CHD Newer Risk Factors An over view on Homocystinemia Dr. R.V.S.N.Sarma M.D., M.Sc., (Canada)

CHDNewer 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

– 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

Weight in kgs

Height2 in mtsBMI =

How much is much ?

70

1.65 x 1.65BMI = = 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

Sedentary Life Style

Less perfect Genetic make-up

Diets rich in Saturated Fat, Chol

Excess body weight/ Obesity

Lipid abnormalities

Atherosclerotic vascular disease

CHD, CVD, PVD

tHcy

ROS

AVD – Clinical Manifestations

Organ Condition Impairment Clinical Presentation

Heart Coronary Heart

Disease (CHD)

Ischemia

Infarction

Angina Pectoris

Myocardial Infarction

Brain Cerebro vascular

Disease (CVD)

Ischemia

Infarction

Transient Ischemia attack

Stroke

Kidney Reno vascular

Disease (RVD)

Ischemia

Infarction

Reno vascular hypertension

Renal impairment

Renal Failure

Leg Muscles

Peripheral Vascular Disease (PVD)

Ischemia

Infarction

Intermittent Claudication

Gangrene

For every thing the common denominator is ED

Lipid Peroxidation

LDL, IDL Not normally taken up by the vessel wall

ROS – Free radicals and Pro-oxidants

Oxidized LDL, IDL

Freely enters the vessel wall

Scavenger pathway

Endothelium Macrophages

Foam Cells Cytokines, GF

Atherosclerosis

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

Homolytic fission of a covalent bond

A B

BAA B

Single covalent bond

Homolytic fission Heterolytic fission

Free radicals Ions

ROS damage biological tissues- membranes

Reactive Oxygen Species

Lipid peroxidation Protein denaturation DNA Damage

Cell Dysfunction and death

Free radicals released

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 Antioxidants

O2 Superoxide

free radical

Superoxide dismutase Vitamin E, -carotene

OH Hydroxyl free radical

Vitamin C

H2O2 Hydrogen peroxide

Glutathione peroxidase

O2 Singlet Oxygen Vitamin A, E

Reactive Oxygen Species (ROS)

Free Radicals Non Radicals

Superoxide O2 Hydrogen peroxide H2O2

Hydroxyl OH Singlet oxygen O2

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

What is Homocysteine ?

Protein diet Methionine 1)Homocysteine

2)Homocystine

3) Homocysteine thiolactone

Generation of ROS

Homocysteine • 1+2+3= homocyst(e)ine

•homocyst(e)ine = tHcy

•Homocyst(e)inemia=hyper - tHcy

Digestion Metabolism

Auto-oxidationProtein synthesis

HS-CH2-CH2-CH-COOH

NH2

• Sulfur-containing amino acid

•By product of methionine metabolism

Homocysteine : Metabolic Pathways

Remethylation Cycle

Demethylation Cycle

Transsulfuration

Pathway

Diet

Methionine

Homocysteine

Tetra hydrofolate

Methyl tetrahydrofolate

Cystathionine

Cysteine

GlutathioneSulphate

Vitamin B6 (C beta S)

Folic acid MTHFR

Vitamin B6 (MS)

MS – Methionine synthaseMTHFR – Methyl tetrahydro folate reductaseC beta S – Cystathionine beta synthase

Hyperhomocyst(e)inemia

Blood Homocyst(e)ine Levels

Classification Values in mol/L

Normal

Moderate

Intermediate

Severe

05 – 15

16 – 30

31 – 100

> 100

• 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

A. Nutritional : Vitamin deficiency

Folic Acid

Vitamin B12

Vitamin B6

B. Genetic : Enzyme Abnormality

C. Drugs :

Methotrexate, Phenytoin, Theophylline

Homocysteine & Pathogenesis of AVD

Homocysteine

Auto-oxidation

Generation of ROS

Lipid peroxidationDamages endothelium

H2O2 OH/O2

Oxidizes LDL

Foam cells (chol)Nitric Oxide formation

Vasodilation

Hypertension

Exposure of smooth muscle, subendothelium

Proliferation of SM cells, Chemotaxis

ATHEROSCLEROSIS

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

A. Nutritional : Vitamin Supplimentation Folic Acid – 5 mg daily (Folvite)

Supplementation of Vitamin B12

Supplementation of Vitamin B6

B. Drugs : Care while using drugs likeMethotrexate, Phenytoin, Theophylline

C. Role of anti-oxidants – no RCTs

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

True !

Eat but not over-eat

Drink but not alcohol

Indulge but not in junk food

Think but not worry

Be quiet but with exercise

Have high Chol but only HDL Cholesterol

Be high spirited but not be on ‘spirits’

Smoke any brand of incense stick, but not cigarettes