1. Non-Invasive Cardiac Monitoring in Type 1 Diabetes Marian Rewers, MD, PhD Professor & Clinical Director Barbara Davis Center for Childhood Diabetes University of Colorado Denver

2. Type 1 diabetes affects mostly adults The U.S., 2003 estimates Number of patients

3. Improving survival among T1 DM patients Allegheny County IDDM Registry 1965-1999

4. Declining cumulative incidence of microvascular complications Steno Clinic, Denmark, 600 Patients with T1 DM onset 1965-84 Hovind P, et al. Diabetes Care 2003 1961-65 1966-70 1971-75 1976-80 Diabetic nephropathyProliferative diabetic retinopathy 1965-69 1970-74 1975-79 1980-84 30 20 10 40

5. Increasing cumulative incidence of Coronary Artery Disease Epidemiology of Diabetic Complications Study, Pittsburgh, U.S. 684 Patients with T1 DM diagnosed 1950-1980, followed up to 2000 % Orchard T, 2003 Diabetes duration

6. The prevalence of T1 DM peaks ~50 yrs of age in the U.S. The survival has improved, largely due to better control of hyperglycemia, hypertension and prevention of acute complications and ESRD. Coronary artery disease became the leading cause of death in people with T1 DM. Diabetic women have 10-30 times higher risk of CAD, and diabetic men have 4-10 times higher risk, compared to the general population. Summary

7. Pilot Study Led to NIH Funding N=135 Baseline examination N=1,416 Pilot Study Participants N=109 CAC Progression Nested Case-Control Study Progressors: n=98, Non-Progressors: n=173 Pilot Study Participants N=98 Coronary Artery Calcification in Type 1 3-yr follow-up examination in progress N=1,211

8. MenWomen T1DM 300 Controls 382 T1DM 352 Controls 382 HbA1c (%) LDL-c (mg/dl) HDL-c (mg/dl) Age (yr) BMI (kg/m²) Ever smoker 7.8* 105* 51* 37 26.7 28% 5.5 122 43 40 27.1 30% 7.9* 98* 60 36 26.0 31% 5.3 105 58 37 25.0 30% Coronary Artery Calcification in Type 1 Diabetes (CACTI) 1,416 participants, CAD-free, aged 20-55 years Including 652 with T1 DM of at least 10 yrs duration

9. Coronary artery lumen (angiography), plaque (IVUS) and calcification (EBT) in a young woman with T1 DM and premature CAD Coronary Artery Calcification CACTI 1448, female DM diagnosis age 8 Angioplasty age 26 Deceased age 28

10. Agatston units

11. Prevalence of Coronary Artery Calcification CACTI Study, n=1,416 Age women men age-adjusted OR=4.2 (2.4-7.5) OR=2.3 (1.5-3.7) Dabelea D, et al. Diabetes 2003

12. Snell-Bergeon et al. Diabetes Care 2003

13. Predictors of 3-year Progression of CAC in T1DM Patients (N=500) Significant predictors OR 95% CI p-value HbA1c > 8.6% vs.  8.6% A Hypertension Y/N B HDL-ch per 10 mg/dl C 1.88 1.05-3.35 0.03 1.83 1.07-3.16 0.03 0.69 0.45-0.89 0.04 Adjusting for age (p=0.007), gender (p=0.16), diabetes duration (p=0.0004), baseline CAC (p<0.0001), smoking, LDL-ch, BMI, CRP, PAI-1, homocystein

14. Hypertension and dyslipidemia remain poorly controlled in patients with T1D, CACTI, 2000-2002 (n=652 ) Hypertension Dyslipidemia Maahs D, Diabetes Care 2005 Wadwa P, Diabetes Care 2005

15. Novel Predictors of 3-Year Progression of CAC 98 progressors vs. 173 controls Adjusting for age, gender, diabetes and baseline CAC OR 95% CI p-value for doubling of level Adiponectin sIL-2R 0.34 0.20-0.60 0.0002 2.09 1.07-4.08 0.03 Maahs D, et al. Circulation 2005; Wadwa P, et al. 2005 Independent of BMI, hypertension, LDL-ch, HDL-ch, smoking, AER CRP, fibrinogen, HbA1c, homocysteine, PAI-1, CD40L

19. Coronary calcification is 2-4 x more frequent in T1D, compared to non-diabetic controls Hyperglycemia, hypertension and low HLD-ch as predict progression of coronary calcification Inflammatory markers - low adiponectin and elevated sIL-2R - are also predictive; CRP levels are of a limited predictive value Hyperglycemia, hypertension and dyslipidemia are not yet optimally controlled in many patients Summary of CACTI results

20. Myocardial Perfusion Reserve Stress Rest RMPR LAD =.76 CX =.73 RCA = 1.1 BasalMidApicalVLA

21. PulseMetric Brachial Artery Distensibility, SVR, CO, LV dP/dt Uses Oscillometric BP cuff

22. Sphygmocor Pulse Wave Velocity & Augmentation Index Uses Arterial tonometer (radial)

23. The Impact of the Early Wave Reflection This earlier return to the heart of the reflected pressure wave (due to stiffening of the arteries) changes the aortic root pressure waveform, … with 3 key clinical implicationsThis earlier return to the heart of the reflected pressure wave (due to stiffening of the arteries) changes the aortic root pressure waveform, … with 3 key clinical implications Central pulse pressure increases... increasing risk of stroke and renal failureCentral pulse pressure increases... increasing risk of stroke and renal failure LV Load increases…. increasing LV mass, and accelerating progress towards LV hypertrophy and heart failureLV Load increases…. increasing LV mass, and accelerating progress towards LV hypertrophy and heart failure Coronary artery perfusion pressure in diastole reduces…. increasing risk of myocardial ischemiaCoronary artery perfusion pressure in diastole reduces…. increasing risk of myocardial ischemia  PP Increased Central Pulse Pressure Increased LV Load Decreased Coronary Artery Perfusion Pressure in Diastole

24. Wadwa P & al. ADA 2005

27. Arterial stiffness, as measured by pulse wave analysis, is related to diastolic blood pressure, duration of diabetes and severity of hyperglycemia in type 1 diabetes Increased arterial stiffness is not associated with the presence or extent of coronary calcification Summary

28. Carotid artery intima-media thickness (IMT)

30. Barth JD 2004

31. Decreased Progression of Carotid IMT in Intensive Treatment Group 6 yr after completion of DCCT DCCT/EDIC Research Group. N Engl J Med. 2003;348:2294 p = 0.01 6-yr IMT progression [mm]

32. Conclusions Electron beam tomography for coronary artery calcification, myocardial perfusion tests, carotid IMT, pulse wave analysis of arterial stiffness, and MRI to study left ventricular dysfunction show promise in patients with diabetes mellitus For details see Wadwa P. & Rewers M. Curr Opin Endocrinol Diabetes 2005;12:267-72. Lippincott Williams & Wilkins.