IHD (ishemic heart disease)

7/28/2019 IHD (ishemic heart disease)

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GENETIC ASPECTS OF

CARDIOVASULAR

DISEASES

Part I. Genetics of Atherosclerosis and

Ischemic Heart Disease


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Incidence of cardiovascular diseases

in Russia (1994)

Ischemic heart disease (IHD)8-10%

Essential Hypertension (EH)20-25%

Cardiomyopathy (CM)0.1%

Heart Arrhythmias (HA)data not available

Mitral Valve Prolapse (MVP)4-10%


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Genetic heterogeneity of

cardiovascular diseases

DiseaseSingle gene

mutation

Additive-polygenic

background

1. IHD 30-35% 60-70%

2. EH 10-20% 80-90%

3. CM Genetic contribution is unknown

4. AS 4-8% >90%

5. MVP up to 90% about 10%


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Risk factors for atherosclerosis and IHD

I. Risk factors with strong geneticcontribution:

positive family history of early IHD in first-degree relatives

increased level of total cholesterol in the plasma

high level of low density lipoproteins (LDL) in the plasma

high level of LDL-cholesterol

decreased level of high-density lipoproteins (HDL) in the

plasma

low level of HDL-cholesterol


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low activity of LDL-receptors

mutations in apolipoprotein ApoB-100

high level of lipoprotein-a in the blood

presence of apolipoprotein ApoE2

presence of essential hypertension and/or diabetes

mellitus

combination of erythrocyte antigenes

I. Risk factors with strong geneticcontribution:



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II. Risk factors with potentially informative genetic

contribution:

high level of very low density lipoproteins in the plasma.

hypertriglyceridemia

disorders in the blood coagulation:

- high level of fibrinogen- high level of thrombin

- low level of endogenous heparin

- decreased activity of fibrinolysis


positive family history of IHD in second-degree relatives


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II. Risk factors with potentially informative genetic

contribution:


increased level of insulin in the plasma

low level of oestradiol in the plasma

abdominal obesity

heterozygous carriage for homocystinuria mutations

combinations of HLA antigenes

impaired glucose tolerance


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III. Risk factors without genetic contribution

(environmental risk factors):


smoking

food overconsumption

hypodynamia

life stress

contraceptive steroid administration


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Table of recurrent risk (%) for IHD in men.(estimated using an information about first-degree relatives)

ParentsCurrent

age(years old)

unaffected one affected both affectednumber of affected siblings

0 1 2 0 1 2 0 1 220-29 2 8 16 8 15 2 27 31 3330-39 2 9 17 9 17 24 30 34 3740-49 4 13 22 16 25 33 40 46 5050-59 10 20 29 26 37 44 52 58 63


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Chylomicrones (CM) transporters of the food(exogenous) triglycerides. They are synthesized in the

intestinal wall.

Basic lipoproteins

VLDL very low-density lipoproteins transporters of

endogenous triglycerides. They are synthesized in the liver.

LDL low-density lipoproteins products of VLDLcatabolism. LDL main transporters of the cholesterol into

peripheral tissues.

HDL low-density lipoproteins. HDL main transporters ofthe cholesterol from peripheral tissues (cell membranes) into

the liver.


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Basic atherogenic apolipoproteins.

Apo-100is presented in the structure of VLDL, IDL,LDL. It recognizes a LDL-receptor, and participates in

the VLDL secretion.

Apo-2is presented in the structure of CM and HDL. Itrecognizes a LDL-receptor, and participates in the

transport of cholesterol.

Apois presented in the structure ofVLDL. Itactivates a lipoprotein lipase, and thereby participates in

the VLDL catabolism.


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Basic atherogenic apolipoproteins.

Apo()is presented in the structure of LP(), and is

an independent risk factor of Ischemic Heart Disease.

Apo1is presented in the structure of HDL, andactivates LCAT (lecithin cholesterol acetyltransferase).


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structure of lipoproteins.

Apolipoprotein functions

transport of lipoproteins in the blood stream from

place of their synthesis to the peripheral tissues.

transport of cholesterol from peripheral tissues to

the liver for metabolizing and excreting.

promote the interaction of lipoproteins with specific

receptors on the cell membranes.

regulate an activity of enzymes of the lipid

metabolism.


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CM

Lipoprotein lipaseremnants

TG

VLDL

IDL

Lipoprotein lipase

TG

LDL

C HDL

C

C

Catabolism

in the liver

VLDLsynthesis

HDLsynthesis

Basic steps of lipoprotein and lipid metabolism

Plasma

cholesterol

into the cells of

peripheral

tissues

Cellular

cholesterol

Absorption of

food triglyceridesinto intestine

Cholesterol

excretion intointestine


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Upper lipid metabolism indices in

plasma depending on the age

Age period Plasmacholesterol(Mg/dl)

Plasma

triglycerides

(Mg/dl)

HDL

cholesterol

(Mg/dl)10-19 205 150 3620-29 210 200 3630-39 240 250 3540-49 260 300 3250-59 280 300 32

60 and older 280 300 32


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Classification of familial hyperlipidemias

(Fredrickson)

HYPERLIPOPROTEINEMIA, TYPE I (LIPOPROTEIN LIPASE

DEFICIENCY).

HYPERCHOLESTEROLEMIA, TYPES IIA AND IIB.

HYPERLIPOPROTEINEMIA, TYPE III.

HYPERTRIGLYCERIDEMIA, TYPE IV.

HYPERLIPOPROTEINEMIA, TYPE V.


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Genetic variants

of familial hypercholesterolemia (IIA)

FH due to structural

defect ofp -100

FH due to

deficiency ordefect of LDL

receptors

Polygenic FH


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Receptor variant of familial

hypercholesterolemia

Prevalence:Heterozygotes 1:200-500

Homozygotes 1:1000000

Type of inheritance: Autosomal dominant

Relative risk of coronary artery disease is 10-20

times higher in patients with receptor variant of

FH than without it.

The frequency of heterozygotes among patients

with myocardial infarction is 1 : 20


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pathogenesis

LDL receptors

are not synthesized

LDL receptors

are synthesized, but they migrate

slowly from reticular network to

Golgi complex

Deficiency of LDL receptors Defect of LDL receptors

LDL receptors

are synthesized, but they are

unable to link with LDLs

LDL receptors

are synthesized, they are ableto

link with LDLs, but the releasing

of cholesterol from LDL is

impaired

Increasing both cholesterol and LDL in plasma




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Clinical manifestations

Males and females are affected with identical frequency

Cholesterol metabolism abnormalities sings are:

Bright yellow tuberous dermal xanthomas at areas of Achilles

tendons, extensors of fingers of the upper and low extremities andalso ulnar and knee joints.

Corneal arcus lipoides and periorbital xanthelasmas

Plantar xanthomas between 1st and 2nd toes.

Onset of IHD : Homozygotes 20-30

Heterozygotes 30




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Familial hypercholesterolemia

Clinical picture

Xanthomatosis at area of ulnar joints


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Tuberous xanthomas at extensor areas

of knee joins


Clinical picture


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Xanthomas at extensor areas of

hands and fingers


Clinical picture


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FH due to Apo -100 defect (IIA)

Prevalence: 1:500-600

Type of inheritance:

Autosomal dominant Clinical manifestations:

as in receptor variant of FH

Onset of IHD:

after 30-50 years


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Pathogenesis

Mutation in gene encoding Apo -100

Weakening the interactions of LDLs with specific

receptors at peripheral tissues

Delayed elimination of LDLs from circulation

Increasing LDL in

plasmaIncreasing

cholesterol in LDL

Hypercholesterolemia

FH due to Apo -100 defect (IIA)


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Polygenic hypercholesterolemia (IIA)

Prevalence: unknown but widespread

Type of inheritance: Additive-polygenic

Clinical manifestations:

Xanthomatosis is not characteristic

Onset of IHD:after 40-50 years

Strong clinical variability of IHD manifestations

Association with essential hypertension and

diabetes mellitus


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Laboratory testing of hypercholesterolemia

Receptor variant of FH

Plasma cholesterol level: Heterozygotes: 300-500 mg/dL

Increased level of LDL in plasma

Absence of functioning LDL receptors

Identification of one of 40 common mutations in the

gene coding LDL receptor

Homozygotes: 500-1000 mg/dL


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Plasma cholesterol level:


Identification of mutations in the gene coding Apo -100

Increased level of LDL-cholesterol

Normal functioning LDL receptors

Delayed clearance of LDLs from circulation


FH due to a defect of Apo B-100

Heterozygotes: 300-500 mg/dL

Homozygotes: 500-1000 mg/dL


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Plasma cholesterol level: 240-400 mg/dL


Presence of Apo 4 allele.

Normal functioning LDL receptors


Polygenic FH

No Apo B-100 gene mutations


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Familial combined hyperlipidemia (IIB)

Prevalence:


Additive-polygenic

1:100-300

Autosomal dominant withhigh penetrance

Frequency among patients with early IHD: 10%

Genetic heterogeneity

Genetic mechanisms: Unknown.


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Clinical picture:Xanthamatosis is not characteristic

Xanthelasmas, Corneal arcus lipoides

Abnormal glucose tolerance test

Family history :

Combined hyperlipidemia, isolated

hypercholesterolemia and hypertriglyceridemia among

relatives of proband.

Onset of IHD: after 30-50 years

Familial combined hyperlipidemia (IIB)


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Increased levels of LDL and VLDL in plasma

Increasing Apo B level in both proband and his / herrelatives

Presence of alleles: Apo -3, Apo-4, lipoprotein

lipase genes

Plasma triglycerides: 200-500 mg/dL

Possible decreasing in HDL level

Laboratory testing of familial combined

hyperlipidemia (IIB)


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Familial disbetalipoproteinemia (III)

Prevalence: 1:1000-5000


Additive-polygenic

Autosomal-recessive


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Impaired interactions of IDL (intermediate DL)and chylomicrons (CM) with LDL receptors


Mutation Apo E-2

abnoramal catabolism of IDL and CM

IDL CM

Pathogenesis


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Clinical picture:

Flat yellow or orange xanthomas at the crimps of

palms, less often at area of elbows

Tuberous xanthomas at knees and buttocks

Atherosclerosis of lower limbs

Onset of IHD: After 30-40 years

Insulin non-dependent diabetes mellitus, obesity


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Laboratory testing of familial

disbetalipoproteinemia (III)


Increased level of IDL and CM in plasma

remnant hyperlipidemia or hypercholesterolemiaamong relatives


Triglycerides: 200-900 mg/dL

Triglicerides/cholesterol ratio 1

Presence of mutation in Apo- gene


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Familial hypertriglyceridemia (IV)

Prevalence:


Autosomal recessive

1:500

Autosomal dominant

Frequency of heterozygotes: 1:100

F ili l h t i l id i (IV)


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Pathogenesis

Mutation of Apo -2

Impaired interaction of Apo -2 VLDL with

tissue lipoprotein lipase (LPL)

Hypertriglyceridemia

LPL is not activated

Abnormal hydrolysis of VLDL


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Clinical picture :

Xanthomatosis is not characteristics



Presence of essential hypertension, diabetes mellitus,

obesity and atherosclerosis of peripheral vessels

Abdominal pains, pancreatitis

Lipid deposition in retina


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hypertriglyceridemia (IV)

> 2,5

Increased level of VLDL in plasma


Mutation of Apo -2

Triglycerides up to 1500 mg/dL

Hyperinsulinism

Triglicerides/cholesterol ratio

Possible decreasing in HDL level

F ili l h li i t i i V


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Familial hyperlipiproteinemia-V

(hyperprebetalipiproteinemia)

Prevalence: uninvestigated


Additive-polygenic

Autosomal recessive

Genetic mechanisms: unknown


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Familial hyperprebetalipiproteinemia (V)

Clinical picture:

Eruptive xanthomas

Abdominal pains, pancreatitis

Atherosclerosis of peripheral vessels


Diabetes mellitus, obesity

Hepatosplenomegaly


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hyperprebetalipiproteinemia (V)

Plasma cholesterol: 300-500 mg/dL

Increased level of

hyperprebetalipiproteinemia or hypertriglyceridemiaamong relatives.


Triglycerides > 400 mg/dL


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Therapy of familial hyperlipidemias

Diet therapy

Changing life style:Arrest of smoking, physical Exercise, body mass

control.

To limit a consumption of food rich by cholesterol,

saturated fatty acids, carbohydrates, salt.

To increase consumption of food enriched by

polyunsaturated fatty acids, and also cellulose and

composite carbohydrates and vitamins


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Hypolipidemic drug therapy(examples):

Statins:

Fibrates:

Probucol

Clofibrate, Fenofibrate

Lovastatin, Simvastatin

Colestipol, Cholestyramine.

Nicotinic acid, Niacin


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Efferent therapy: Enterosorbtion

Hemodialysis

Plasmapheresis / LDL-pheresis

Gene therapy:

Possible for receptor variant of familialhypercholesterolemia

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IHD (ishemic heart disease)

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