Atherosclerosis Coronary heart disease Angina pectoris Myocardial infarction

1. AtherosclerosisCoronary heart diseaseAngina pectorisMyocardial infarction

2. Causes of death in Europe • men • coronary heart disease (MI) 21% • trauma and poisoning 12% • stroke 11% • pulmonary carcinoma 6% • carcinomas in GIT 4% • women • coronary heart disease 21% • stroke 18% • other CVS diseases 15% • trauma and poisoning 5% • breast carcinoma 3%

3. Atherosclerosis • syndrome affecting large and medium-sized arteries • artery wall thickenings – lipid infiltration - atheroma creation • chronic inflammatory response in the walls of arteries • hardening of the artery wall (loss of elasticity) • Result - insufficient blood supply to the heart – myocardial infarction (heart attack) to the brain – stroke to the legs – claudicatio

4. Tunica intima Endothelial cells Tunica adventicia Tunica media Smooth muscle cells

5. Atherosclerosis

6. Atherosclerotic plague Thrombus Endothelial cells Rupture of fibrous cap Platellets Smooth muscles cells Foam cells Lipid core

7. Stages of atherosclerotic plaque development • Type I – isolated foam cells • macrophages with a droplet of fat in intima • Type II – fatty streaks • foam cells layer • Type III • higher amount of lipids under the foam cells layer • Type IV – atheroma • lipid core, fibrous cap • Type V • more collagen and smooth muscle cells in fibrous cap • Type VI • atheroma with complications - thrombosis

9. Coronary heart (artery) disease • result of the ateromatous plaques within the walls of the coronary arteries • limitation of blood flow to the heart → ischaemia • Result Angina pectoris Myocardial infarction

10. physical acitivy (emotional stress) activation of sympathicus  heart rate and contraction  demand after oxygen supply Coronary heart disease coronary artery obstruction due to atherosclerosis lack of blood (oxygen) supply PAIN

11. Risk factors (CHD, IM) • Basic biological • age, gender, family history (= genes) • Biochemical, classical • cholesterol, LDL-CH, TAG, ¯ HDL-CH, apoproteins, Lp(a), indexes • Biochemical, new • fibrinogen, homocysteine, ferritin • small dense LDL, oxidized LDL • Nutrition and life style • too much fat, sugar, antioxidant and fiber deficiency • SMOKING, SEDENTARY LIFE STYLE • Diseases • obesity, diabetes (IR!), hypertension, kidney failure • Genetic RF • LDL receptor (FH), apo E variants and many others

12. Basic biological factors • age • men > 45 years • women after menopause • gender • men > women

13. Obesity obesity hyperinsulinaemia dyslipidaemia central typ

14. Hypertension • endothelium damage

15. Smoking • nicotine • effect on lipid metabolism • vasoconstriction • CO • carboxyhaemoglobin • increased coagulation cascade activity

16. Endothel • Intelligent interface between blood and vessel wall/tissues • 1500 g, football field (1000 m2) • Endocrine, paracrine and autocrine functions • vessel tonus, coagulation, adhesion, cell replication • Organ specificity, differences in arteries, capillaries a venes • Dysfunction in hypertension, diabetes, dyslipidemia...

17. Lipoproteins

18. Cholesterol, free and esters with fatty acids • 275 mmol in the body • 50 mmol LP, GIT, liver • 25 mmol fat tissue • 90 mmol muscles & vessel wall • 110 mmol nervous system • 3 mmol/d exchange • Cholesterol • In: food and synthesis in cells (from CoA) • Breakdown: no • Out: bile (enterohepatal circuit); stool • LDL cholesterol • The normal level (3,1 – 3,9 mmol/l) is not normal for the endothel • Newborns & atherosclerosis resistant animals only » 0,8 mmol/l

19. Triacylglycerols &fatty acidsTAG & FFA • 15 kg in nonobese subjects • 570 000 kJ; enough for 3 months • Thermal isolation, fertility, body shape • Intake & synthesis: 80 – 170 mmol/d • Different fatty acids – saturated, unsaturated, polyunsaturated (eikosanoids), shorter and longer chain • Rapid turnover dependent on diet and alcohol intake, breakdown through physical activity (FFA – minutes)

20. Lipoproteins • water-soluble particles, that transport water-insoluble lipids in the blood lipids Free cholesterol Phospholipids Triacylglycerols Cholesterol esters proteins Apolipoproteins

22. Apoproteins

23. 3 lipoprotein families (LP) • spherical or discoid particles synthesised in guts or liver • Hydrophilic surface (phospholipids, cholesterol esters and apoproteins) • Hydrophobic inner part (TAG, CH) • Dynamic interaction with vessel wall and each other • Chylomicrons Þ chylomicron remnants • VLDL Þ IDL Þ LDL (heterogenous group) • HDL nascent Þ HDL3Û HDL2

24. Chylomicrons • Enterocytes • apoB48, others from HDL • TAG into fat and other tissues, LPL • CH into liver (from bile and food) • Peak 3 – 6 h after meal, t1/2 30 min, after 9 h Ø • Remnants into liver through receptor cytotoxic and atherogenic

25. VLDL – LDL family • Liver, endogeneous TAG, CH • B100 and others • functions and metabolism similar to CHY • VLDL t1/2 2 – 4 hod, transformation to IDL, LDL • LDL has a slow turnover, can be modified – oxidation, glycation • small dense LDL • Receptor and scavenger receptor

26. LDL classes

27. Small dense LDL • small • easy transport to intima of vessels • higher density • higher TAG concentration • easy oxidation Lipoprotein(a) • LDL with apoproteine(a) – glykoprotein very similar to plasminogen • higher risk of thrombosis Oxidized LDL (oxLDL) • high atherogenity • higher macrophage afinity - 8 - 10x higher than to LDL

28. Reverse transport of cholesterol by HDL • Liver, enterocytes and fromCHY as nascent „disc“ • Lot of apoproteins • LCAT and CEPT • lecitin-cholesterol acyltransferase, esterifies CH • cholesterol ester transfer protein transprots CH-E from HDL into other LPs • Takes out cholesterol from tissues, disc is filled to HDL3 • Exchanges CH-E for TAG with other LPs transforms to HDL2 • Binds through AI to specific receptor in liver

29. liver HDL3 HDL2 nascent HDL vessel tissues

30. Apolipoprotein E • 3 allels - APOE2, APOE3, APOE4 • APOE4 - high cholesterol and LDL-chol, high risk of complications of atherosclerosis E3 = 112 Cys, 158 Arg E2 = 112 Arg, 158 Arg E4 = 112 Cys, 158 Cys

31. Normal (desired) values • T-CH < 5,0 mmol/l 4,55 – 5,45 • HDL-CH > 1,0 mmol/l 0,87 – 1,13 • LDL-CH < 3,0 mmol/l 2,65 – 3,35 • TAG < 2,0 mmol/l 1,70 – 2,30 INDEXES • T-CH/HDL-CH < 5,0 • NONHDL-CH < 3,8 • LDL-CH/HDL-CH < 3,0 • Klimov (T-CH – HDL-CH)/HDL-CH < 4,2 • APO AI/APO B > 1,3 ???

32. Other laboratory methods • Special • Apo B, Apo AI, Lp(a) • homocysteine, coagulation and fibrinolytic factors. • Very special • LDL receptors • Apo C, E, LPL, CETP, LCAT • classes of LDL, HDL • Yesterday • total lipids, phospholipids, fatty acid esters • elektrophoresis • Tomorrow - genomics

33. Hyperlipoproteinemias

34. Classifications • Fredrickson 1967, WHO 1970 • I, IIa, IIb, III, IV, V, VI - partly history • Therapeutical 1992, European task force • CH, TAG, both • Etiological – future • primary and secondary DLP is not sufficient! • most primary DLP are not exactly characterized

35. “Primary DLP” • Familiar hypercholesterolemia (LDL rec.) • Familiar defect of ApoB100 (FDB) • Polygenous hypercholesterolemia • Polygeneous hypertriglcyceridemia • Dysbetalipoproteinemia (IDL) • Familiar type V hyperlipidemia

36. “Secondary DLP” • Nutrition and lifestyle • including smoking, alcohol and micronutrient deficiency • Obesity • Diabetes mellitus • type 2 usually, decompensated type 1 (BG 20 – extreme TAG) • Kidney failure • Liver disease • Endocrine diseases – ßthyroid function • Drugs • Hormones – anticonception, gravidity, postmenopausal, anabolics

37. Familial hypercholesterolaemia • AD inherited • defect of LDL receptor (> 300 mutations of LDLR) • Symptoms • increased LDL-chol concentration • atherosclerosis (high risk of MI, homozygouts in 2. -3. decenium) LDL LDL receptor

38. Symptoms and signs xantelasma palpebrarum xantomas arcus lipoides corneae atherosclerosis and CHD

39. Angina pectoris • severe chest pain due to ischaemia of the heart muscle, due to obstruction of the coronary arteria • Symptoms • after exertion, emotional stress, in the rest • chest pain (or discomfort) • lasting several minutes • referred pain to the arms, shoulders, neck, chin • exacerbated by full stomach or cold temperature • breathlessness, sweating, nausea • pain relieved by nitroglycerin

40. Types of angina pectoris • Stable AP • stable atherosclerotic plaque • retrosternal pain precipitaded by activity (walking, running) • no pain in rest • 3 – 5 min • referred pain to the arms, shoulders, back... • Unstable AP • „crescendo“ angina • unstable atherosclerotic plaque • at rest • > 10 min. • more serious symptoms • Variant (Prinzmetal´s, vasospastic) AP • caused by vasospasm • unknown mechanism (dysfunction of endothelium?) • atherosclerotic changes – not necessary • at rest (at night, early morning)

41. Myocardial infarction • Acute myocardial infarction • Heart attack • Necrosis of the heart cells due to interruption of blood supply to the part of the heart Causes • rupture of the ustable atherosclerotic plaque → trombosis • coronary artery obstruction by the stable plaque

42. Signs and symptoms • sudden chest pain radiating to the left arm, shoulder, neck, chin... • pain not relieved by nitroglycerin • anxiety • nausea, vomiting, sweating • dyspnea • pale, cold skin • cardiogenic shock symptoms • arterial pressure decrease • tachycardia • sometimes silent ischaemia – without pain (e.g. diabetic neuropathy)

43. Pain left shoulder neck chest right shoulder epigastrium arm

44. ECG diagnosis T wave inverion ST segment elevation patological Q wave

45. Complication of MI • dysrhythmias • heart failure • shock and hypotension • myocardial rupture • valve defects • embolisation • pericarditis

46. Cardiac markers • myoglobin (Mb) • troponin I (TnI), T (TnT) • creatine kinase (CK) • heart MB subtype (CK-MB) • lactate dehydrogenase (LD) • aspartate aminotranspherase (AST)

47. CK-MB myoglobin troponin I serum concentration time (days) 0 1 2 3 4 5 6 7 14

48. activity CK-MB AST LD time (days) 0 1 2 3 4 5 6 7

49. Complication of MI • dysrhythmias • heart failure • shock and hypotension • myocardial rupture • valve defects • embolisation • pericarditis