Chd newer risk factors
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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

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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


Ros and their antioxidants

ROS and their Antioxidants


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


Chd newer risk factors

True !


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