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CHD Newer Risk Factors. An over view on Homocystinemia. Dr. R.V.S.N.Sarma M.D., M.Sc., (Canada). All are One. This not about the GOD There is only one disease – Over nutrition Its faces are many such as Over weight / Obesity Diabetes mellitus, IR, Syndrome X

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Chd newer risk factors

CHDNewer Risk Factors

An over view on

Homocystinemia

Dr. R.V.S.N.Sarma

M.D., M.Sc., (Canada)


All are one
All are One

  • This not about the GOD

  • There is only one disease – Over nutrition

  • Its faces are many such as

    • Over weight / Obesity

    • Diabetes mellitus, IR, Syndrome X

    • Atherosclerosis – HT- CHD – CVD – RVD – PVD

    • Hyper lipidemias – endothelial dysfunction

    • Wear and tear of joints …. So on

  • What are we to do ? - Avoid over-indulgence


How much is much
How much is much ?

BMI =

Weight in kgs

Height2 in mts

70

1.65 x 1.65

BMI =

= 25.71

Underweight < 20 Over weight > 25 to 30

Normal 20 to 25 Obesity >30

Waist / Hip ratio = 35” /38” = 0.92

Normal for Males < 0.90, Females <0.80


Macro vascular disease

Diets rich in Saturated Fat, Chol

Sedentary Life Style

Excess body weight/ Obesity

Less perfect Genetic make-up

Lipid abnormalities

Atherosclerotic vascular disease

CHD, CVD, PVD

Macro-vascular Disease

ROS

tHcy


Avd clinical manifestations
AVD – Clinical Manifestations

For every thing the common denominator is ED


Lipid peroxidation
Lipid Peroxidation

LDL, IDL

Not normally taken up by the vessel wall

ROS – Free radicals and Pro-oxidants

Freely enters the vessel wall

Oxidized LDL, IDL

Macrophages

Endothelium

Scavenger pathway

Foam Cells

Cytokines, GF

Atherosclerosis


Risk factors for avd
Risk Factors for AVD

  • Hyperhomocyst(e)inemia

  • Diabetes mellitus

  • Hypertension

  • Dyslipidemia

  • Positive family history,

    Smoking, obesity and

    physical inactivity

Oxidative

Stress

AVD


Free radical formation
Free Radical Formation

Homolytic fission of a covalent bond

Single covalent bond

A

B

Homolytic fission

Heterolytic fission

B

A

A

B

Free radicals

Ions


Ros damage biological tissues membranes
ROS damage biological tissues- membranes

Reactive Oxygen Species

Lipid peroxidation

Protein denaturation

DNA Damage

Free radicals released

Cell Dysfunction and death


Classification
Classification

  • Preventive antioxidants

    -Ceruloplasmin, transferrin, lactoferrin

  • Enzyme antioxidants

    -Superoxide dismutase, catalase, glutathione peroxidase

  • Scavenging or ‘chain-breaking’ or ‘sacrificial’antioxidants

    -Vitamins A,C, and E



Reactive oxygen species ros
Reactive Oxygen Species (ROS)

ROS are highly reactive….and can damage biological tissues and membranes


What is homocysteine
What is Homocysteine ?

Metabolism

Digestion

Protein diet

Methionine

1)Homocysteine

Auto-oxidation

Protein synthesis

2)Homocystine

3) Homocysteine thiolactone

HS-CH2-CH2-CH-COOH

Generation of ROS

NH2

Homocysteine

  • 1+2+3= homocyst(e)ine

  • homocyst(e)ine = tHcy

  • Homocyst(e)inemia=hyper - tHcy

  • Sulfur-containing amino acid

  • By product of methionine metabolism


Homocysteine metabolic pathways
Homocysteine : Metabolic Pathways

Remethylation Cycle

Demethylation Cycle

Diet

Tetra hydrofolate

Methionine

Folic acid MTHFR

Vitamin B6 (MS)

Methyl tetrahydrofolate

Homocysteine

Vitamin B6 (C beta S)

MS – Methionine synthase

MTHFR – Methyl tetrahydro folate reductase

C beta S – Cystathionine beta synthase

Cystathionine

Transsulfuration

Pathway

Cysteine

Sulphate

Glutathione


Hyperhomocyst e inemia
Hyperhomocyst(e)inemia

Blood Homocyst(e)ine Levels

  • Moderate to severe hyper – tHcy : established risk factor for AVD 1-4

  • Hyper – tHcy

  • - 5-7 % of the general population

  • - 12-47 % of patients with AVD


Causes of hyperhomocyst e inemia
Causes of Hyperhomocyst(e)inemia

  • Nutritional : Vitamin deficiency

    Folic Acid

    Vitamin B12

    Vitamin B6

  • Genetic : Enzyme Abnormality

  • Drugs :

    Methotrexate, Phenytoin, Theophylline


Homocysteine pathogenesis of avd
Homocysteine & Pathogenesis of AVD

Homocysteine

Auto-oxidation

Generation of ROS

H2O2 OH/O2

Oxidizes LDL

Damages endothelium

Lipid peroxidation

Exposure of smooth muscle, subendothelium

¯ Nitric Oxide formation

Foam cells (chol)

Proliferation of SM cells, Chemotaxis

¯ Vasodilation

Hypertension

ATHEROSCLEROSIS


Physicians health study
Physicians Health Study

  • 271 male physicians who had MI and matched controls were studied

  • Various risk factors were analyzed

  • Plasma tHcy is significantly higher in those with MI compared to controls

  • The R.R for tHcy levels above 13 is 3.4 after adjusting for all other risk factors

  • 482 hyperlipedemic subjects – 72 % with ↑tHcy had atheroscleoris v/s 44 % without


Treatment of hyperhomocyst e inemia
Treatment of Hyperhomocyst(e)inemia

  • Nutritional : Vitamin Supplimentation

    Folic Acid – 5 mg daily (Folvite)

    Supplementation of Vitamin B12

    Supplementation of Vitamin B6

  • Drugs : Care while using drugs like

    Methotrexate, Phenytoin, Theophylline

    C. Role of anti-oxidants – no RCTs


Lp a or little a
Lp (a) or Little a

  • Similar to LDL molecule

  • a single apo-A is attached by a disulfide bond to apo-B 100

  • Primary determinant is genetic

  • Normal value 20 mg %, > 30 high risk

  • It may compete with plasminogen because of structural similarity and so interfere with plasmin synthesis and thrombolytic pathway

  • Nicotinic acid, ? Benzafibrate, estrogens lower it



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