Professional Documents
Culture Documents
Intima (endothelium)
Media
Adventitia
The main endothelium functions
Vasodilation: Anti-thrombotic:
Pro:
Pro: Plasminogen (t-PA)
Prostacyclin
NO (EDRF)
Thrombomodulin, heparan-
Prostacycline sulphate
Against:
Bradykinin PAI 1
Acetylcholine Tissue factor (prothrombin)
von Willebrand factor
Against:
Angiotensin II - ACE Anti-inflammatory anti-proliferative:
Pro:
Endothelin
NO
Cathecolamines Against:
Thromboxane The lack of NO
AT-II, aldosterone
Na++ in excess
IL-6, VCAM, ICAM
MCP, MCSF, PDGF, FGF
Atherosclerosis: definition
Athre: porridge, gruel; skleros: rigid
lymphocytes
Bacteria
Chronic mechanical stress:
Chlamydia
hypertension
Immunologic disease
Smoking
Genetic factors
Toxic factors: i.e. homocysteine,
Extracellular
VLDL
matrix
LDL
Collagen
fibers
foam cells
T-cells
Foam cells
Macroscopic view
80% 70%
Atherosclerosis
prevalence (%)
60% 47%
40%
22%
20%
0%
< 25 years 25-35 years >35 years old
Nissen
Nissen S.
S. Am
Am JJ Cardiol
Cardiol 2001:87(suppl):15A-20A.
2001:87(suppl):15A-20A.
3. Fibrous plaque
cholesterol loaded macrophages:
foam cells
in fibroblasts
Lumen
Variable calcium load (osteopontin)
Intraplaque haemorrhage
Vb: calcification
National
National Cholesterol Education
Education Program.
Program. Adult
Adult Treatment
Treatment Panel
Panel III.
III. JAMA
JAMA 2001;285:2486-97.
2001;285:2486-97.
Serum lipoprotein structure
Differences between serum LP are due to different types of apo and % of lipid loads
Apo-lipoproteins: Phosfolipids
formation and secretion of LP
structurala integrity of LP
or selective uptake of a
Cholesterol
esters
Serum lipoproteins
Lipoprotein Density Major lipid Major apo- Electrophoretic
(g/ml) constituent lipoprotein migration
Chilomicrons <0.95 Food triglycerides B48 Origin
phospholipids
Lp(a) 1.055 - 1.085 Cholesterol esters B100, (a) Slow pre-
Relative dimensions of serum LP
- explains electrophoretic migration -
Endogenous lipoprotein metabolism
LPL LPL
LPL
HL
HL
Oxidation
CETP
CD36
SR-A
Recycled Macrophage
(foam cell)
LCAT ABCA1
LCAT Nascent
HDL Arterial wall
Brewer HB et al. Am J Cardiol 2003;92:10K-16K.
Genetic dyslipidemias 1
Type II hyperlipidemia (familial hypercholesterolemia):
High LDL by a gene mutation of the LDL receptor
Prevalence: 1 / 250-500 in Caucasians
autosomal co-dominant hereditary transmission
Gerontoxon, xantelasma, tendinous xanthomas
High risk of early coronary disease (3rdrd and 4thth decade; 10 years delayed onset in F)
Subcutaneous xanthomas
Secondary dyslipidemias
Metabolic Diabetes mellitus
Lipodystrophias Glicogenosis
Women > 88 cm
triglycerides
Pro-inflammatory status
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
2. Systemic HT
Increased incidence of:
Atherogenesis
Coronary disease
Pathogenesis:
Endothelial dysfunction (CO, nicotine)
Abstinence reduces AS complications and may induce lesion regression; irrespective of age
Smoking is the main preventable cause of death in USA
Produces 438.000 deaths every year
35% are due to cardiovascular causes
8% of deaths are due to second-hand smoking
Smoking leads to a total loss of 5 million years of life per year in the world
97
100 91 Non-smoking doctors
94 81 Smoking doctors
80
81
Survival at every
59
60 59
age (%)
10 years
40
24
20 26
2
4
0
40 50 60 70 80 90 100
Age (years)
Doll
Doll R
R et
et al. BMJ
BMJ 2004;328:151927.
2004;328:151927.
4. Diabetes mellitus
Increased risk for CAD: 2-3 x more in M, 3-5 x more in F
25% of ACS survivors have DM, > 50% have anomalies of glucose metabolism
Increased Lp(a)
Increased LDL
Endothelial dysfunction
Bio-mechanical factors:
Sudden in BP
Sudden in HR
Vasospasm
Rupture of vulnerable plaque
The thickness of fibrous cap
Large lipid core, thin fibrous cap
Vulnerable plaque Stable plaque
Lipid core
lipid core
Erosion:
- 25% of lesions
- associated with smoking
- more frequent in F
Rupture:
- 75% of lesions; n = 298 pts
- abnormal lipid prophile
Erosion
Treatment of dyslipidemias: drugs
Mechanism of
Drug Adverse effects Clinical trials results
action
Atorvastatin (10-80 mg)
Fluvastatin (20-80 mg)
HMG CoA reductase Liver enzymes, Major coronary events,
Lovastatin (20-80 mg)
Statins inhibition in myopathy, rash, digestive coronary mortality,
Pravastatin (20-40 mg) hepatocytes disturbances AVC
Rosuvastatin (10-40 mg)
Simvastatin (20-80 mg)
Cholesterol
Selective block of Major coronary events
absorbtion Ezetimibe (10 mg)
NPC1L1 in enterocytes
Idem statins
(over statins)
inhibitors
National
National Cholesterol
Cholesterol Education
Education Program.
Program. Adult
Adult Treatment
Treatment Panel
Panel III.
III. JAMA
JAMA 2001;285:2486-97.
2001;285:2486-97.
THE THERAPEUTIC EFFECTS OF THE MAIN
DRUGS USED TO TREAT DYSLIPIDEMIA
RESINS 15 30% - 3 5%
Dose (mg)
10 20 40 80
0
Rosuvastatin
10
LDL-C reduction vs
Atorvastatin
baseline (%)
20 Simvastatin
X
X Pravastatin
30 n=485
X
40 X
FU = 6
X n=648
weeks
50 * n=634
n=473
60
Jones
Jones PH
PH et
et al.
al. STELLAR
STELLAR Study.
Study. Am
Am JJ Cardiol
Cardiol 2003;92:15260.
2003;92:15260.
PCSK-9 inhibitors: the new kids on the block