atherosclerosis coronary heart disease angina pectoris myocardial infarction
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Atherosclerosis Coronary heart disease Angina pectoris Myocardial infarction. 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%

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atherosclerosis coronary heart disease angina pectoris myocardial infarction

AtherosclerosisCoronary heart diseaseAngina pectorisMyocardial infarction

causes of death in europe
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%
atherosclerosis
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

slide4

Tunica intima

Endothelial cells

Tunica adventicia

Tunica media

Smooth muscle cells

atherosclerotic plague
Atherosclerotic plague

Thrombus

Endothelial cells

Rupture of fibrous cap

Platellets

Smooth muscles cells

Foam cells

Lipid core

stages of atherosclerotic plaque development
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
coronary heart artery disease
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

coronary heart disease

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

ri s k fa c tor s ch d im
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
basic biological factors
Basic biological factors
  • age
    • men > 45 years
    • women after menopause
  • gender
    • men > women
obesity
Obesity

obesity

hyperinsulinaemia

dyslipidaemia

central typ

hypertension
Hypertension
  • endothelium damage
smoking
Smoking
  • nicotine
    • effect on lipid metabolism
    • vasoconstriction
  • CO
    • carboxyhaemoglobin
  • increased coagulation cascade activity
endothel
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...
c holesterol free and esters with fatty acids
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
tri acyl glycerol s fatty acids tag ffa
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)
slide20

Lipoproteins

  • water-soluble particles, that transport water-insoluble lipids

in the blood

lipids

Free cholesterol

Phospholipids

Triacylglycerols

Cholesterol esters

proteins

Apolipoproteins

3 lipoprotein families lp
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
chylomicrons
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
vldl ldl family
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
slide27
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
rever se transport of cholesterol by hdl
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
slide29

liver

HDL3 HDL2

nascent HDL

vessel

tissues

slide30

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

norma l desired values
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

???

other laborat o r y met ho d s
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
classifications
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
primary dlp
“Primary DLP”
  • Familiar hypercholesterolemia (LDL rec.)
  • Familiar defect of ApoB100 (FDB)
  • Polygenous hypercholesterolemia
  • Polygeneous hypertriglcyceridemia
  • Dysbetalipoproteinemia (IDL)
  • Familiar type V hyperlipidemia
secondary dlp
“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
slide37

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

slide38

Symptoms and signs

xantelasma palpebrarum

xantomas

arcus lipoides corneae

atherosclerosis and CHD

angina pectoris
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
types of angina pectoris
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)
myocardial infarction
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
slide42
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)
slide43
Pain

left shoulder

neck

chest

right shoulder

epigastrium

arm

slide44

ECG diagnosis

T wave inverion

ST segment elevation

patological Q wave

slide45
Complication of MI
    • dysrhythmias
    • heart failure
    • shock and hypotension
    • myocardial rupture
    • valve defects
    • embolisation
    • pericarditis
cardiac markers
Cardiac markers
  • myoglobin (Mb)
  • troponin I (TnI), T (TnT)
  • creatine kinase (CK)
  • heart MB subtype (CK-MB)
  • lactate dehydrogenase (LD)
  • aspartate aminotranspherase (AST)
slide47

CK-MB

myoglobin

troponin I

serum concentration

time (days)

0 1 2 3 4 5 6 7 14

slide48

activity

CK-MB

AST

LD

time (days)

0 1 2 3 4 5 6 7

slide49
Complication of MI
    • dysrhythmias
    • heart failure
    • shock and hypotension
    • myocardial rupture
    • valve defects
    • embolisation
    • pericarditis
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