0.63 (24). Earlier sex-specific analyses (25) suggested that nephropathy was a particularly strong CAD risk factor in men, whereas waist-to-hip ratio and hypertension predominated in women. Intriguingly, glycemic control was not a predictor of CAD, either as a baseline predictor (6) or using a cumulative glycemic exposure measure (26).

Eurodiab, with an 8-year follow-up, largely confirmed these findings, although sex-specific results differed, with proteinuria being independently predictive of CHD in both sexes and waist-to-hip ratio in men (7). Again, HbA1c (A1C) was not independently associated with either events or left ventricular hypertrophy (27). Case ascertainment varied across studies, with ECG abnormalities responsible for more than half the events in Eurodiab, compared with only 19% in EDC. The WESDR also confirmed these findings, where a more limited range of standard risk factors supplemented with detailed retinal characteristics also predicted CVD events, although nephropathy appeared to confound these associations and emerged as a stronger predictor (28). A1C similarly showed only a weak association with MI (P = 0.08) and no association with angina.

A number of important observations emerge from these data and bear on the second question posed, i.e., specific risk factors in type 1 diabetes. First, nephropathy clearly emerges as a major predictor, as has been recognized for many years (29,30) and repeatedly confirmed (31,32). However, even without nephropathy, CAD rates in type 1 diabetes are still greatly increased (30). Another complication often implicated in CAD risk is autonomic neuropathy (33,34,35). In patients with long-standing type 1 diabetes, the response of myocardial blood flow to sympathetic stimulation, as assessed by a variety of methods, is impaired in myocardial regions with autonomic dysinnervation, indicating impaired vasodilator response of coronary resistance vessels. Perturbations of the autonomic nervous system are, however, strongly associated with renal disease (36), control for which (37,38) may account for much of the high mortality risk associated with autonomic neuropathy, as first noted in Ewing’s classic article (34). Numerous mechanisms may account for premature cardiac death in CAD including associations with subclinical but advanced coronary atherosclerosis, abnormalities in coronary vasomotor capacity, changes in systolic and diastolic function, and lastly, life-threatening arrhythmia, the threshold for which is lower in the setting of a relative increase in sympathetic tone, a situation commonly seen in diabetic individuals with sympathovagal imbalance.

Another possibility that may contribute to the enhanced CAD risk in type 1 diabetes is that the effects of standard risk factors are altered. For example, although HDL cholesterol inversely predicts CHD mortality in type 1 diabetes, as in the general population, HDL cholesterol levels are generally ∼10 mg/dl higher in type 1 diabetes, probably reflecting a number of factors including enhanced lipoprotein lipase and reduced hepatic lipase activity due to systemic insulin administration and altered HDL metabolism (39). Intriguingly, in a nested case-control study from the Pittsburgh EDC using nuclear magnetic resonance technology, the intermediate (H3) fraction was increased in those with subsequent CAD compared with noncases (40), while the large (H4 and H5) fractions were protective, as in the general population. A lower paraoxonase activity, compromising HDLs ability to retard LDL oxidation, has also been proposed (41).

As shown above, the most logical explanation for the high-CAD risk, hyperglycemia, has in virtually all studies shown only a weak relationship with CAD events. One exception is a small study (42) of older-onset type 1 diabetic Finnish subjects without nephropathy, which is discussed later. Further exploration of the Pittsburgh EDC and WESDR studies indicate that glycemia does strongly predict peripheral arterial disease (43), amputation (44), and stroke (28). Why then does glycemia predict the presence and the rate of progression of peripheral, but not coronary, arterial events?

We hypothesize that while glycemia greatly increases atherosclerosis in general, a lower proportion of the plaques formed in diabetic persons are vulnerable. It is rupture of vulnerable plaques that generally leads to coronary events such as MI or CAD death, while plaque rupture has a small role in peripheral arterial disease. This “glucose stabilization” hypothesis would, therefore, predict a stronger relation of glycemia to chronic stable atherosclerotic manifestations (as in occlusive stroke or lower-extremity arterial disease) than to acute coronary events (such as MI and unstable angina) in which plaque rupture is a predominant feature, exactly the epidemiologic pattern seen. A number of observations support this concept. These include the general observation that diabetes complications in other locations, such as the kidney (glomerulosclerosis), eye (fibrous proliferative disease), and joints and connective tissue (stiff joint syndrome), involve a sclerosing or thickening process. This most likely results from glycoxidation of tissue with advanced glycation end product formation and protein cross linking (45). Why should the arterial tree be immune to this aspect of diabetes?

Furthermore, in diabetes, diffuse coronary disease reflecting a greater proportion of concentric lesions (46) and maladaptive remodeling (47) is a common finding that may lead to lumen reduction with a lower frequency of more vulnerable “eccentric” plaques (46,48). Another consistent observation is the complete reversal in the proportion of the two key precipitating factors for acute coronary syndrome (ACS) events in diabetes, namely plaque rupture and plaque erosion. Whereas in the general population ACS is generally precipitated by rupture, in diabetes ACS is much more likely to be precipitated by erosion (49–51). Online appendix Table 5 lists the morphologic studies that provide relevant data. Though the main conclusion is that many morphological features of plaque in diabetes, especially type 1 diabetes, are consistent with a greater tendency toward plaque stability (e.g., ↑ fibrous content, ↓ cell/macrophage/lipid content, and ↑ concentric, ↓ eccentric location of lesions), two important studies suggest that carotid and coronary plaques taken from type 2 diabetic patients undergoing coronary atherectomy (52) or carotid endarterectomy (53) have more inflammatory characteristics than those from matched nondiabetic subjects. A recent postmortem study also suggests greater inflammatory cell infiltration in coronary plaques in diabetes (54). As many of these studies have selection biases, e.g., are event or procedure driven and therefore unlikely to represent the nature and distribution of atherosclerotic lesions in the total diabetes population, a detailed investigation of the morphology of plaque in type 1 diabetes, using representative diabetic and nondiabetic populations, is clearly needed.

In contrast to the relatively weak observational association between glycemia and coronary events, the DCCT/EDIC has recently reported (55), in a 17-year follow-up of the DCCT, that intensive insulin therapy during the 6-year trial was associated with a 42% lower risk of any cardiovascular event and a stunning 57% reduction in major CVD events (stroke, MI, or CAD death) compared with the conventional group. This was despite the two groups having almost identical glycemic control in the 11 years following the trial. This effect of intensive insulin therapy can be largely explained in statistical models by the mean A1C during the DCCT phase.

RECONCILING THE DCCT/EDIC TRIAL DATA WITH PRIOR EPIDEMIOLOGIC OBSERVATIONS—

There are a number of possible reasons why the epidemiologic data are consistently negative in terms of a strong relation of glycemia with CAD risk, whereas the DCCT/EDIC trial results are convincingly positive, all of which may contribute to this paradox (online appendix Table 6).

First, the epidemiology studies may simply be wrong, perhaps because glycemia is based on a single A1C measure. This does not, however, apply to the EDC data, which include a cumulative measure (26). It is also striking that single measures of 25 other risk factors were all significant predictors, whereas HbA1 was not. While a number of studies do suggest a relationship between glycemia and various surrogate markers of atherosclerosis, only one small study (n = 177) of older-onset (>30 years) type 1 diabetic subjects without nephropathy reports a link with events (42). Two reports showed A1C/carotid IMT relationships (56,57), whereas an intriguing study from the Turku PET Centre showed a relationship between lifetime (but not concurrent) glycemic exposure and coronary vasoreactivity (58). Chan et al. (59) also suggested that poorer control may be related to lower acetyl choline–stimulated nitric oxide production. Though two studies have shown poorer left ventricular function in those with poor glycemic control (60,61), two others have shown no association between angiographic findings and A1C (20,62). Both the intravascular ultrasound–determined coronary intima thickening that was omniprevalent in type 1 diabetic subjects in the Oslo study (21) and coronary plaque development were correlated with mean 18-year A1C levels (P = 0.04). These studies, using surrogate markers rather than clinical events, are thus not inconsistent with the above glucose stabilization hypothesis, nor with the epidemiology studies based on clinical events.

Population characteristics also differ between the DCCT and the EDC/WESDR/Eurodiab studies. Particularly notable is the relatively shorter diabetes duration of DCCT/EDIC subjects at baseline (mean 6 years) compared, for example, with a mean of 19 years for EDC and 14 years for Eurodiab. It thus seems likely that the DCCT/EDIC hypothesis of the benefits of early imprinting may be particularly relevant. Another difference is the low CAD risk of the DCCT population resulting from the exclusion of obese, hypertensive, and hypercholesterolemic subjects at baseline. The DCCT/EDIC results are thus derived from a relatively healthy, compliant, early onset, low CVD risk subgroup of the type 1 population, features that may contribute to the differences under discussion.

Another potential contributor is the lower level of glycemic control achieved in the DCCT/EDIC intensive group (A1C 7.4% compared with 9.1% in the conventional group), which suggests that the benefit of improved glycemic control may only occur if sufficiently low levels are achieved. Yet another potential explanation is that the DCCT/EDIC trial data reflect other factors beyond improved glycemic control; thus, the ability of mean DCCT A1C to explain the treatment group effects may reflect how good a marker it is of being in the intensive therapy group rather than glycemia per se. A major reduction in the DCCT treatment group effect occurred after controlling for microalbuminuria or worse (P value increased from 0.005 to 0.04) (55). In EDC, 71% of incident CAD cases had microalbuminuria or worse at baseline, and a further 11% developed microalbuminuria at or before the first CAD event, suggesting that 80% of events may be associated with renal disease. Unfortunately, the frequency of developing microalbuminuria or worse before CAD is not reported for DCCT/EDIC, making it difficult to fully quantify the impact of early renal disease on CAD risk in DCCT/EDIC. Apart from renal disease, other factors may have contributed but have not yet been included in multivariable analyses. For example, though LDL cholesterol at the end of DCCT was not different between the groups, during the trial, total and LDL cholesterol and triglycerides were all lower (P < 0.01) in those receiving intensive therapy.

It would thus seem, given the population differences, the lower A1C levels achieved in the DCCT, and the current incomplete adjustment for potential mediators of the treatment group effect, that the paradox may not be so puzzling after all. As >80% of CAD in type 1 diabetes may be associated with renal disease in general cohorts and insulin resistance is a strong predictor of both CAD (6) and renal disease (63), insulin resistance is likely the major pathogenetic pathway for the majority of cases. The potential importance of insulin resistance is further underscored by the observations that a family history of type 2 diabetes predicts CAD in type 1 diabetes (64) and that a subgroup of type 1 diabetic subjects gain excessive weight, show insulin resistance, and have adverse lipoprotein changes when given intensive insulin therapy (65,66). Thus, a subgroup of type 1 diabetes may have type 2 diabetes/insulin resistance genes and be at increased CAD risk. Nonetheless, glycemia per se may particularly relate, as the Finnish data suggest (42), to the nonrenal CAD cases, which are likely to be more predominant in the DCCT because of the lower risk of renal disease resulting from better glycemic control.

NOVEL PREDICTORS—

Over the past decade, atherosclerosis has increasingly been considered, at least partly, an inflammatory disease (67). Several newly recognized factors may contribute to this development and are discussed below (45,67–69).

The oxidative modification of LDL, and the immune response it produces, may be one of these key factors, as an association between antibodies to oxidized LDL and incident CAD has been reported (70). The resulting immune complexes may induce foam cell formation and damage the endothelium (71), activating macrophages and endothelial cells and impairing the physiologic action of nitric oxide, leading to vascular cell cytotoxicity (67,72). The adherence of monocytes is also a key step in this process (67,73), and it is of interest that E-selectin shows a strong, independent prediction of heart disease in type 1 diabetes (74).

Other regulators of adhesion molecules include cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β (75). These and other markers of inflammation have not been extensively studied in the development of CAD. However, the Eurodiab study group, using a Z score based on combined levels of C-reactive protein, IL-6, and TNF-α (76), reported a significant difference between those with and without CAD (P < 0.001) after adjustment for age, sex, A1C, diabetes duration, and systolic blood pressure. In further reports, no cross-sectional association between homocysteine concentration and CVD was seen in Eurodiab (77), while the EDC study failed to show any independent prediction of CAD by plasminogen activator inhibitor-1 or tissue plasminogen activator inhibitor-1 (78). In contrast, soluble IL-2 receptor, a marker of T-cell activation, has been associated with progression of CAC in type 1 diabetes (79). Additionally, increased CD40 ligand expression and upregulation of soluble CD40 ligand have been reported in type 1 diabetes (80,81) and appear to play a role in endothelial cell activation and monocyte recruitment.

The adipokine adiponectin, one of the most abundant circulating proteins in human plasma (82), which preferentially accumulates in the subintimal space of the arterial wall when the vascular endothelium is injured, has received much attention (83). It inhibits TNF-α–induced cell adhesion in human aortic endothelial cells and expression of cellular adhesion molecules in a dose-response manner (84) and may act both as an antiatherogenic and an anti-inflammatory molecule. Studies in type 1 diabetes are limited and confusing because despite the high rates of atherosclerosis, markedly elevated adiponectin concentrations have been observed in type 1 diabetes compared with both type 2 diabetes and normal glucose tolerance (85,86). Since insulin is implicated in the regulation of adiponectin expression (87), the relatively high systemic levels of insulin in type 1 diabetes may play a role. Higher rates of macroalbuminuria in the type 1 populations examined may also contribute, as increased adiponectin concentration has been noted in renal disease (88,89,90). Nevertheless, a remarkable 63% lower CAD risk per 1 SD (6.3 μg/ml) increase in serum adiponectin concentration has been reported among type 1 diabetic individuals in the EDC study (90) after adjustment for traditional risk factors, including urinary albumin excretion. Investigators from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study have also reported that low plasma adiponectin levels were independently associated with greater CAC progression in type 1 diabetes (91). However, whether the high levels in type 1 diabetes (or renal disease) reflect an attempt to counteract the atherogenicity of the condition, or are merely reflective of this state, remains unclear.

GENETIC STUDIES—

A number of studies have demonstrated a familial effect on CVD risk in general and in type 1 diabetes (64,92,93). However, only a few studies (online appendix Table 7) have focused on a genetic predisposition to CAD in type 1 diabetes.

Receptor for advanced glycation end products

Receptor for advanced glycation end products, located on chromosome 6p21.3 in the class III region of the major histocompatibility complex and an important locus for type 1 diabetes pathogenesis, is involved in key mechanisms leading to vascular disease development during chronic hyperglycemia (53,94,95). The AA genotype at position −374 of the promoter region has been associated with lower CVD risk in type 1 diabetes compared with the TT + TA genotypes (96), and in type 2 diabetes and the general population as well (97,98).

ACE insertion/deletion polymorphism

This polymorphism accounts for a large proportion of the individual variation of serum and tissue ACE activity (99,100) and contributes, in some reports, to the risk of persistent microalbuminuria/severe nephropathy in type 1 diabetes (101,102). The association of this polymorphism with CAD is complex and inconsistent, with the ACE II genotype being reported to have a significantly lower MI risk in one (103) but not all (104) studies. The situation is further complicated by the associations of the I-allele with insulin resistance (105) and the D-allele with nephropathy, the major risk factor for CAD in type 1 diabetes (106).

Neuropeptide Y

A leucine to proline polymorphism (Leu7Pro) of the neuropeptide Y gene localized on chromosome 7p15.1 may contribute to the genetic susceptibility to CHD in type 1 diabetes, possibly by influencing glycemic control and lipid metabolism (107,108). However, the association with A1C was not confirmed in another recent nondiabetic study (109).

Hepatic lipase

The hepatic lipase gene promoter polymorphism −480C/T (or −514C/T, depending on identification of transcription start localization), a functional variant influencing hepatic lipase activity (110), has been associated with a higher frequency of CAC independent of HDL cholesterol in type 1 diabetes (111) and premature CHD (112,113), as well as CAC (114), in a variety of populations. Intriguingly, reports of higher CAD risk and lower HDL concentrations among those with the −480C rather than the −480T allele also exist (115,116). The LIPC −480C/T polymorphism has been recently associated with insulin resistance (117,118).

Apolipoprotein A-IV

Apolipoprotein A-IV (ApoA-IV) is a structural glycoprotein of chylomicrons, HDL, and VLDL and plays an important role in the reverse cholesterol transport from peripheral cells to the liver (119). A common polymorphism (glutamine to histidine at position 360 near the carboxyl terminus) generates two isoforms, apoA-IV1 (360Gln) and apoA-IV2 (360His). The latter has been associated with a significantly higher risk of subclinical CAD progression (relative risk 3.3, P = 0.003) in type 1 diabetic patients (120) and MI in type 2 diabetic patients (121) but not in nondiabetic control subjects (120).

Von Willebrand factor

The Von Willebrand factor Thr789Ala polymorphism has been associated with increased CHD risk among type 1 diabetic patients with long diabetes durations (odds ratio 4.2 for Ala/Ala homozygotes) (122). Von Willebrand factor, a carrier of coagulation factor VIII, has been identified as a risk factor for MI in the general population (123).

Further exploration of the genetic basis of CAD in type 1 diabetes

Research to date has shown a number of promising avenues to further explore the relationship between genes and CAD in type 1 diabetes, particularly in the realm of specific gene-environmental interactions. Future research might reasonably focus on genes not having a proatherogenic effect or those mildly associated with CAD in nondiabetic populations that become strongly “activated” in the diabetes milieu, e.g., genes associated with glucose metabolism and/or insulin resistance. Adiponectin would also be of particular interest, given the growing evidence that genetic variants of the APM1 gene (11391G/−11377G haplotype T45G, G276T) affect adiponectin levels and are associated with cardiovascular risk in type 2 diabetes and nondiabetic control subjects (124,125,126) and nephropathy in type 1 diabetes (127).

CONCLUSIONS AND CLINICAL IMPLICATIONS—

It is clear that type 1 diabetes is associated with an increased risk for CHD and that this risk is evident at a young age. Underlying this enhanced risk is a wide range of modifiable risk indicators such as standard CAD risk factors (blood pressure, lipids, and smoking), as well as specific elements such as renal disease. The relation of glycemia to clinical events is multifactorial and complex. Unfortunately, clinical trial data specific to type 1 diabetes and CAD prevention are largely limited to the DCCT/EDIC study, which suggests a very strong benefit for early, intensive glycemic management, although to what degree this finding is mediated via other pathways (e.g., lipids) is currently unknown.

There are few outcome data on primary prevention of CHD in type 1 diabetes, and current guidelines in type 1 diabetic patients mirror those established for type 2 diabetes. The Heart Protection Study (128) suggested a benefit of simvastatin in the type 1 diabetic subgroup (128). In general, we must infer that the benefits of pharmacotherapy for CHD prevention as established in numerous trials in the general and type 2 diabetic populations would apply equally to type 1 diabetes. Highlights of current American Diabetes Association (ADA) (129) and American Heart Association (AHA) (130,131) recommendations are summarized in online appendix Table 8. Both the ADA and AHA advocate moderately vigorous lipid and blood pressure control and even initiating drug therapy in childhood if medical nutrition therapy has failed to reduce LDL cholesterol to <160 mg/dl (or <130 mg/dl in the presence of an adverse CVD risk profile). Similarly, blood pressure should be treated with drugs if consistently >95th percentile or 130/80 mg/dl, whichever is lower. These strong recommendations are to be encouraged, especially as adequate blood pressure and lipid awareness and control is low in the type 1 diabetic population (132,133). Both organizations also provide extensive discussion of these issues as they apply to youth (131,134), although specific age cutoffs for drug therapy have not been firmly established. What is evident, however, is that a greater number of CHD risk factors accumulate in type 1 diabetic persons at an early age, such that many of them may qualify for risk factor intervention by the time they reach 25 years of age (135). In addition, more young people today are overweight and obese, and the development of insulin resistance with its associated atherogenic risk factors in type 1 diabetes may further increase the CHD risk.

The role of screening for CAD in diabetes has been debated for many years. To assess candidacy for renal transplantation in type 1 diabetic patients, screening is not debated, as up to 50% of these patients have asymptomatic significant CAD (136). The AHA Prevention VI Conference (130) suggested that noninvasive testing may be useful for management in type 1 diabetes but acknowledged that there were no evidence-based recommendations. A 1998 ADA consensus development conference also provided a categorization of high-risk subjects in whom screening might be considered appropriate. Recommendations for selection of testing modality were also made (137). Recent data suggest that the criteria put forth by the 1998 ADA conference are not predictive as to who will have CAD when screened (138). Given that CHD is a major cause of death in type 1 diabetes, more studies are needed to investigate the proper role of screening and whether new imaging modalities such as computed tomography angiography should change our approach to the patient with type 1 diabetes. Meanwhile, clinician and patient are urged to minimize cardiovascular risk by rigorous glycemic, lipid, and blood pressure control.

Acknowledgments

This work was partially supported by National Institutes of Health Grant DK34818.

We thank Drs. Helen Colhoun (P.I. of the London Study) and Marion Rewers (P.I. of the Denver CACTI Study) for their collaboration.

Footnotes

  • Additional information for this article can be found in an online appendix at http://care.diabetesjournals.org.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted August 15, 2006.
    • Received June 5, 2006.

References

  1. ↵
    Deckert T, Poulsen JE, Larsen M: Prognosis of diabetics with diabetes onset before the age of thirty-one. II. Factors influencing the prognosis. Diabetologia 14:371–377, 1978
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    Christlieb AR, Warram JH, Krolewski AS, Busick EJ, Ganda OP, Asmal AC, Soeldner JS, Bradley RF: Hypertension: the major risk factor in juvenile-onset insulin-dependent diabetics. Diabetes 30(Suppl. 2):90–96, 1981
    OpenUrl
  3. ↵
    Dorman JS, LaPorte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL: The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) Morbidity and Mortality Study: mortality results. Diabetes 33:271–276, 1984
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Krolewski AS, Kosinski EJ, Warram JH, Leland OS, Busick EJ, Asmal AC, Rand LI, Christlieb AR, Bradley RF, Kahn CR: Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 59:750–755, 1987
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    Moss SE, Klein R, Klein BE: Cause-specific mortality in a population-based study of diabetes. Am J Public Health 81:1158–1162, 1991
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    Orchard TJ, Olson JC, Erbey JR, Williams K, Forrest KY, Smithline Kinder L, Ellis D, Becker DJ: Insulin resistance-related factors, but not glycemia, predict coronary artery disease in type 1 diabetes. Diabetes Care 26:1374–1379, 2003
    OpenUrlAbstract/FREE Full Text
  7. ↵
    Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, Michel G, Manes C, Fuller JH, the EURODIAB Prospective Complications Study Group: Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study. Diabetes Care 27:530–537, 2004
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Pambianco G, Costacou T, Ellis D, Becker DJ, Klein R, Orchard TJ: The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes 55:1463–1469, 2006
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Diabetes Epidemiology Research International Mortality Study Group: International evaluation of cause-specific mortality and IDDM. Diabetes Care 14:55–60, 1991
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Bosnyak Z, Nishimura R, Hagan Hughes M, Tajima N, Becker D, Tuomilehto J, Orchard TJ: Excess mortality in black compared with white patients with type 1 diabetes: an examination of underlying causes. Diabet Med 22:1636–1641, 2005
    OpenUrlCrossRefPubMed
  11. ↵
    Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR, Bingley PJ, Patterson CC: Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia 46:760–765, 2003
    OpenUrlCrossRefPubMedWeb of Science
  12. ↵
    Nordwall M, Bojestig M, Arnqvist HJ, Ludvigsson J: Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of type 1 diabetes: the Linköping Diabetes Complications Study. Diabetologia 47:1266–1272, 2004
    OpenUrlPubMedWeb of Science
  13. ↵
    Hovind P, Tarnow L, Rossing P, Eising S, Larsen N, Binder C, Parving HH: Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 26:1258–1264, 2003
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O’Leary DH, Genuth S, the Diabetes Control and Complications Trial Epidemiology of Diabetes Interventions and Complications Research Group: Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 348:2294–2303, 2003
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    Dabelea D, Kinney G, Snell-Bergeon JK, Hokanson JE, Eckel RH, Ehrlich J, Garg S, Hamman RF, Rewers M: Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. Diabetes 52:2833–2839, 2003
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Colhoun HM, Rubens MB, Underwood SR, Fuller JH: The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification. J Am Coll Cardiol 36:2160–2167, 2000
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    Olson JC, Edmundowicz D, Becker DJ, Kuller LH, Orchard TJ: Coronary calcium in adults with type 1 diabetes. Diabetes 49:1571–1578, 2000
    OpenUrlAbstract
  18. ↵
    Crall FV Jr, Roberts WC: The extramural and intramural coronary arteries in juvenile diabetes mellitus: analysis of nine necropsy patients aged 19 to 38 years with onset of diabetes before age 15 years. Am J Med 64:221–230, 1978
    OpenUrlCrossRefPubMedWeb of Science
  19. Valsania P, Zarich SW, Kowalchuk GJ, Kosinski E, Warram JH, Krolewski AS: Severity of coronary artery disease in young patients with insulin-dependent diabetes mellitus. Am Heart J 122:695–700, 1991
    OpenUrlCrossRefPubMedWeb of Science
  20. ↵
    Pajunen P, Taskinen M-R, Nieminen MS, Syvänne M: Angiographic severity and extent of coronary artery disease in patients with type 1 diabetes mellitus. Am J Cardiol 86:1080–1085, 2000
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    Larsen J, Brekke M, Sandvik L, Arnesen H, Hanssen KF, Dahl-Jorgensen K: Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control. Diabetes 51:2637–2641, 2002
    OpenUrlAbstract/FREE Full Text
  22. ↵
    Jarvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimaki T, Ronnemaa T, Viikari J, Raitakari OT: Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 109:1750–1755, 2004
    OpenUrlAbstract/FREE Full Text
  23. ↵
    Singh TP, Groehn H, Kazmers A: Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. J Am Coll Cardiol 41:661–665, 2003
    OpenUrlCrossRefPubMedWeb of Science
  24. ↵
    Williams D, Erbey J, Becker D, Orchard TJ: Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes 49:626–632, 2000
    OpenUrlAbstract
  25. ↵
    Lloyd CE, Kuller LH, Becker DJ, Ellis D, Wing RR, Orchard TJ: Coronary artery disease in IDDM: gender differences in risk factors, but not risk. Arterioscler Thromb Vasc Biol 16:720–726, 1996
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Forrest KY, Becker DJ, Kuller LH, Wolfson SK, Orchard TJ: Are predictors of coronary heart disease and lower extremity arterial disease in type 1 diabetes the same? A prospective study. Atherosclerosis 148:159–169, 2000
    OpenUrlCrossRefPubMedWeb of Science
  27. ↵
    Giunti S, Bruno G, Veglio M, Gruden G, Webb DJ, Livingstone S, Chaturvedi N, Fuller JH, Perin PC: Electrocardiographic left ventricular hypertrophy in type 1 diabetes: prevalence and relation to coronary heart disease and the cardiovascular risk factors: the Eurodiab IDDM Complications Study. Diabetes Care 28:2255–2257, 2005
    OpenUrlFREE Full Text
  28. ↵
    Klein BEK, Klein R, McBride PE, Cruickshanks KJ, Palta M, Knudtson ML, Moss SE, Reinke JO: Cardiovascular disease, mortality, and retinal microvascular characteristics in type 1 diabetes: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch Intern Med 164:1917–1924, 2004
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T: Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without nephropathy: incidence and risk factors. Diabetologia 30:144–148, 1987
    OpenUrlCrossRefPubMedWeb of Science
  30. ↵
    Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type I diabetes. Am J Med 78:785–794, 1985
    OpenUrlCrossRefPubMedWeb of Science
  31. ↵
    Tuomilehto J, Borch-Johnsen K, Molarius A, Forsén T, Rastenyte D, Sarti C, Reunanen A: Incidence of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland. Diabetologia 41:784–790, 1998
    OpenUrlCrossRefPubMedWeb of Science
  32. ↵
    Torffvit O, Lövestam-Adrian M, Agardh E, Agardh C-D: Nephropathy, but not retinopathy, is associated with the development of heart disease in type 1 diabetes: as 12-year observation study of 462 patients. Diabet Med 22:723–729, 2005
    OpenUrlCrossRefPubMedWeb of Science
  33. ↵
    May O, Arildsen H, Damsgaard EM, Mickley H: Cardiovascular autonomic neuropathy in insulin-dependent diabetes mellitus: prevalence and estimated risk of coronary heart disease in the general population. J Inter Med 248:483–491, 2000
    OpenUrlCrossRef
  34. ↵
    Ewing DJ, Campbell IW, Clarke BF: Mortality in diabetic autonomic neuropathy. Lancet 1:601–603, 1976
    OpenUrlCrossRefPubMedWeb of Science
  35. ↵
    Veglio M, Giunti S, Stevens LK, Fuller JH, Perin PC, the EURODIAB IDDM Complications Study Group: Prevalence of Q-T interval dispersion in type 1 diabetes and its relation with cardiac ischemia: the EURODIAB IDDM Complications Study Group. Diabetes Care 25:702–707, 2002
    OpenUrlAbstract/FREE Full Text
  36. ↵
    Stella P, Ellis D, Maser RE, Orchard TJ: Cardiac autonomic neuropathy (expiration and inspiration ratio) in type 1 diabetes: incidence and predictors. J Diabetes Complications 14:1–6, 2000
    OpenUrlCrossRefPubMedWeb of Science
  37. ↵
    Rathmann W, Ziegler D, Jahnke M, Haastert B, Gries FA: Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med 10:820–824, 1993
    OpenUrlPubMedWeb of Science
  38. ↵
    Orchard TJ, Lloyd CE, Maser RE, Kuller LH: Why does diabetic autonomic neuropathy predict IDDM mortality? An analysis from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Res Clin Pract 34 (Suppl.):S165–S171, 1996
  39. ↵
    Valabhji J, Donovan J, McColl AJ, Schachter M, Richmond W, Elkeles RS: Rates of cholesterol esterification and esterified cholesterol net mass transfer between high-density lipoproteins and apolipoprotein B-containing lipoproteins in type 1 diabetes. Diabet Med 19:424–428, 2002
    OpenUrlCrossRefPubMed
  40. ↵
    Soedamah-Muthu SS, Chang Y-F, Otvos J, Evans RW, Orchard TJ: Lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy improve the prediction of coronary artery disease in type 1 diabetes: a prospective report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 46:674–682, 2003
    OpenUrlPubMedWeb of Science
  41. ↵
    Mackness B, Durrington PN, Boulton AJ, Hine D, Mackness MI: Serum paraoxonase activity in patients with type 1 diabetes compared to healthy controls. Eur J Clin Invest 32:259–264, 2002
    OpenUrlCrossRefPubMedWeb of Science
  42. ↵
    Lehto S, Rönnemaa T, Pyörälä K, Laakso M: Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy. Arterioscler Thromb Vasc Biol 19:1014–1019, 1999
    OpenUrlAbstract/FREE Full Text
  43. ↵
    Olson JC, Erbey JR, Forrest KY, Williams K, Becker DJ, Orchard TJ: Glycemia (or, in women, estimated glucose disposal rate) predict lower extremity arterial disease events in type 1 diabetes. Metabolism 51:248–254, 2002
    OpenUrlCrossRefPubMedWeb of Science
  44. ↵
    Moss SE, Klein BEK, Klein R: The 14-year incidence of lower-extremity amputations in a diabetic population: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 22:951–959, 1999
    OpenUrlAbstract
  45. ↵
    Jenkins AJ, Best JD, Klein RL, Lyons TJ: Lipoproteins, glycoxidation and diabetic angiopathy. Diabetes Metab Res Rev 20:349–368, 2004
    OpenUrlCrossRefPubMed
  46. ↵
    Calton R, Calton R, Dhanoa J, Jaison TM: Angiographic severity and morphological spectrum of coronary artery disease in non insulin dependent diabetes mellitus. Indian Heart J 47:343–348, 1995
    OpenUrlPubMed
  47. ↵
    Kornowski R, Mintz GS, Lansky AJ, Hong MK, Kent KM, Pichard AD, Satler LF, Popma JJ, Bucher TA, Leon MB: Paradoxic decreases in atherosclerosis plaque mass in insulin-treated diabetic patients. Am J Cardiol 81:1298–1304, 1998
    OpenUrlCrossRefPubMedWeb of Science
  48. ↵
    Kasaoka S, Okuda F, Satoh A, Miura T, Kohno M, Fujii T, Katayama K, Ogawa H, Matsuzaki M: Effect of coronary risk factors in coronary angiographic morphology in patients with ischemic heart disease. Jpn Circ J 61:390–395, 1997
    OpenUrlCrossRefPubMed
  49. ↵
    Silva JA, Escobar A, Collins TJ, Ramee SR, White CJ: Unstable angina: a comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation 92:1731–1736, 1995
    OpenUrlAbstract/FREE Full Text
  50. Davies MJ: Stability and instability: two faces of coronary atherosclerosis: the Paul Dudley White Lecture 1995. Circulation94:2013–2020, 1996
    OpenUrlFREE Full Text
  51. ↵
    Davies MJ: The composition of coronary-artery plaques. N Engl J Med 336:1312–1314, 1997
    OpenUrlCrossRefPubMedWeb of Science
  52. ↵
    Moreno PR, Murcia AM, Palacios I, Leon MN, Bernardi VH, Fuster V, Fallon JT: Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation 102:2180–2184, 2002
    OpenUrl
  53. ↵
    Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A: The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation 108:1070–1077, 2003
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Burke AP, Kolodgie FD, Zieske A, Fowler DR, Weber DK, Varghese PJ, Farb A, Virmani R: Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb Vasc Biol 24:1266–1271, 2004
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005
    OpenUrlCrossRefPubMedWeb of Science
  56. ↵
    Larsen JR, Brekke M, Bergengen L, Sandvik L, Arnesen H, Hanssen KF, Dahl-Jorgensen K: Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes. Diabetologia 48:776–779, 2005
    OpenUrlCrossRefPubMed
  57. ↵
    Jensen-Urstad KJ, Reichard PG, Rosfors JS, Lindblad LEL, Jensen-Urstad MT: Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM. Diabetes 45:1253–1258, 1996
    OpenUrlAbstract/FREE Full Text
  58. ↵
    Jenkins AJ, Steele JS, Janus ED, Best JD: Increased plasma apolipoprotein(a) levels in IDDM patients with microalbuminuria. Diabetes 40:787–790, 1991
    OpenUrlAbstract/FREE Full Text
  59. ↵
    Chan NN, Vallance P, Colhoun HM: Endothelium-dependent and -independent vascular dysfunction in type 1 diabetes: role of conventional risk factors, sex, and glycemic control. Arterioscler Thromb Vasc Biol 23:1048–1054, 2003
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Shishehbor MH, Hoogwerf BJ, Schoenhagen P, Marso SP, Sun JP, Li J, Klein AL, Thomas JD, Garcia MJ: Relation of hemoglobin A1c to left ventricular relaxation in patients with type 1 diabetes mellitus and without overt heart disease. Am J Cardiol 91:1514–1517, 2003
    OpenUrlCrossRefPubMedWeb of Science
  61. ↵
    Farid NR, Barnard JM, Pepper B, Noel EP, Kelly F, Davis AJ, Hobeika C, Marshall WH: The association of HLA with juvenile diabetes mellitus in Newfoundland. Tissue Antigens 12:215–222, 1978
    OpenUrlCrossRefPubMed
  62. ↵
    Senior PA, Welsh RC, McDonald CG, Paty BW, Shapiro AMJ, Ryan EA: Coronary artery disease is common in nonumeric, asymptomatic type 1 diabetic islet transplant candidates. Diabetes Care 28:866–872, 2005
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Orchard TJ, Chang Y-F, Ferrell RE, Petro N, Ellis DE: Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int 62:963–970, 2002
    OpenUrlCrossRefPubMedWeb of Science
  64. ↵
    Erbey JR, Kuller LH, Becker DJ, Orchard TJ: The association between a family history of type 2 diabetes and coronary artery disease in a type 1 diabetes population. Diabetes Care 21:610–614, 1998
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD: Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT: Diabetes Control and Complications Trial. JAMA 280:140–146, 1998
    OpenUrlCrossRefPubMedWeb of Science
  66. ↵
    Purnell JQ, Dev RK, Steffes MW, Cleary PA, Palmer JP, Hirsch IB, Hokanson JE, Brunzell JD: Relationship of family history of type 2 diabetes, hypoglycemia, and autoantibodies to weight gain and lipids with intensive and conventional therapy in the Diabetes Control and Complications Trial. Diabetes 52:2623–2629, 2003
    OpenUrlAbstract/FREE Full Text
  67. ↵
    Ross R: Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126, 1999
    OpenUrlCrossRefPubMedWeb of Science
  68. Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, Hsueh W, Rewers M, Roberts BT, Savage PJ, Skarlatos S, Wassef M, Rabadan-Diehl C, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus: Report of the National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation 111:3489–3493, 2005
    OpenUrlFREE Full Text
  69. ↵
    Baynes JW, Thorpe SR: Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9, 1999
    OpenUrlAbstract
  70. ↵
    Orchard TJ, Virella G, Forrest KYZ, Evans RW, Becker DJ, Lopes-Virella MF: Antibodies to oxidized LDL predict coronary artery disease in type 1 diabetes: a nested case-control study from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes 48:1454–1458, 1999
    OpenUrlAbstract
  71. ↵
    Lopes-Virella MF, Virella G: Immune mechanisms of atherosclerosis in diabetes mellitus. Diabetes 41(Suppl. 2):86–91, 1992
    OpenUrl
  72. ↵
    Diaz MN, Frei B, Vita JA, Keaney JF: Antioxidants and atherosclerotic heart disease. N Engl J Med 337:408–416, 1997
    OpenUrlCrossRefPubMedWeb of Science
  73. ↵
    Springer TA, Cybulsky MI: Traffic signals on endothelium for leukocytes in health, inflammation, and atherosclerosis. In Atherosclerosis and Coronary Artery Disease. Vol. 1. Fuster V, Ross R, Topol EJ, Eds. Philadelphia, Lippincott-Raven, 1996, p. 511–538
  74. ↵
    Costacou T, Lopes-Virella MF, Zgibor J, Virella G, Otvos J, Walsh M, Orchard TJ: Markers of endothelial dysfunction in the prediction of coronary artery disease in type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complication Study. J Diabetes Complications 19:183–193, 2005
    OpenUrlCrossRefPubMedWeb of Science
  75. ↵
    Bevilacqua MP: Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 11:767–804, 1993
    OpenUrlCrossRefPubMedWeb of Science
  76. ↵
    Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CDA: Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes: the Eurodiab Prospective Complications Study. Diabetologia 48:370–378, 2005
    OpenUrlCrossRefPubMedWeb of Science
  77. ↵
    Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD, the Eurodiab Prospective Complications Study Group: Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study. J Intern Med. 258:450–459, 2005
    OpenUrlCrossRefPubMedWeb of Science
  78. ↵
    Bosnyak Z, Forrest KYZ, Becker D, Orchard TJ: Do plasminogen activator inhibitor (PAI-1) or tissue plasminogen activator PAI-1 complexes predict complications in type 1 diabetes? The Pittsburgh Epidemology of Diabetes Complications Study. Diabet Med 20:147–151, 2003
    OpenUrlCrossRefPubMed
  79. ↵
    Wadwa RP, Kinney GL, Ogden L, Snell-Bergeon JK, Maahs DM, Cornell E, Tracy RP, Rewers M: Soluble interleukin-2 receptor as a marker for progression of coronary artery calcification in type 1 diabetes. Int J Biochem Cell Biol 38:996–1003, 2006
    OpenUrlCrossRefPubMed
  80. ↵
    Cipollone F, Chiarelli F, Davì, Ferri C, Desideri G, Fazia M, Iezzi A, Santilli F, Pini B, Cuccurullo C, Tumini S, Del Ponte A, Santucci A, Cuccurullo F, Mezzetti A: Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia 48:1216–1224, 2005
    OpenUrlCrossRefPubMed
  81. ↵
    Harding SA, Sommerfield AJ, Sarma J, Twomey PJ, Newby DE, Frier BM, Fox KAA: Increased CD40 ligand and platelet-monocyte aggregates in patients with type 1 diabetes mellitus. Atherosclerosis 176:321–325, 2004
    OpenUrlCrossRefPubMed
  82. ↵
    Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y: Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83, 1999
    OpenUrlCrossRefPubMedWeb of Science
  83. ↵
    Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M, Igura T, Inui Y, Kihara S, Nakamura T, Yamashita S, Miyagawa J, Funahashi T, Matsuzawa Y: An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 32:47–50, 2000
    OpenUrlCrossRefPubMedWeb of Science
  84. ↵
    Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y: Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein, adiponectin. Circulation 100:2473–2476, 1999
    OpenUrlAbstract/FREE Full Text
  85. ↵
    Imagawa A, Funahashi T, Nakamura T, Moriwaki M, Tanaka S, Nishizawa H, Sayama K, Uno S, Iwahashi H, Yamagata K, Miyagawa J, Matsuzawa Y: Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes. Diabetes Care 25:1665–1666, 2002
    OpenUrlFREE Full Text
  86. ↵
    Perseghin G, Lattuada G, Danna M, Sereni LP, Maffi P, De Cobelli F, Battezzati A, Secchi A, Del Maschio A, Luzi L: Insulin resistance, intramyocellular lipid content, and plasma adiponectin in patients with type 1 diabetes. Am J Physiol Endocrinol Metab 285:E1174–E1181, 2003
    OpenUrlAbstract/FREE Full Text
  87. ↵
    Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270:26746–26749, 1995
    OpenUrlAbstract/FREE Full Text
  88. ↵
    Looker HC, Krakoff J, Funahashi T, Matsuzawa Y, Tanaka S, Nelson RG, Knowler WC, Lindsay RS, Hanson RL: Adiponectin concentrations are influenced by renal function and diabetes duration in Pima Indians with type 2 diabetes. J Clin Endocrinol Metab 89:4010–1017, 2004
    OpenUrlCrossRefPubMedWeb of Science
  89. ↵
    Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Seminara G, Rapisarda F, Fatuzzo P, Buemi M, Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y: Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 13:134–141, 2002
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Costacou T, Zgibor JC, Evans RW, Otvos J, Lopes-Virella MF, Tracy RP, Orchard TJ: The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 48:41–48, 2005
    OpenUrlCrossRefPubMedWeb of Science
  91. ↵
    Maahs DM, Ogden LG, Kinney GL, Wadwa P, Snell-Bergeon JK, Dabelea D, Hokanson JE, Ehrlich J, Eckel RH, Rewers M: Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation 111:747–753, 2005
    OpenUrlAbstract/FREE Full Text
  92. ↵
    Earle K, Walker J, Hill C, Viberti G-C: Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med 326:673–677, 1992
    OpenUrlCrossRefPubMedWeb of Science
  93. ↵
    Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK, Ferrannini E: Parental history of diabetes is associated with increased cardiovascular risk factors. Arteriosclerosis 9:928–933, 1989
    OpenUrlAbstract/FREE Full Text
  94. ↵
    Hudson BI, Stickland MH, Futers TS, Grant PJ: Study of the −429 T/C and −374 T/A receptor for advanced glycation end products promoter polymorphisms in diabetic and nondiabetic subjects with macrovascular disease (Letter). Diabetes Care 24:2004, 2001
    OpenUrlFREE Full Text
  95. ↵
    Prevost G, Fajardy I, Besmond C, Balkau B, Tichet J, Fontaine P, Danze PM, Marre M, the Genediab and D.E.S.I.R. studies: Polymorphisms of the receptor of advanced glycation endproducts (RAGE) and the development of nephropathy in type 1 diabetic patients. Diabetes Metab 31:35–39, 2005
    OpenUrlCrossRefPubMed
  96. ↵
    Pettersson-Fernholm K, Forsblom C, Hudson BI, Perola M, Grant PJ, Groop PH, the Finn-Diane Study Group: The functional −374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients. Diabetes 52:891–894, 2003
    OpenUrlAbstract/FREE Full Text
  97. ↵
    Hudson BI, Stickland MH, Grant PJ: Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups. Diabetes 47:1155–1157, 1998
    OpenUrlPubMedWeb of Science
  98. ↵
    Falcone C, Campo I, Emanuele E, Buzzi MP, Zorzetto M, Sbarsi I, Cuccia M: Relationship between the −374T/A RAGE gene polymorphism and angiographic coronary artery disease. Int J Mol Med 14:1061–1064, 2004
    OpenUrlPubMedWeb of Science
  99. ↵
    Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F: An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346, 1990
    OpenUrlCrossRefPubMedWeb of Science
  100. ↵
    Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, Schunkert H: Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 92:1387–1388, 1995
    OpenUrlAbstract/FREE Full Text
  101. ↵
    Boright AP, Paterson AD, Mirea L, Bull SB, Mowjoodi A, Scherer SW, Zinman B, the DCCT/EDIC Research Group: Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 54:1238–1244, 2005
    OpenUrlAbstract/FREE Full Text
  102. ↵
    Hadjadj S, Belloum R, Bouhanick B, Gallois Y, Guilloteau G, Chatellier G, Alhenc-Gelas F, Marre M: Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study. J Am Soc Nephrol 12:541–549, 2001
    OpenUrlAbstract/FREE Full Text
  103. ↵
    Marre M, Jeunemaitre X, Gallois Y, Rodier M, Chatellier G, Sert C, Dusselier L, Kahal Z, Chaillous L, Halimi S, Muller A, Sackmann H, Bauduceau B, Bled F, Passa P, Alhenc-Gelas F: Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group. J Clin Invest 99:1585–1595, 1997
    OpenUrlPubMedWeb of Science
  104. ↵
    van Ittersum FJ, de Man AM, Thijssen S, de Knijff P, Slagboom E, Smulders Y, Tarnow L, Donker AJ, Bilo HJ, Stehouwer CD: Genetic polymorphisms of the renin-angiotensin system and complications of insulin-dependent diabetes mellitus. Nephrol Dial Transplant 15:1000–1007, 2000
    OpenUrlAbstract/FREE Full Text
  105. ↵
    Panahloo A, Andrès C, Mohamed-Ali V, Gould MM, Talmud P, Humphries SE, Yudkin JS: The insertion allele of the ACE gene I/D polymorphism: a candidate gene for insulin resistance? Circulation 92:3390–3393, 1995
    OpenUrlAbstract/FREE Full Text
  106. ↵
    Wong JS, Pearson DW, Murchison LE, Williams MJ, Narayan V: Mortality in diabetes mellitus: experience of a geographically defined population. Diabet Med 8:135–139, 1991
    OpenUrlPubMedWeb of Science
  107. ↵
    Pettersson-Fernholm K, Karvonen MK, Kallio J, Forsblom CM, Koulu M, Pesonen U, Fagerudd JA, Groop PH, the FinnDiane Study Group: Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients. Diabetes Care 27:503–509, 2004
    OpenUrlAbstract/FREE Full Text
  108. ↵
    Nordman S, Ding B, Ostenson CG, Karvestedt L, Brismar K, Efendic S, Gu SF: Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men. Exp Clin Endocrinol Diabetes 113:282–287, 2005
    OpenUrlCrossRefPubMed
  109. ↵
    Pihlajamaki J, Karhapaa P, Vauhkonen I, Kekalainen P, Kareinen A, Viitanen L, Pesonen U, Kallio J, Uusitupa M, Laakso M: The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism. Metabolism 52:643–646, 2003
    OpenUrlCrossRefPubMedWeb of Science
  110. ↵
    Jansen H, Verhoeven AJ, Weeks L, Kastelein JJ, Halley DJ, van den Ouweland A, Jukema JW, Seidell JC, Birkenhager JC: Common C-to-T substitution at position −480 of the hepatic lipase promoter associated with a lowered lipase activity in coronary artery disease patients. Arterioscler Thromb Vasc Biol 17:2837–2842, 1997
    OpenUrlAbstract/FREE Full Text
  111. ↵
    Hokanson JE, Cheng S, Snell-Bergeon JK, Fijal BA, Grow MA, Hung C, Erlich HA, Ehrlich J, Eckel RH, Rewers M: A common promoter polymorphism in the hepatic lipase gene (LIPC-480C>T) is associated with an increase in coronary calcification in type 1 diabetes. Diabetes 51:1208–1213, 2002
    OpenUrlAbstract/FREE Full Text
  112. ↵
    Andersen RV, Wittrup HH, Tybjaerg-Hansen A, Steffensen R, Schnohr P, Nordestgaard BG: Hepatic lipase mutations, elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 41:1972–1982, 2003
    OpenUrlCrossRefPubMedWeb of Science
  113. ↵
    Ji J, Herbison CE, Mamotte CD, Burke V, Taylor RR, van Bockxmeer FM: Hepatic lipase gene −514 C/T polymorphism and premature coronary heart disease. J Cardiovasc Risk 9:105–113, 2002
    OpenUrlCrossRefPubMedWeb of Science
  114. ↵
    Dugi KA, Feuerstein IM, Hill S, Shih J, Santamarina-Fojo S, Brewer HB Jr, Hoeg JM: Lipoprotein lipase correlates positively and hepatic lipase inversely with calcific atherosclerosis in homozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 17:354–364, 1997
    OpenUrlAbstract/FREE Full Text
  115. ↵
    Shohet RV, Vega GL, Anwar A, Cigarroa JE, Grundy SM, Cohen JC: Hepatic lipase (LIPC) promoter polymorphism in men with coronary artery disease: allele frequency and effects on hepatic lipase activity and plasma HDL-C concentrations. Arterioscler Thromb Vasc Biol 19:1975–1978, 1999
    OpenUrlAbstract/FREE Full Text
  116. ↵
    Fan YM, Salonen JT, Koivu TA, Tuomainen TP, Nyyssonen K, Lakka TA, Salonen R, Seppanen K, Nikkari ST, Tahvanainen E, Lehtimaki T: Hepatic lipase C-480T polymorphism modifies the effect of HDL cholesterol on the risk of acute myocardial infarction in men: a prospective population based study. J Med Genet 41:e28, 2004
    OpenUrlFREE Full Text
  117. ↵
    Gomez P, Perez-Jimenez F, Marin C, Moreno JA, Gomez MJ, Bellido C, Perez-Martinez P, Fuentes F, Paniagua JA, Lopez-Miranda J: The −514 C/T polymorphism in the hepatic lipase gene promoter is associated with insulin sensitivity in a healthy young population. J Mol Endocrinol 34:331–338, 2005
    OpenUrlAbstract/FREE Full Text
  118. ↵
    Stefan N, Schafer S, Machicao F, Machann J, Schick F, Claussen CD, Stumvoll M, Haring HU, Fritsche A: Liver fat and insulin resistance are independently associated with the −514C>T polymorphism of the hepatic lipase gene. J Clin Endocrinol Metab 90:4238–4243, 2005
    OpenUrlCrossRefPubMedWeb of Science
  119. ↵
    Ostos MA, Conconi M, Vergnes L, Baroukh N, Ribalta J, Girona J, Caillaud JM, Ochoa A, Zakin MM: Antioxidative and antiatherosclerotic effects of human apolipoprotein A-IV in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 21:1023–1028, 2001
    OpenUrlAbstract/FREE Full Text
  120. ↵
    Kretowski A, Hokanson JE, McFann K, Kinney GL, Snell-Bergeon JK, Maahs DM, Wadwa RP, Eckel RH, Ogden LG, Garg SK, Li J, Cheng S, Erlich HA, Rewers M: The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes. Diabetologia 49:1946–1954, 2006
    OpenUrlCrossRefPubMed
  121. ↵
    Rewers M, Kamboh MI, Hoag S, Shetterly SM, Ferrell RE, Hamman RF: ApoA-IV polymorphism associated with myocardial infarction in obese NIDDM patients: the San Luis Valley Diabetes Study. Diabetes 43:1485–1489, 1994
    OpenUrlAbstract/FREE Full Text
  122. ↵
    Lacquemant C, Gaucher C, Delorme C, Chatellier G, Gallois Y, Rodier M, Passa P, Balkau B, Mazurier C, Marre M, Froguel P: Association between high von Willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. Kidney Int 57:1437–1443, 2000
    OpenUrlCrossRefPubMed
  123. ↵
    Whincup PH, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Rumley A, Lowe GD: von Willebrand factor and coronary heart disease: prospective study and meta-analysis. Eur Heart J 23:1764–1770, 2002
    OpenUrlAbstract/FREE Full Text
  124. ↵
    Lacquemant C, Froguel P, Lobbens S, Izzo P, Dina C, Ruiz J: The adiponectin gene SNP+45 is associated with coronary artery disease in type 2 (non-insulin-dependent) diabetes mellitus. Diabet Med 21:776–781, 2004
    OpenUrlCrossRefPubMedWeb of Science
  125. ↵
    Bacci S, Menzaghi C, Ercolino T, Ma X, Rauseo A, Salvemini L, Vigna C, Fanelli R, Di Mario U, Doria A, Trischitta V: The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients. Diabetes Care 27:2015–2020, 2004
    OpenUrlAbstract/FREE Full Text
  126. ↵
    Qi L, Li T, Rimm E, Zhang C, Rifai N, Hunter D, Doria A, Hu FB: The +276 polymorphism of the APM1 gene, plasma adiponectin concentration, and cardiovascular risk in diabetic men. Diabetes 54:1607–1610, 2005
    OpenUrlAbstract/FREE Full Text
  127. ↵
    Hadjadj S, Aubert R, Fumeron F, Pean F, Tichet J, Roussel R, Marre M, the SURGENE Study Group, the DESIR Study Group: Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetes subjects. Diabetologia 48:1088–1092, 2005
    OpenUrlCrossRefPubMedWeb of Science
  128. ↵
    Collins R, Armitage J, Parish S, Sleigh P, Peto R, the Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361:2005–2016, 2003
    OpenUrlCrossRefPubMedWeb of Science
  129. ↵
    American Diabetes Association: Standards of Medical Care–2006 (Position Statement). Diabetes Care 29(Suppl. 1):4–42, 2006
    OpenUrl
  130. ↵
    Grundy SM, Howard B, Smith S Jr, Eckel R, Redberg R, Bonow RO: Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive Summary: Conference proceeding for healthcare professionals from a special writing group of the American Heart Association. Circulation 105:2231–2239, 2002
    OpenUrlFREE Full Text
  131. ↵
    Kavey REW, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K: American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 107:1562–1566, 2003
    OpenUrlFREE Full Text
  132. ↵
    Zgibor JC, Wilson RR, Orchard TJ: Has control of hypercholesterolemia and hypertension in type 1 diabetes improved over time? Diabetes Care 28:521–526, 2005
    OpenUrlAbstract/FREE Full Text
  133. ↵
    Wadwa RP, Kinney GL, Maahs DM, Snell-Bergeon J, Hokanson JE, Garg SK, Eckel RH, Rewers M: Awareness and treatment of dyslipidemia in young adults with type 1 diabetes. Diabetes Care 28:1051–1056, 2005
    OpenUrlAbstract/FREE Full Text
  134. ↵
    Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, Deeb L, Grey M, Anderson B, Holzmeister LA, Clark N, the American Diabetes Association: Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 28:186–212, 2005
    OpenUrlFREE Full Text
  135. ↵
    Schwab KO, Doerfer J, Hecker W, Grulich-Henn J, Wiemann D, Kordonouri O, Beyer P, Holl RW, the DPV Initiative of the German Working Group for Pediatric Diabetology: Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV). Diabetes Care 29:218–225, 2006
    OpenUrlAbstract/FREE Full Text
  136. ↵
    Ramanathan V, Goral S, Tanriover B, Feurer ID, Kazancioglu R, Shaffer D, Helderman JH: Screening asymptomatic diabetic patients for coronary artery disease prior to renal transplantation. Transplantation 79:1453–1458, 2005
    OpenUrlCrossRefPubMedWeb of Science
  137. ↵
    American Diabetes Association: Consensus development conference on the diagnosis of coronary heart disease in people with diabetes. Diabetes Care 21:1551–1559, 1998
    OpenUrlFREE Full Text
  138. ↵
    Scognamiglio R, Negut C, Ramondo A, Tiengo A, Avogaro A: Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus. J Am Coll Cardiol 47:65–71, 2006
    OpenUrlCrossRefPubMedWeb of Science
  139. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R: Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 336:1276–1282, 1997
    OpenUrlCrossRefPubMedWeb of Science
  140. McAlpine RR, Morris AD, Emslie-Smith AM, James P, Evans JM: The annual incidence of diabetic complications in a population of patients with type 1 and type 2 diabetes. Diabet Med 22:348–352, 2005
    OpenUrlCrossRefPubMed
  141. Lewis S, MacLeod M, McKnight J, Morris A, Peden N, Prescott R, Walker J, the Royal College of Physicians of Edinburgh Diabetes Register Group: Predicting vascular risk in type 1 diabetes: stratification in a hospital based population in Scotland. Diabet Med 22:164–171, 2005
    OpenUrlCrossRefPubMed
  142. Soedamah-Muthu SS, Fuller JH, Mulnier HE, Raleigh VS, Lawrenson RA, Colhoun HM: High risk of cardiovascular disease in patients with type 1 diabetes mellitus in the UK, a cohort study using the General Practice Research Database. Diabetes Care 29:798–804, 2006
    OpenUrlAbstract/FREE Full Text
  143. Frost D, Friedl A, Beischer W: Determinants of early carotid atherosclerosis progression in young patients with type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 110:92–94, 2002
    OpenUrlCrossRefPubMed
  144. Hayaishi-Okano R, Yamasaki Y, Katakami N, Ohtoshi K, Gorogawa S, Kuroda A, Matsuhisa M, Kosugi K, Nishikawa N, Kajimoto Y, Hori M: Elevated C-reactive protein associates with early stage carotid atherosclerosis in young subjects with type 1 diabetes. Diabetes Care 25:1432–1438, 2002
    OpenUrlAbstract/FREE Full Text
  145. Jarvisalo MJ, Putto-Laurila A, Jartti L, Lehtimaki T, Solakivi T, Ronnemaa T, Raitakari OT: Carotid artery intima-media thickness in children with type 1 diabetes. Diabetes 51:493–498, 2002
    OpenUrlAbstract/FREE Full Text
  146. Yavuz T, Akcay A, Omeroglu RE, Bundak R, Sukur M: Ultrasonic evaluation of early atherosclerosis in children and adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 15:1131–1136, 2002
    OpenUrlPubMedWeb of Science
  147. Gunczler P, Lanes R, Lopez E, Esaa S, Villarroel O, Revel-Chion R: Cardiac mass and function, carotid artery intima-media thickness and lipoprotein (a) levels in children and adolescents in type 1 diabetes mellitus of short duration. J Pediatr Endocrinol Metab 15:181–186, 2002
    OpenUrlPubMed
  148. Berger E, Sochett E, Parikh A, Daneman D: Carotid artery structure and function in young adults with type 1 diabetes (Abstract). Diabetes 52(Suppl. 1):A45, 2003
    OpenUrl
  149. Kowalewski MA, Urban M, Florys B, Peczynska J: Late potentials: are they related to cardiovascular complications in children with type 1 diabetes? J Diabetes Complications 16:263–270, 2002
    OpenUrlCrossRefPubMedWeb of Science
  150. Haller MJ, Samyn M, Nichols WW, Brusko T, Wasserfall C, Schwartz RF, Atkinson M, Shuster JJ, Pierce GL, Silverstein JH: Radial artery tonometry demonstrates arterial stiffness in children with type 1 diabetes. Diabetes Care 27:2911–2917, 2004
    OpenUrlAbstract/FREE Full Text
  151. Sundell J, Janatuinen T, Ronnemaa T, Naum A, Laine H, Luotolahti M, Nuutila P, Raitakari OT, Knuuti J: Lifetime glycaemic exposure predicts reduced coronary vasoreactivity in type 1 diabetic subjects. Diabet Med 22:45–51, 2005
    OpenUrlCrossRefPubMed
  152. Jorgensen L, Jenssen T, Joakimsen O, Heuch I, Ingebretsen OC, Jacobsen BK: Glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the Tromso study. Circulation 110:466–470, 2004
    OpenUrlAbstract/FREE Full Text
  153. Gyongyosi M, Yang P, Hassan A, Weidinger F, Domanovits H, Laggner A, Glogar D: Coronary risk factors influence plaque morphology in patients with unstable angina. Coron Artery Dis 10:211–219, 1999
    OpenUrlPubMedWeb of Science
  154. Henry P, Makowski S, Richard P, Beverelli F, Casanova S, Louali A, Boughalem K, Battaglia S, Guize L, Guermonprez JL: Increased incidence of moderate stenosis among patients with diabetes: substrate for myocardial infarction? Am Heart J 134:1037–1043, 1997
    OpenUrlCrossRefPubMedWeb of Science
  155. Spagnoli LG, Mauriello A, Palmieri G, Santeusanio G, Amante A, Taurino M: Relationships between risk factors and morphological patterns of human carotid atherosclerotic plaques: a multivariate discriminant analysis. Atherosclerosis 108:39–60, 1994
    OpenUrlPubMed
  156. Mautner SL, Lin F, Roberts WC: Composition of atherosclerotic plaques in the epicardial coronary arteries in juvenile (type I) diabetes mellitus. Am J Cardiol 70:1264–1268, 1992
    OpenUrlCrossRefPubMed
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Diabetes Care: 29 (11)

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November 2006, 29(11)
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Type 1 Diabetes and Coronary Artery Disease
Trevor J. Orchard, Tina Costacou, Adam Kretowski, Richard W. Nesto
Diabetes Care Nov 2006, 29 (11) 2528-2538; DOI: 10.2337/dc06-1161
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