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Table 1. Selected incidence studies of coronary artery disease in type 1 diabetes Reference / Study Study population / Results Comments hypothesis Deckert et al. Prognosis of 289 patients diagnosed Myocardial infarction was the Clinical manifestations of late diabetics with diabetes before 1933 and before the cause of death in 25% of diabetes complications were onset before the age of patient was thirty-one years deceased patients. Of the total considerably less common in patients thirty-one. I. Survival, old were followed to assess population, 21% exhibited who were still alive after more than causes of death, and the incidence and cause of objective signs of myocardial forty years of diabetes than in patients complications. mortality. infarction. who died before their fortieth year of Diabetologia 14:363-370, diabetes. 1978. (1) Dorman et al. The 1966 type 1 diabetes patients Standardized mortality ratios for Before age 20, the primary excess in Pittsburgh Insulin- diagnosed between 1950 and cardiovascular disease in mortality was within 6 months after Reference / Study Study population / Results Comments hypothesis Dependent Diabetes 1981 were followed to patients with type 1 diabetes onset, and due to acute diabetic Mellitus (IDDM) morbidity assess survival. compared to the general U.S. complications. After age 20, the and mortality study. population were 1137 for white annual mortality risk was Mortality Results. Diabetes males and 1591 for white approximately 2%, which was more 33:271-276, 1984. (3) females. than 20 times greater than for the U.S. population. Krolewski et al. Magnitude 292 patients with juvenile- Of the 292 patients in the study, CAD mortality risk was similar by and determinants of onset, type 1 diabetes 80 died by January 1, 1981. gender. Age at diabetes onset and eye coronary artery disease in mellitus were followed for CAD accounted for 35% of all complications did not contribute to juvenile-onset, insulin- 20 to 40 years to assess the deaths, far higher than in non- CAD mortality risk. dependent diabetes incidence of coronary artery diabetic men (8%) and women mellitus. Am J Cardiol. disease (CAD) mortality. (4%) in the Framingham study. 59:750-755, 1987. (4) Reference / Study Study population / Results hypothesis Diabetes Epidemiology Mortality status was There were a total of 147 deaths Research International determined for all (1.8%). Of those, 6% were Mortality Study Group. individuals diagnosed with attributed to coronary artery International-evaluation type 1 diabetes at the age of disease / cerebrovascular cause-specific mortality and <18 years between 1965 and IDDM. Diabetes Care 1979, who were taking 14:55–60, 1991. (9) insulin at the time of hospital discharge in population-based cohorts from Japan (n=1394), Israel (n=611), Allegheny County (n=986), and Finland (n=5146). Mortality was accident. Comments Reference / Study Study population / Results Comments hypothesis determined as of January 1, 1985. Moss et al. Cause-specific Cause-specific age-sex Age-sex standardized mortality Cause of death was determined from mortality in a population- standardized mortality ratios ratios were significantly high death certificates. Diabetic persons based study of diabetes. were assessed in a (p<0.05) in younger onset experienced very high mortality, Am J Public Health geographically defined persons for all heart disease especially from vascular diseases, 81:1158-1162, 1991. (5) population of younger onset (9.1), ischemic heart disease compared to the general population. (diagnosed <30 years and (10.1), and other heart disease taking insulin, n=1200) (6.3). persons followed for 8.5 years. Tuomilehto et al. Incidence A prospective analysis of the Of 5148 patients, 159 had a There were virtually no cases of Reference / Study Study population / Results Comments hypothesis of cardiovascular disease in incidence of cardiovascular cardiovascular event (58 had cardiovascular disease before 12 Type 1 (insulin-dependent) disease was performed in all coronary heart disease; 57 years diabetes duration. The presence diabetic subjects with and 5148 type 1 subjects in the stroke; 44 other heart disease). of nephropathy in type 1 diabetes without diabetic Finnish Type 1 diabetes The cumulative incidence of subjects increased the risk of nephropathy in Finland. mellitus register diagnosed cardiovascular disease by 40 coronary heart disease and that of Diabetologia 41:784-90, before the age of 18 years years of age was 43% in stroke tenfold. 1998. (31) between 1 January 1965 and patients with diabetic 31 December 1979 nephropathy, compared with nationwide. 7% in patients without diabetic nephropathy, similarly in men and women. Laing et al. Mortality from 23,751 patients with insulin- Of the 1437 deaths during Patients were defined as having type heart disease in a cohort of treated diabetes, diagnosed follow-up, 536 were from 1 diabetes if diagnosed under the age Reference / Study Study population / Results Comments hypothesis 23,000 patients with under the age of 30 years cardiovascular disease (369 of 30 years and if on insulin insulin-treated diabetes. and from throughout the from ischaemic heart disease). treatment. Diabetologia 46:760-765, United Kingdom, was Ischaemic heart disease 2003. (11) identified during the period mortality rates per 100,000 1972 to 1993 and followed person-yrs in the cohort were for mortality until December higher than in the general 2000. population (107 in men, 73 in women). Standardized mortality ratios were 44.8 (20.5-85.0) at ages 20-29 and 41.6 (26.7-61.9) at ages 30-39 in women and 11.8 (5.4-22.4) and 8.0 (5.111.9) respectively in men. Reference / Study Study population / Results Comments hypothesis Wisconsin Epidemiologic Persons with type 1 diabetes The 20-year age-adjusted Study of Diabetic who were receiving care in cumulative incidences were Retinopathy (Klein et al. 11 counties in Wisconsin 18.1% for angina, 14.8% for Arch Intern Med. 164:1917- (n=996) were examined at myocardial infarction (MI), and 1924, 2004.) (28) 5.9% for stroke. baseline (1980-1982), and 4, 10, 14, and 20 years later. McAlpine et al. The annual Patients (942 who had, and Using a mid year estimate of Patients were defined as having type incidence of diabetic 29 who developed type 1 patients with diabetes the 1 diabetes if diagnosed at <35 years complications in a diabetes) alive and annual mortality rate was 14.6 / of age and either insulin-treated, or population of patients with registered with a Tayside, 1000. The incidence rates of initially treated with oral type 1 and type 2 diabetes. Scotland, GP for the complications per 1000 patients hypoglycemic medications or diet Diabet Med. 22:348-352, duration of 1997 or who were: angina 8.8 and alone but progressed to insulin within 2004. (141) died during this time. myocardial infarction 8.6. 1 month. Reference / Study Study population / Results Comments hypothesis Soedamah-Muthu et al. Baseline risk factors and 151 (6.5%) patients developed Type 1 diabetes was defined as Risk factors for coronary coronary heart disease CHD. The 7-year incidence diabetes diagnosed before the age of heart disease in type 1 (CHD) at follow-up were rate was 8.0 (per 1,000 person- 36 years with a continuous need for diabetic patients in Europe: assessed in 2,329 type 1 years) in men and 10.2 in insulin within 1 year of diagnosis. the EURODIAB diabetic patients without women. Prospective Complications prior CHD from 31 centers Study. Diabetes Care in 16 European countries. 27:530-537, 2004. (7) Lewis et al. Predicting Baseline information was During six to nine years of Patients were defined as having type vascular risk in type 1 collected for 2136 patients follow up, 110 patients (5%) 1 diabetes if diagnosed at <35 years diabetes: stratification in a with type 1 diabetes using developed macrovascular of age. hospital based population in the Royal College of disease. Reference / Study Study population / Results hypothesis Scotland. Diabet Med. Physicians of Edinburgh 22:164-171, 2005. (142) Diabetes Register in order to assess their the absolute cardiovascular risk. Soedamah-Muthu et al. Subjects with type 1 The cumulative incidence of High risk of cardiovascular diabetes (n=7479) and age cardiovascular disease was 3% disease in patients with type and sex-matched controls (219/7479) in type 1 diabetes 1 diabetes mellitus in the (n=38116) were followed for and 0.76% (289/38116) in UK, a cohort study using 7 years to assess major controls, for a 4.5 fold greater the General Practice cardiovascular events. risk in diabetes. Women with Research Database. type 1 diabetes experienced Diabetes Care 29:798-804, greater relative risks of heart 2006. (143) disease than men, compared to Comments Reference / Study Study population / Results Comments hypothesis those without diabetes. Pambianco et al. The 30 The cumulative incidence of No change in cumulative The number of CAD cases was lower Year Natural History of diabetes complications was incidence was observed by 30 than for other complications reported Type 1 Diabetes assessed in the Pittsburgh years of diabetes duration (ESRD, neuropathy, mortality), Complications. The Epidemiology of Diabetes (p=0.84). which showed a decline. Pittsburgh Epidemiology of Complications (EDC) study Diabetes Complications cohort at 20, 25, and 30 Study Experience. years of type 1 diabetes. Diabetes 55:1463-1469, 2006. (8) Table 2. Selected studies of coronary arteries and surrogate markers of atherosclerosis in type 1 diabetes: principal findings Reference / Study Study population / hypothesis Results Carotid intima medial wall thickness Nathan et al. Intensive diabetes The progression of carotid Adjusting for other risk factors, progression of the intima- therapy and carotid intima-media intima-media thickness was media thickness was significantly less in the group that had thickness in type 1 diabetes examined in 611 persons who received intensive therapy during the DCCT than in the group mellitus. N Engl J Med had been randomly assigned to that had received conventional therapy. 348:2294-2303, 2003. (14) receive conventional diabetes treatment during the DCCT and in 618 who received intensive diabetes treatment. Frost et al. Determinants of early The course of carotid artery In a multiple linear regression analysis, the changes of plaque Reference / Study Study population / hypothesis Results carotid atherosclerosis intima-media thickness was frequency and of the nephropathy status between baseline and progression in young patients determined over a period of 2.5 follow-up examinations were independent predictors of the with type 1 diabetes mellitus. years in 102 patients with Type 1 annual progression rate of carotid artery intima-media Exp Clin Endocrinol Diabetes Diabetes (age <40 years, 110:92-94, 2002. (144) diabetes duration >2 years at thickness. baseline examination). Hayaishi-Okano et al. Elevated The mean and maximum intima- Multivariate regression analyses for both diabetic and C-reactive protein associates with media thicknesses of the carotid nondiabetic subjects as a single group showed that hs-CRP early-stage carotid atherosclerosis artery were assessed using levels are independently correlated with the mean intima- in young subjects with type 1 ultrasound B-mode imaging in media thicknesses and maximum intima-media thicknesses diabetes. Diabetes Care 25:1432- 55 patients with Type 1 Diabetes levels (p=0.002 and p=0.023, respectively) as well as with 1438, 2002. (145) (22 men, 33 women, aged diastolic blood pressure, sex, and duration of diabetes. In 22.1+3.6 years, diabetes duration Type 1 Diabetes, hs-CRP concentration (p=0.01) and sex 14.2+5.7 years) and 75 age- (p=0.01) interacted independently of maximum intima-media Reference / Study Study population / hypothesis Results matched healthy nondiabetic thicknesses; HbA1c was not a significant correlate. subjects (28 men, 47 women). Jarvisalo et al. Carotid artery Carotid intima-media thickness In a multivariate model for all subjects, independent correlates intima-media thickness in was measured in 85 children for intima-media thickness were the diabetic state (p<0.001), children with type 1 diabetes. (mean age, 11+2 years): 50 with LDL cholesterol level (p<0.001), and systolic blood pressure Diabetes 51:493-8, 2002. (146) type 1 diabetes (mean duration, (p<0.001). In children with diabetes but not in controls, LDL 4.4+3.0 years) and 35 controls oxidizability correlated significantly with mean intima-media matched for age, sex, and body thickness (r=0.47, p<0.05), and this relationship remained size. significant after controlling for LDL cholesterol. Yavuz et al. Ultrasonic Intimal medial thickness was Patients and control subjects showed no association between evaluation of early atherosclerosis evaluated in 52 children and intima-media thickness and sex, systolic blood pressure, in children and adolescents with adolescents (aged 3-18 years) diastolic blood pressure, serum lipid levels or left ventricular type 1 diabetes mellitus. J with uncomplicated Type 1 ejection fraction. However, age correlated with carotid Reference / Study Study population / hypothesis Results Pediatr Endocrinol Metab. Diabetes and 43 age- and arterial wall thickness in both diabetic and control groups. 15(8):1131-6, 2002. (147) gender-matched controls. Gunczler et al. Cardiac mass and Intimal medial thickness was Carotid intima-media thickness was similar between groups, function, carotid artery intima- evaluated in 20 children and as were LV ejection fraction at rest and pulmonary venous media thickness and lipoprotein adolescents (10 males, 10 flow velocities. LDL cholesterol and Lpa levels were (a) levels in children and females) with Type 1 Diabetes increased in patients compared to controls (p<0.01), while adolescents with type 1 diabetes before 3.4+3.3 years (mean age total cholesterol, HDL cholesterol and serum triglyceride mellitus of short duration. J 11.9+3.6 years, HbA1c: levels were similar. Pediatr Endocrinol Metab. 8.0+1.9%) and 20 controls aged 15(2):181-6, 2002. (148) 12.1+3.4 years, matched for sex, height and weight. Berger et al. Carotid artery To investigate changes in carotid Subjects with Type 1 Diabetes did not differ from controls in structure and function in young artery structure and function carotid artery distensibility or compliance. Carotid artery Reference / Study Study population / hypothesis Results adults with type 1 diabetes over a 3-yr follow-up period, 28 intimal-medial thickness was slightly, but not significantly (abstract). Diabetes 52(Suppl. (of 33 at baseline) subjects with greater in Type 1 Diabetes subjects versus controls (p=0.07). 1):A45, 2003. (149) Type 1 Diabetes were compared to 28 age and sex-matched controls (both groups 17 males; DMs 18.8±1.3, controls 18.7±2.0 yr; DM duration 12.6±3.4 yr). Singh et al. Vascular function To evaluate endothelium- Endothelium-dependent vasodilation was significantly lower and carotid intimal-medial dependent vasodilation and in diabetic compared with healthy children (p<0.001), but thickness in children with insulin- carotid intimal-medial thickness, there was no difference in endothelium-independent dependent diabetes mellitus. J 31 diabetic (age 15.0+2.4 years; vasodilation or mean carotid intimal-medial thickness Am Coll Cardiol. 41:661-665, diabetes duration 6.8+3.9 years) between the groups. 2003. (23) and 35 age-matched healthy children (age 15.7+2.7 years) Reference / Study Study population / hypothesis Results were studied. Coronary artery calcification Colhoun et al. The effect of type Coronary artery calcification and Among control subjects, men were more likely to have 1 diabetes mellitus on the gender coronary risk factors were coronary artery calcification compared to women (OR 4.5, difference in coronary artery compared in 199 type 1 diabetes p<0.0001, adjusted OR 2.2). However, among individuals calcification. J Am Coll Cardiol. patients and 201 controls of with type 1 diabetes, women were 3 times more likely to 36:2160-2167, 2000. (16) similar age (30-55 years) and present with coronary artery calcification compared to men gender (50% male) distribution. (p=0.02). Olson et al. Coronary calcium in The relationship of coronary Coronary artery calcification had 84 and 71% sensitivity for adults with type 1 diabetes: a artery calcification with total CAD in men and women, respectively, and 100% stronger correlate of clinical prevalent clinical coronary artery sensitivity for MI or obstructive CAD. In subjects with coronary artery disease in men disease and established angina only, calcification sensitivity was 83% in men and Reference / Study Study population / hypothesis Results than in women. Diabetes cardiovascular disease (CVD) 46% in women. Calcification was an independent correlate of 49:1571-1578, 2000. (17) risk factors was studied in 302 CAD in men and overall, and of MI or obstructive CAD in type 1 diabetes subjects from the both sexes. However, coronary artery calcification was not Pittsburgh Epidemiology of independently associated with angina and ischemic ECG in Diabetes complications study. either sex. Dabelea et al. Effect of type 1 To examine whether estimated Insulin resistance was associated with coronary artery diabetes on the gender difference insulin resistance and insulin calcification in both type 1 diabetes and control subjects (OR in coronary artery calcification: a resistance-related factors are 1.6 and 1.4, respectively, p<0.001), independent of CAD risk role for insulin resistance? The associated with coronary artery factors. There was a male excess of calcification in controls Coronary Artery Calcification in calcification (CAC), a total of (OR 2.7, adjusted for age, smoking, LDL and HDL Type 1 Diabetes (CACTI) Study. 656 patients with type 1 diabetes cholesterol) and in type 1 diabetic patients (OR 2.2, adjusted Diabetes 52:2833-2839, 2003. and 764 control subjects aged for the same factors and diabetes duration). Gender (15) 20-55 years was selected from differences in insulin resistance associated fat distribution the CACTI study. seemed to explain the increased coronary calcification in Reference / Study Study population / hypothesis Results women compared to men. Angiographic / intravascular ultrasound Crall et Roberts. The extramural Clinical and morphologic The patients with diabetes had significantly more extramural and intramural coronary arteries observations of the coronary coronary luminal narrowing by atherosclerotic plaques than in juvenile diabetes mellitus: arteries in 9 patients with type 1 the controls. The lumens of one or more of the 4 major analysis of nine necropsy patients diabetes (average age at onset, 9 epicardial coronary arteries were narrowed more than 75% in aged 19 to 38 years with onset of years) were compared to those of cross-sectioned area in 6 of the diabetic patients and in none diabetes before age 15 years. Am 9 controls (mean age, 29 years). of the control subjects. Valsania et al. Severity of Clinical and angiographic Compared to non-diabetic individuals, persons with diabetes coronary artery disease in young findings were examined in 32 were more likely to have severe narrowings, to have patients with insulin-dependent patients with type 1 diabetes and narrowings in all three major coronary arteries, and to have J Med. 64:221-30, 1978. (18) Reference / Study Study population / hypothesis Results diabetes mellitus. Am Heart J. in 31 non-diabetic subjects narrowings in distal segments. Severe narrowing of multiple 122:695-700, 1991. (19) (matched for age and symptoms) vessels was more prevalent in men compared to women and in undergoing elective cardiac individuals with hypercholesterolemia. catheterization for evaluation of coronary artery disease. Pajunen et al. Angiographic This retrospective angiography Persons with type 1 diabetes had greater global severity severity and extent of coronary study comprised 64 (24 women (p<0.001), global extent (p<0.001), and global atheroma artery disease in patients with and 40 men) type 1 diabetic burden (p<0.001) indexes than control subjects. Quantitative type 1 diabetes mellitus. Am J patients and nondiabetic control coronary angiographic-derived indexes of CAD were, on Cardiol. 86:1080-1085, 2000. subjects. To estimate the average, 1.4- to 4.3-fold higher in persons with diabetes (20) severity, extent, and overall compared to controls, and particularly affected women. "atheroma burden" of CAD. Angiographic indices did not relate to HbA1c in the Type 1 Diabetes subjects, but did to HDL cholesterol. Reference / Study Study population / hypothesis Results Larsen et al. Silent coronary Coronary atheromatosis was Fifteen percent of patients had abnormal exercise ECGs, and atheromatosis in type 1 diabetic evaluated in patients with type 1 34% had angiographic diameter stenosis >50% in one or more patients and its relation to long- diabetes in the Oslo study with of the main coronary arteries. All patients examined with term glycemic control. Diabetes no symptoms of CAD by intracoronary ultrasound had developed atherosclerotic 51:2637-2641, 2002. (21) exercise electrocardiogram plaques with an increased intimal thickness (>0.5 mm) in one (ECG) in 39 patients and or more of the coronary arteries. Coronary artery plaque quantitative coronary formation (by ultrasound) was significantly related to mean angiography and by HbA1c during 18 years after adjustment for total cholesterol intravascular ultrasound (IVUS) and age (p<0.05). examinations in 29 patients. Kowalewski et al. Late To assess the influence of The nonlinear regression model showed that duration of potentials: are they related to cardiovascular complications on diabetes, cardiac autonomic neuropathy, and left ventricular cardiovascular complications in the occurrence of late ventricular posterior wall were the strongest independent parameters of children with Type 1 Diabetes? J potentials, 72 children (36 boys, late ventricular potentials occurrence (p<.001, 0.01 and 0.005, Reference / Study Study population / hypothesis Results Diabetes Complications 16:263- 36 girls) with Type 1 Diabetes respectively). 270, 2002. (150) (6.5+2.8 years duration) and 55 sex- and age-matched healthy children were studied. Giunti et al. Electrocardiographic The prevalence of ECG left In multivariate logistic regression analysis variables left ventricular hypertrophy in ventricular hypertrophy and its independently related to ECG left ventricular hypertrophy type 1 diabetes: prevalence and association with coronary heart after adjustment for age, sex, and diabetes duration were relation to coronary heart disease disease (CHD), microvascular CHD, QTc, SBP, triglycerides, and waist to hip ratio. and cardiovascular risk factors: complications, QTc, and QTd the Eurodiab IDDM was assessed in 3,250 type 1 Complications Study. Diabetes European diabetic subjects. Care 28:2255-2257, 2005. (27) Senior et al. Coronary artery CAD prevalence was determined CAD was associated with age, diabetes duration, Reference / Study Study population / hypothesis Results disease is common in nonuremic, by ECG stress testing and hypertension, and smoking. Although specific, ECG stress asymptomatic Type1 Diabetic myocardial perfusion imaging in testing and myocardial perfusion imaging were not sensitive islet transplant candidates. 60 consecutive type 1 diabetic as correlates of CAD on angiography (specificity 0.97 and Diabetes Care 28:866-872, 2005. islet transplant candidates 0.93, sensitivity 0.17 and 0.04, respectively) but helped (62) (average age 46 years, 23 men, identify 2/3 subjects requiring revascularization. and 47% ever smokers). Other studies Haller et al. Radial artery Radial artery tonometry was Heart rate corrected augmentation index was increased in type tonometry demonstrates arterial performed in 98 children with 1 diabetes suggesting arterial stiffness. stiffness in children with type 1 type 1 diabetes and 57 controls. diabetes. Diabetes Care 27:29112917, 2004. (151) Reference / Study Study population / hypothesis Results Sundell et al. Lifetime glycaemic The effect of lifetime glycemic Hyperemic myocardial blood flow was inversely associated exposure predicts reduced exposure on coronary with log HbA1c months both in the fasting state (r = -0.70, coronary vasoreactivity in Type 1 vasoreactivity was examined in p<0.05) and during clamp (r = -0.35, p<0.05) adjusting for diabetic subjects. Diabet Med. 43 otherwise healthy type 1 lipids, blood pressures, sex, smoking, body mass index and 22:45-51, 2005. (152) diabetic subjects. age. However, no significant correlation was detected between hyperemic flow and HbA1c or plasma glucose values measured immediately preceding the PET study. Table 3. Coronary artery calcification in type 1 diabetes – the C3T1 pooled dataset Males Diabetes Control Females Overall Diabetes Control Diabetes Control Mean (SD) CAC score (Agatston) in those with any calcification Age (yrs) 20-29 5.1 (7.9) 4.5 (8.3) 27.7 (97.4) 4.1 (2.2) 15.0 (64.7) 4.4 (6.9) 30-39 68.4 (165.6) 24.5 (83.1) 62.8 (103.6) 6.0 (11.8) 66.0 (142.2) 19.9 (72.7) >40 285.1 (548.1) 94.5 (249.8) 306.6 (446.6) 20.3 (45.5) 294.9 (503.8) 75.3 (218.5) 21.1% (19) 16.7 (9) 12.5% (15) 4.7 (4) 16.2% (34) 9.3 (13) Prevalence of any CAC (>0) Age (yrs) 20-29 Males Females Overall Diabetes Control Diabetes Control Diabetes Control 30-39 39.2% (96) 31.5 (64) 26.9% (71) 10.7 (21) 32.8% (167) 21.3 (85) >40 72.0% (154) 57.5 (126) 57.7% (128) 21.4 (44) 64.7% (282) 40.0 (170) <20 32.5% (55) Not applicable 16.4% (32) Not applicable 23.9% (87) Not applicable 20-29 42.5% (94) 32.2% (76) 37.2% (170) 30-39 72.2% (91) 55.0% (77) 63.2% (168) >40 87.9% (29) 82.9% (29) 85.3% (58) Diabetes duration (yrs) Age and diabetes duration (yrs) Age 20-34 yrs Diabetes duration <20 yrs 24.0% (25) Diabetes duration >20 yrs 30.0% (30) Age >35 yrs Not applicable 11.6% (17) 23.4% (29) Not applicable 16.8% (42) 26.3% (59) Not applicable Males Females Overall Diabetes Control Diabetes Control Diabetes Control Diabetes duration <20 yrs 46.2% (30) Not applicable 30.6% (15) Not applicable 39.5% (45) Not applicable Diabetes duration >20 yrs 65.7% (184) 53.3% (153) 59.4% (337) Table 4. Predictors of coronary artery disease (CAD) in type 1 diabetes (prospective cohort studies) Study Population Multivariable predictors Comments Lehto et al. Arterioscler 177 patients with type 1 By follow-up, 20 (11.3%) patients died of Thromb Vasc Biol. 19:1014- diabetes (87 men and 90 CHD and 28 (15.8%) had a serious CHD 1019, 1999. (42) women) without event. A previous history of MI (HR 8.0, nephropathy, age 45 to 64 p<0.001), high HbA1 (>10.4%, the highest years at baseline and >30 tertile, HR 5.4, p=0.01), and diabetes years at the time of diabetes duration (>16 years, the highest tertile, HR diagnosis were followed for 4.2, p=0.01) were associated with CHD 7 years. death and incidence of all CHD events. The Pittsburgh A cohort of 603 individuals Blood pressure, lipid levels, inflammatory Subjects were diagnosed Epidemiology of Diabetes with childhood onset (<17 markers, renal disease, and peripheral with type 1 diabetes (or Complications (EDC) study years of age) type 1 diabetes vascular disease showed a positive gradient seen within 1 year of Study Population Multivariable predictors Comments (Orchard et al. Diabetes diagnosed between 1950 and across the groups of no CAD, angina, and diagnosis) at the Care 26:1374-1379, 2003.) 1980 were followed from hard CAD, whereas estimated glucose Children’s Hospital of (6) 1986 to 1998. At study disposal rate (eGDR) and physical activity Pittsburgh. entry, mean age was 28 years showed inverse associations (all p-values and mean diabetes duration for trend <0.01). Moreover, depressive was 19 years. A total of 108 symptomatology predicted angina (p=0.02), CAD events occurred during whereas HbA1 showed no association with follow-up. subsequent CAD. The EURODIAB A clinic-based cohort of Independent predictors of CHD included Type 1 diabetes was Prospective Complications 2329 type 1 diabetes patients age (hazard ratio 1.5), albumin excretion defined as diabetes Study (Soedamah-Muthu et aged between 15-60 years rate (1.3 in men and 1.6 in women), waist to diagnosed prior to 36 al. Diabetes Care 27:530- were recruited from 27 hip ratio (1.3 in men), smoking (1.5 in years of age with a 537, 2004) (7) centers in 16 European men), triglycerides (1.3 in women) or HDL continuous need for countries and were followed cholesterol (0.74 in women), and systolic insulin within the first Study Population Multivariable predictors Comments for 7 years. At study entry, blood pressure (1.3 in women). HbA1 year of diagnosis. mean age was 33 and mean univariately predicted CHD in men (but not diabetes duration 15 years. multivariably) and did not predict CHD in During follow-up, 151 women at all. patients developed coronary heart disease (CHD). Wisconsin Epidemiologic Persons with type 1 diabetes The 20-year age-adjusted cumulative Study of Diabetic who were receiving care in incidences were 18.1% for angina, 14.8% Retinopathy (Klein et al. 11 counties in Wisconsin for myocardial infarction (MI), and 5.9% Arch Intern Med. 164:1917- (n=996) were examined at for stroke. Severity of diabetic retinopathy 1924, 2004) (28) baseline (1980-1982), and 4, was associated with angina and stroke. 10, 14, and 20 years later. Arteriovenous ratio was associated with MI. Of 273 deaths, 176 involved heart disease. The severity of retinopathy and Study Population Multivariable predictors arteriovenous ratio was associated with heart disease mortality. Nephropathy was more informative about the cardiovascular end points than were the blood vessel characteristics. HbA1 was a significant predictor for stroke incidence only. Comments Table 5. Morphological studies of Coronary Artery Disease in Diabetes Reference Number of Population Findings Subjects with carotid artery Risk for carotid plaques Circulation plaques not diagnosed with increases continuously with 110:466-470, 2004 diabetes increasing HbA1c. HbA1c subjects (total / diabetic) Jorgensen et al. 5960/0 (153) is positively related to risk of hard but not soft plaques. Burke et al. 122/66 Sudden coronary deaths Diabetic atherosclerotic Arterioscler with acute thrombic or plaques have higher Thromb Vasc Biol. severe atherosclerosis inflammatory cell infiltrate. 24:1266-1271, postmortem study. 2004 (54) Moreno et al. 95/47 Diabetic patients who had Number of vessels with Circulation directional coronary >50% lesion and the 102:2180-2184, atherectomy for acute percentage of total area with 2000 (52) ischemic event compared to lipid-rich plaque was Reference Number of Population Findings matched controls without greater for those with diabetes. diabetes. Diabetes is subjects (total / diabetic) associated with more macrophage content in plaques (did not differ among diabetics receiving different treatment: insulin, sulphonylureas, diet). Gyongyosi et al. Patients with new onset of Diabetes associated with Coron Artery Dis. severe/accelerated angina, significantly greater target 10:211-219, 1999 angina at rest or angina plaque and EEM CSA. (154) within 2 weeks of acute MI Differences in constrictive undergoing angiography remodeling; though higher and IVUS. in diabetes - NS. Patients with chronic Those with insulin treated Am J Cardiol. anginal syndrome and de diabetes had less reference 81:1298-1304, novo native coronary and stenosis plaque, and Kornowski et al. 60/13 827/120 Reference Number of Population Findings stenosis, undergoing smaller reference and angiography and IVUS. stenosis arterial areas than subjects (total / diabetic) 1998 (47) those with diabetes not treated with insulin. Impaired remodeling of arterial shrinkage. Henry et al. Am 820/115 Patients with and without Diabetes is an independent Heart J. 134:1037- diabetes who underwent risk factor for moderate (but 1043, 1997 (155) coronary angiography. not severe) stenosis, and also for , more distal and triple vessel disease Cipollone et al. Circulation 60/30 Patients undergoing carotid RAGE overexpression, atherectomy enhanced inflammatory 108:1070-1077, reaction and COX- 2003 (53) 2/mPGES-1 expression in Type 2 diabetes samples Reference Number of Population Findings Patients undergoing Hypercholesterolemia has Circ J. 61:390-395, coronary angiography with greater influence on 1997 (48) only one of the following severity of coronary artery risk factors: Diabetes, lesions than hypertension Hypertension, and diabetes. Diabetes Hypercholesterolemia. associated with fewer short subjects (total / diabetic) Kasaoka et al. Jpn 204/24 eccentric lesions but more 'tubular regular' lesions. Burke et al. N Eng 113/??? J Med. 336:1276- Men with coronary disease Glycosylated hemoglobin who died suddenly. not significantly associated 1282, 1997 (140) with acute thrombosis nor plaque rupture. Calton et al. Indian 75/75 Type 2 & non-diabetic Those with type 2 diabetes Heart J. 47:343- patients with CAD had more severe coronary 348, 1995 (46) artery disease than did nondiabetics, and more concentric stenosis. Reference Number of Population Findings subjects (total / diabetic) Females with type 2 diabetes had more severe and more diffuse disease than did males, but type 2 diabetes did not overall have greater diffuse disease. Spagnoli et al. Patients affected by Fibrous plaque, increased Atherosclerosis transient ischemic attacks connective tissue, few foam 108:39-60, 1994 (TIA) or by stroke, with cells and rare thrombosis (156) angiographic stenosis >50% correlated with diabetes. Deceased people who had Plaques in those with type 1 type 1 diabetes are comprised mostly (91%) Mautner et al. Am J Cardiol. 70:12641268, 1992 (157) 180/56 8/8 of fibrous tissue (significantly more so than older patients and young females with fatal CAD). Table 6. Why are the cardiovascular results of DCCT / EDIC so different from the Epidemiologic studies? Reasons for discrepancy between the results of DCCT / EDIC and Epidemiologic findings Epidemiologic studies are simply wrong o Positive studies; Finnish older onset without nephropathy, carotid IMT, IVUS, LV and endothelial function Population differences o Duration (shorter in DCCT / EDIC) o CVD risk status (lower in DCCT / EDIC) Level of glycemic control achieved (better in DCCT / EDIC) DCCT / EDIC effect due partly to other risk factors (? LDLc and triglycerides) Two types of CAD in Type 1 Diabetes (renal / insulin resistance and glycemia susceptibility) Table 7. The association studies of CAD candidate genes in type 1 diabetes Reference Gene name/ polymorphism Gene locus Genetic Phenotype variant Pettersson-Fernholm et al. (96) RAGE 6p21.3 -374AA Lower frequency of CAD, MI 17q23 II ACE Lower frequency of CHD T(-374)A van Ittersum et al. (104) ACE Insertion/Deletion Hokanson et al. (111) Hepatic lipase Genotype 15q21 T allele 11q23 360His allele Higher proportion of CAC LIPC-480C/T Kretowski et al. (120) ApolipoproteinA-IV Gln360His Pettersson-Fernholm et al. (107) NPY Higher risk of CAC progression 7p15.1 Pro7 12p12-pter 789A1a High frequency of CAD Leu7Pro Lacquemant et al. (122) VonWillebrand factor Thr789Ala Higher risk of CHD Table 8. Coronary Artery Disease Prevention and Screening Guidelines in Type 1 Diabetes Mellitus ADA 2006 (129) AHA 2002/3 Prevention Conference VI: Diabetes and Limited clear direction for type 1 diabetes adults, e.g. for Lipids “Although the data are not definitive, consideration should be given Cardiovascular Disease (130) for similar lipid lowering therapy in type 1 diabetic patients as in type 2, particularly if Endorse <100 mg/dl LDL goal for children and adolescents with type 1 diabetes. Though generally those with diabetes are they have other cardiovascular risk factors or considered at maximum risk, “...there may features of the metabolic syndrome”. be special considerations, such as patients Advocate ACE use if any degree of with type 1 diabetes…, in whom albuminuria irrespective of BP in type 1 noninvasive testing would be useful for diabetes. making management decisions.” Aspirin therapy >40 years. Consider aspirin therapy in those 30-40 years if other risk factors. No aspirin <21 years (Reye’s syndrome). AHA Scientific Statement: Guidelines for Primary Prevention of Atherosclerotic Cardiovascular Disease Beginning in Childhood (131) For children and adolescents screen for lipids at 12 years or earlier if family history of 3 baseline measures hypercholesterolemia or early CVD (<55 MNT including soluble fiber (5-10 gm + years); drug therapy if MNT fails to lower LDL <160 mg/dl, or <130 mg/dl if adverse age up to age 15 years) Though goal is LDLc < 100 mg/dl (as CVD risk profile. Goal LDL<100 mg/dl. opposed to 160 mg/dl in general), drug BP treated with drugs if >95 pc (or 130/80 initiation level is still 160 mg/dl. which ever is lower). Routine screening for CAD in diabetes is not clearly recommended as “…there are no evidence-based guidelines for screening the asymptomatic diabetic patient for CAD”.