Total risk management of Cardiovascular diseases Nobuhiro Yamada

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1 Nobuhiro Yamada

2 The worldwide burden of cardiovascular diseases (WHO) To prevent cardiovascular diseases Beyond LDL Multiple risk factors With common molecular basis

3 The Current Burden of CVD CVD is responsible for one third of all deaths worldwide and almost half of all deaths in the developed world Cause of death CVDs Percentage of deaths Infectious/parasitic diseases Malignant neoplasms Respiratory infections Respiratory diseases Unintentional injuries Perinatal conditions Digestive diseases Intentional injuries Neuropsychiatric conditions Diabetes mellitus Worldwide Developed world World Health Organization Burden of Disease Estimates 2002.

4 Burden of Disease: Leading Risk Factors in Developed Countries (2000) Tobacco Low fruit and vegetable intake BP Alcohol Lipids Overweight Physical inactivity Illicit drugs Unsafe sex Iron deficiency DALYs* (%) *Disability-adjusted life years. The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002.

5 Incremental Risk Associated With Multiple Risk Factors BP (SBP 150 mm Hg) Lipids (TC 260 mg/dl [6.7 mmol/l]) x1.5 x2.8 x3.5 x6.2 x4 x2.3 x1.8 Glucose Intolerance Risk shown is compared with the baseline risk for a 40-year-old male nonsmoker with SBP 120 mm Hg, TC of 185 mg/dl (4.8 mmol/l), no glucose intolerance, who is electrocardiographic left ventricular hypertrophy (ECG-LVH) negative, and has a probability of developing CVD of 15/1000 (or 1.5%) in 8 years. Clustering of risk factors in US men aged 40 to 74 years. Kannel WB. In: Genest J et al, eds. Hypertension: Physiopathology and Treatment. New York, NY: McGraw-Hill, Inc; 1977:

6 Prevalence (%) J-LIT Primary prevention study Adjusted by LDL-C and HDL-C levels The Lipid, 2001; 12: 239

7 Progression of atherosclerosis and plaque rapture Risk factors for events Established by RCT LDL, TG/HDL Blood pressure Blood glucose Smoking Anti-thrombosis thrombosis Pepine C. Am J Cardiol ;82(suppl 10A):23S-27S. 27S.

8 Metabolic Syndrome Increases Risk for CHD and Type 2 Diabetes SREBP-2 High LDL-C SREBP-1,PPAR,FKH: Metabolic Syndrome Glucose, BP, TG/HDL, Obesity Type 2 Diabetes Coronary Heart Disease Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:

Metabolic Syndrome Combination of risk factors and near risk factors of metabolic origin that predict increased risk CHD Diabetes They occur together too frequently to be coincidence The

9 Metabolic Syndrome Combination of risk factors and near risk factors of metabolic origin that predict increased risk CHD Diabetes They occur together too frequently to be coincidence The individual factors produce additive risk, allowing the identification of large number of people at risk who would be missed if focused on individual factors (definition of dyslipidemia, HT, diabetes)

10 Components of Metabolic Syndrome Insulin resistance Obesity High TG Low HDL Hypertension Hyperglycemia

11 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: Important Components of the Metabolic Syndrome Abdominal obesity (waist circumference) Men: >102 cm (40 in) Women: >88 cm (35 in) Atherogenic dyslipidemia Elevated triglycerides Small LDL particles Low HDL-C Raised BP (>130/80 mm Hg) Insulin resistance ( glucose intolerance) Prothrombotic state Pro-inflammatory state

12 Coronary risk factors and insulin ( insulin) Systolic and Diastolic Blood Pressure <157 <209 <272 <370 All BMI diabetes Triglycerides (mg/dl) <157 <209 <272 < diabetes Cholesterol (mg/dl) HDL-Cholesterol (mg/dl) <157 <209 <272 < diabetes 44 <157 <209 <272 < diabetes insulin insulin

13 Atherosclerosis LDL vs Metabolic Syndrome Blood pressure, lipids, glucose platelet, inflammatory cells :Metabolic Syndrome Fibrous cap LDL cholesterol

14 LDL : independent risk factor Exess in blood LDL receptor is saturated with 25 mg/dl LDL

15 Excess LDL and physiological LDL 25 mg/dl LDL is physiologically enough to keep human functions through LDL receptor, and cells synthesize cholesterol de novo. No physiological system to store excess LDL in human, therefore excess LDL (approximately greater than 50 mg/dl) generates atherosclerotic plaque with aging. The lower, the better

16 Plaque formation LDL cholesterol > 50 mg/dl Other risk factors accelerate the progression of atherosclerosis, in particular, metabolic syndrome

18 Japan Diabetes Complication Study

19 Protocol : Design and Setting A randomized, prospective, intervention trial. 59 Japanese institutes that specialize in diabetes care 2205 patients with previously diagnosed type 2 diabetes. The first large-scale prospective trial focusing on a Japanese diabetic population.

20 JDCS 8 year report Incidence of Macroangiopathy JDCS Hisayama-DM HisayamanonDM UKPDS (cont/intensive) IHD /14.7 Stroke / 5.0

21 JDCS 8 year report Risk factors of Macroangiopathy IHD and Stroke 1 st.hba 1C (.004), 2 nd.sbp (.036), 2 nd.tg (.036) IHD 1 st.ldl (.001), 2 nd.tg (.003) Stroke 1 st.sbp (.089) Beyond glucose (Logistic regression, p<0.05)

22 Total Care Steno-2 Study primary endpoint 60 No. at Risk Usual care Total care endpoint (%) Usual care Total care mean S.E. P=0.007 (log-rank test) Steno-2 2 Study Peter Gæde et al.: N ENGL J MED 348(5): , 2003

23 Steno-2 Study %acievement of treatment goal 7.8 year 80 Total care P<0.001 P= Usual care P=0.19 subjects (%) P= P= HbA1c <6.5% cholesterol <175mg/dL triglyceride <150mg/dL Systolic BP <130mmHg Diastolic BP <80mmHg Steno-2 2 Study Peter Gæde et al.: N ENGL J MED 348(5): , 2003

24 Management of Atherosclerotic diseases Individual managemant LDL Hypertension Diabetes Mellitus Smoking Total management Metabolic syndrome

25 Pathophysiology of Metabolic syndrome Excess Nutrition Future target cell dysfunction Low insulin secretion Diabetes Obesity Energy expenditure>store Gene expressin/transcription Glucose/lipid/BP Insulin resistance High glucose TG/HDL Hypertension Vascular events Physical inactivity Genetics, Aging

26 TFE3 E box (CANNTG)

2003 World Health Organization (WHO) / International Society of Hypertension (ISH) Statement on Management of Hypertension.

2003 World Health Organization (WHO) / International Society of Hypertension (ISH) Statement on Management of Hypertension Writing Group: Background Hypertension worldwide causes 7.1 million premature