الرحيم بسمبسم الرحمن الرحيم الله الرحمن الله

أشكر )) أن أوزعني أشكر رب أن أوزعني ربالتي التي نعمتك أنعمتعلي أنعمتعلي نعمتك

وأن والدي وأن وعلي والدي صالحا وعلي صالحا أعمل أعمل0000000000ترضاهترضاه ))

العظيم الله العظيم صدق الله صدق

By By Ragab Abd El Salam (MD)Ragab Abd El Salam (MD)

Prof. of CardiologyProf. of Cardiology

IntroductionIntroduction- MS Affects- MS Affects approximately 47 plus approximately 47 plus

million Americansmillion Americans-Of them-Of them approximately 20% develop type II approximately 20% develop type II

DMDM-The remaining-The remaining 80% will be able to resist 80% will be able to resist

for a time by beta-cell expansion, for a time by beta-cell expansion, hypertrophy & hyperplasia.hypertrophy & hyperplasia.

--But this without pay :,But this without pay :, the price will be a the price will be a condition of hyperinsulinimia & condition of hyperinsulinimia & hypermylinemia which place the patients hypermylinemia which place the patients at higher risk for at higher risk for hypertension & CAD.hypertension & CAD.

*Metabolic syndrome –X Vs Cardiac *Metabolic syndrome –X Vs Cardiac syndrome –X:syndrome –X:

The other typeThe other type of syndrome –X is cardiac: it is of syndrome –X is cardiac: it is described as :described as :

- Typical Anginal pain- Typical Anginal pain

- Positive ETT- Positive ETT

- Normal coronary angiography- Normal coronary angiography

Metabolic syndrome –XMetabolic syndrome –X is usualy associated is usualy associated with cardiac syndrome –X , while the reverse is with cardiac syndrome –X , while the reverse is not the case not the case

In some instancesIn some instances both syndromes are both syndromes are coincident coincident

• We try to live this day to die in We try to live this day to die in another day:another day:

Due to improvedDue to improved treatment of complication treatment of complication associated with HTN & CAD , more patients associated with HTN & CAD , more patients with this trio now live long enough for the with this trio now live long enough for the clinical syndrome of clinical syndrome of heart failure .heart failure .

Currently ,Currently ,we are at an intersection we are at an intersection (crossroads)(crossroads) of the decreasing mortality curve of the decreasing mortality curve from CAD-CHD and the increasing mortality from CAD-CHD and the increasing mortality curve from CHF curve from CHF

What is the metabolic syndromeWhat is the metabolic syndrome??

It is characterized by a group of risk It is characterized by a group of risk factors in one personfactors in one person

1-Central obesity1-Central obesity

2-Atherogenic dyslipidemia2-Atherogenic dyslipidemia

3-Raised blood pressure3-Raised blood pressure

4-Insulin resistance4-Insulin resistance

5-Prothrombetic sate5-Prothrombetic sate

6-Proinflamatory state.6-Proinflamatory state.

The underlying causes are:The underlying causes are: 1-Overweight/obesity1-Overweight/obesity 2-Physical inactivity2-Physical inactivity 3-Genetic factors3-Genetic factors

People with MS are at increased risk of:People with MS are at increased risk of:

1-CAD 1-CAD

2-CHF2-CHF

3-Type 2 DM, 3-Type 2 DM,

4-HPN , 4-HPN ,

5-Cardiomyopathy.5-Cardiomyopathy.

6-Other diseases related to plaque 6-Other diseases related to plaque buildups in artery walls (e.g: stroke & buildups in artery walls (e.g: stroke & peripheral VD)peripheral VD)

Who has MS ?Who has MS ?

11-It is closely associated with insulin resistance -It is closely associated with insulin resistance

22-genetically predisposed people to insulin -genetically predisposed people to insulin resistanceresistance

33-Acquired factors :-Acquired factors :

-excess body fat-excess body fat

-physical inactivity-physical inactivity

-central obesity-central obesity

NBNB:-any patient:-any patient with family history of type 2 DM with family history of type 2 DM shuod be evaluated for glucose intolerance & shuod be evaluated for glucose intolerance & blood pressure abnormalities. blood pressure abnormalities.

*Obesity & metabolic syndrome:*Obesity & metabolic syndrome:• It is directlyIt is directly related to MS & T2DM . related to MS & T2DM .

• It is importantIt is important to single out obesity as it to single out obesity as it plays an important role in the development plays an important role in the development of HTN ,CAD , & CHF;of HTN ,CAD , & CHF;

• Ther is a gradedTher is a graded increase in the risk of increase in the risk of CHF CHF acrossacross categories of body mass categories of body mass index.index.

• For each incrementFor each increment of 1 inch in the BMI of 1 inch in the BMI there will an increase in CHF of 5% for there will an increase in CHF of 5% for men & 7% for women men & 7% for women

**Obesity increasesObesity increases the prevalence of most of the prevalence of most of cardiovascular risk factors cardiovascular risk factors

*Moreover*Moreover obesity shifts the obesity shifts the manifestation of these risk factors to younger manifestation of these risk factors to younger age groups such that cardiac events become age groups such that cardiac events become clinically overt prematurely.clinically overt prematurely.

* For all of these* For all of these we may find in the near we may find in the near future that the prevalence & incidence of future that the prevalence & incidence of cardiovascular events may be increasing in cardiovascular events may be increasing in a younger age population. a younger age population.

Insulin Resistance (IR)

IR describes the condition whereby there

is a resistance to insulin-mediated glucose

uptake by cells is central to clustering of metabolic abnormalities.

HyperglycemiaIGT,IFG & T 2 DM

hypertension

microalbum& hyperurimia

IR

Obesity&

dyslipidemia

IR

Hyperinsulinemia AMYLIN

*Clinical link of IS & MS*Clinical link of IS & MS 1-strong family history of DM.1-strong family history of DM.

2-High risk ethnic background2-High risk ethnic background

3-Obesity3-Obesity

4-Macrosomia4-Macrosomia

5-Multiparity5-Multiparity

6-Gastational DM6-Gastational DM

7-Polysystic ovary syndrome7-Polysystic ovary syndrome

8-Impaired glucose intolerance8-Impaired glucose intolerance

9-Impaired fasting glucose 9-Impaired fasting glucose

10-Aging 11-Hypertenson10-Aging 11-Hypertenson

12-Dyslipidemia 12-Dyslipidemia

LookingLooking at the “at the “whole forest”whole forest” instead instead of looking at individual of looking at individual trees:trees:

ThisThis is a global MS approach of is a global MS approach of cardiovascular risk assessment & it is cardiovascular risk assessment & it is important to treat the whole disease not important to treat the whole disease not an individual factor.an individual factor.

This trueThis true as each component of MS as each component of MS plays a role in CAD & also in the future plays a role in CAD & also in the future development of cardiovascular events.development of cardiovascular events.

*Redox Homeostasis:*Redox Homeostasis:-It the-It the process of reduction & oxidation in process of reduction & oxidation in

order to re-pair order to re-pair unstable ,damaging ,reduced reactive unstable ,damaging ,reduced reactive oxygen species(ROS) which will include: oxygen species(ROS) which will include:

OFR( superoxide & -OH-hydroxyl radical) , OFR( superoxide & -OH-hydroxyl radical) , hydrogen peroxide& reactive nitrogen hydrogen peroxide& reactive nitrogen species.species.

-This is-This is the homeostasis balance the homeostasis balance between (ROS) & antioxidant capacitybetween (ROS) & antioxidant capacity

*endothelial Nitric Oxide (eNO)*endothelial Nitric Oxide (eNO)The protective role of eNOThe protective role of eNO

1-promotes vasodilatation1-promotes vasodilatation

2-Counteract smooth muscle cell proliferation2-Counteract smooth muscle cell proliferation

3-Decrease the adhesiveness to WBCs3-Decrease the adhesiveness to WBCs

4-decreases platelets adhesivness4-decreases platelets adhesivness

5-anti-iflammatory5-anti-iflammatory

6=anti-oxidant 6=anti-oxidant

7-anti-fibrotic7-anti-fibrotic

Pathophysiology:Pathophysiology:

(I) The (I) The A-FLIGHTA-FLIGHT multiple metabolic multiple metabolic toxisties:toxisties:

-It is the -It is the acronymacronym of the toxic trio of MS -this of the toxic trio of MS -this results in an elevated tension of redox stress oxygen results in an elevated tension of redox stress oxygen species(ROS)& activation of remodeling pathways in species(ROS)& activation of remodeling pathways in the cells & tissues.the cells & tissues.

-Each-Each of the metabolic toxicities play s a role in the of the metabolic toxicities play s a role in the pathogenesis prior the diagnosis of overt DM. pathogenesis prior the diagnosis of overt DM.

The A-FLIGHT toxicities:The A-FLIGHT toxicities:

AA

-Amylin -Amylin

-Angiotensin II-Angiotensin II

-Advanced glycation end product-Advanced glycation end product

-Advanced lipoxidation end product-Advanced lipoxidation end product

-Absnce of antioxidant netwark-Absnce of antioxidant netwark

-Aging -Aging

-Atherosclerotic nephropathy -Atherosclerotic nephropathy

FF=Free fatty acid toxicity=Free fatty acid toxicity

L=lipotoxicityL=lipotoxicity lipid triad: lipid triad: -FFA -FFA -ALE-ALE -Long chain acyl-COA-Long chain acyl-COA

I= Insulin toxicityI= Insulin toxicity Insulin resistanceInsulin resistance Insulin defienicyInsulin defienicy Inflammatory toxicityInflammatory toxicity

G= GG= Glucotoxicitylucotoxicity

H= H= Hypeertension toxicityHypeertension toxicity

Homocysteine toxicityHomocysteine toxicity

T= T= Triglyceride toxicityTriglyceride toxicity

ThrombotictoxicityThrombotictoxicity

Taurine(antioxidant) Taurine(antioxidant)

depletion depletion

**Pathophysiologic ConsequencePathophysiologic Consequence

1-Excess (ROS) production1-Excess (ROS) production 2- Inflammation begets 2- Inflammation begets inflammationinflammation 3- Cytotoxicity3- Cytotoxicity 4-Apoptosis4-Apoptosis 5-Atheroembolization5-Atheroembolization

6-Ischemia / injury6-Ischemia / injury

7-remodeling , systolic & diastolic 7-remodeling , systolic & diastolic dysfunction dysfunction

8-decreased nitrous oxide (NO)8-decreased nitrous oxide (NO)

9 -Endothelial cell injury9 -Endothelial cell injury

10 -ROS begets ROS10 -ROS begets ROS

11-Islets of Amyloid polypeptide 11-Islets of Amyloid polypeptide deposition deposition

(II) Redox stress:(II) Redox stress: Redox imbalance –a contraction of Redox imbalance –a contraction of

reduction & oxidation: implies of loss of reduction & oxidation: implies of loss of redox homeostasis resulting in an excess redox homeostasis resulting in an excess production of (ROS) via the process of production of (ROS) via the process of reduction or oxidation .reduction or oxidation .

(III) Oxidative stress:(III) Oxidative stress: Implies loss of redox homeostasis with an Implies loss of redox homeostasis with an

increase in (ROS) via sigular process of increase in (ROS) via sigular process of oxidation.oxidation.

Origins of (ROSOrigins of (ROS)) 11-Excess oxygen ( oxygen therapy)-Excess oxygen ( oxygen therapy)

22-Absorption of radiant energy-Absorption of radiant energy

33-exosure to toxins-exosure to toxins

44-Reduction-oxidation of normals-Reduction-oxidation of normals

55-Ischemia-ischemia reperfusion inury-Ischemia-ischemia reperfusion inury

66-Inflammatory processes.-Inflammatory processes.

77-Autocatalytic reaction-Autocatalytic reaction(ROS beget ROS)(ROS beget ROS)

**Role of (ROS):Role of (ROS):-elevated tension of redox stress.-elevated tension of redox stress.-tremendous local energy production-tremendous local energy production-this will lead to damage of the surroundings-this will lead to damage of the surroundings-consume NO-consume NO

ONOO which also consumes & inactivate NOONOO which also consumes & inactivate NONB:It wasNB:It was known for a time that (ROS) are toxic via known for a time that (ROS) are toxic viaA) lipid peroxidationA) lipid peroxidationB) DNA damage leading to mutation& death B) DNA damage leading to mutation& death

( apoptosis)( apoptosis)C) Cross-linkage to stiff aged proteins C) Cross-linkage to stiff aged proteins --

““A thief in the nightA thief in the night I It points to t points to Homocysteine:Homocysteine:

-As it consumes the endogenous antioxidant -As it consumes the endogenous antioxidant NO”& the antioxidant enzymes.NO”& the antioxidant enzymes.

-Not only ” -Not only ” a rubbera rubber “but also Hcy acts as an “but also Hcy acts as an accelerant to a fire where the fire is ROS & accelerant to a fire where the fire is ROS & redox stressredox stress

-In addition-In addition to his Hcy allows other to his Hcy allows other

A-FLIGHT A-FLIGHT toxicities to take a greater toll & toxicities to take a greater toll & overwhelm the endogenous antioxidant overwhelm the endogenous antioxidant mechanisms within myocardium..mechanisms within myocardium..

How is the metabolic syndrome How is the metabolic syndrome diagnosed?diagnosed?

The metabolic syndrome is diagnosed by the The metabolic syndrome is diagnosed by the presence of three or more of the following : presence of three or more of the following :

1- Central obesity(as1- Central obesity(as measured by waist measured by waist circumferance) circumferance)

-Men—greater than 40 inches-Men—greater than 40 inches -Women—greater than 35 inches -Women—greater than 35 inches 2-FB Triglyc.2-FB Triglyc. is more than 150 mg/dl is more than 150 mg/dl 3-Blood HDL:3-Blood HDL: -Men-less than 40 mg/dl-Men-less than 40 mg/dl -Women –less than 50mg/dl -Women –less than 50mg/dl

44-Blood pressure is-Blood pressure is equal to or greater than equal to or greater than 130/85 130/85 mmHgmmHg

55-fasting blood-fasting blood glucose is equal to or greater glucose is equal to or greater than than 110110 mg/dl mg/dl

This diagnostic criteria are according to the This diagnostic criteria are according to the Adult Treatment Panel- III (ATP Adult Treatment Panel- III (ATP))

NB:NB: ATP-III did not find evidence to recommend ATP-III did not find evidence to recommend routine assessment of insulin resistance ( e.g. routine assessment of insulin resistance ( e.g. increased fasting insulin level) ,pro-thrombotic increased fasting insulin level) ,pro-thrombotic states & pro-inflammatory statestates & pro-inflammatory state

MS & Cardiomyopathy:MS & Cardiomyopathy:Mechanisms:Mechanisms: 11- Basement membrane thickening- Basement membrane thickening

22- Fibrosis (perivascular & interstitial)- Fibrosis (perivascular & interstitial)

3- 3- PAS+hyaline staining of interstitiumPAS+hyaline staining of interstitium

44- Decreased Capillary density & capillary - Decreased Capillary density & capillary microangiopathy.microangiopathy.

55- Endothelial cell proliferation- Endothelial cell proliferation

66- Myocardial-myocyte hypertrophy(Myocytolysis)- Myocardial-myocyte hypertrophy(Myocytolysis)

7- 7- Accelerated atherosclerosis(atheroscleropathy)Accelerated atherosclerosis(atheroscleropathy)

8- 8- Microangiopathy.Microangiopathy.

The trigger trios in MS includes:The trigger trios in MS includes: 1-1-ththe multiple metabolice multiple metabolic A-FLIGHT A-FLIGHT toxicitiestoxicities

2-elevated tension of redox stress2-elevated tension of redox stress

3-Nitric oxide3-Nitric oxide inhibition inhibition

4- Vascular paradox:4- Vascular paradox: Accelerated Accelerated Angiogenesis( capillary vessel formation) & Angiogenesis( capillary vessel formation) & impaired arteriogenesis( collateral vessels impaired arteriogenesis( collateral vessels formation)formation)

5-Elevated plasminogen activator5-Elevated plasminogen activator inhibitor- inhibitor-1(PA1-1) so , there is not only impaired 1(PA1-1) so , there is not only impaired fibrinolysis but also impaired remodeling & fibrinolysis but also impaired remodeling & collateralization. collateralization.

Atherosclerosis & MS:Atherosclerosis & MS:Atherosclerosis is accelerated in MS along Atherosclerosis is accelerated in MS along

several mechanisms:several mechanisms:1-Endothelial dysfunction1-Endothelial dysfunction with decreaese in NO with decreaese in NO2-Metabolic A-FLIGHT toxicities2-Metabolic A-FLIGHT toxicities3-ROS with its bad effects3-ROS with its bad effects4-Homocysteine ( a theif in the night.4-Homocysteine ( a theif in the night.5-The eNOS gene, enzyme & eNOS reaction:5-The eNOS gene, enzyme & eNOS reaction: -defect in the eNOS gene is associated with -defect in the eNOS gene is associated with

insulin resistance , hypertension & insulin resistance , hypertension & dyslipidemia.dyslipidemia.

-The Glu-Asp gene polymorphism:-The Glu-Asp gene polymorphism:

It is associated with increased incidence It is associated with increased incidence hypertension & spastic anginahypertension & spastic angina

*Higher frequency of abnormal *Higher frequency of abnormal angiographic findingsangiographic findings

*Significant decrease in basal NO *Significant decrease in basal NO productionproduction

* Not only this , but also this gene could * Not only this , but also this gene could iteract with other gene polymorphism iteract with other gene polymorphism and specialand special environmental conditions environmental conditions as(smoking , obesity, & the A-FLIGHT as(smoking , obesity, & the A-FLIGHT toxicities of MS) toxicities of MS)

MS & Remodeling:MS & Remodeling: It is defined as any change in an existence It is defined as any change in an existence

or native structure.or native structure.

- The trigger may- The trigger may be tear-down or degrade be tear-down or degrade the existencethe existence

-The matrix-The matrix metalloproeinases(MMPs) are metalloproeinases(MMPs) are the degrading enzymes responsible for the degrading enzymes responsible for degradation of the existence structures degradation of the existence structures

- Normally these- Normally these enzymes are present in enzymes are present in an inactive latent zymogen ( proMMPs) an inactive latent zymogen ( proMMPs)

Types of Remodeling:Types of Remodeling:A) Passive remodelingA) Passive remodeling : occurs at the : occurs at the

local site of ischemia & is related to local site of ischemia & is related to myocyte necrosis & is also termed myocyte necrosis & is also termed surragate fibrosis.surragate fibrosis.

B) Active remodeling:B) Active remodeling: occurs at a site occurs at a site remote of injury or ischemia in non-remote of injury or ischemia in non-infarcted area & is not associated with infarcted area & is not associated with myocyte nerosis& also termed interstitial myocyte nerosis& also termed interstitial fibrosis fibrosis

MMPs are activated in MS by several MMPs are activated in MS by several factors :factors :

e.g. ROS & plasminAdvanced glycation e.g. ROS & plasminAdvanced glycation end products(AGE)end products(AGE)

-- once once MMPs MMPs are activated degradation of are activated degradation of collagen starts first , followed by elastin & collagen starts first , followed by elastin & then stiffer matrix occurs with then stiffer matrix occurs with myocardial remodeling (decreasing vent. myocardial remodeling (decreasing vent. compliance , relaxation & filling).compliance , relaxation & filling).

MS & Diastolic Dysfunction(Dd):MS & Diastolic Dysfunction(Dd):

- - ItIt may be observed in about of 40 % of may be observed in about of 40 % of cases free of CAD & other factors cause cases free of CAD & other factors cause Dd Dd

- The global systolic function is usually - The global systolic function is usually normal.normal.

- Other associated factors of MS increases - Other associated factors of MS increases the incidence of Dd in this syndrome.the incidence of Dd in this syndrome.

* Mechanisms of Dd in MS:* Mechanisms of Dd in MS:1-Marked increased interstitial & perivascular 1-Marked increased interstitial & perivascular

fibrosis of ECM.fibrosis of ECM.

2-The presence of a concederable amount of 2-The presence of a concederable amount of Periodic Acid Schiff positive material( in the Periodic Acid Schiff positive material( in the interstitium, arterial wall & basement interstitium, arterial wall & basement membrane.)membrane.)

3-Myocardial remodeling.3-Myocardial remodeling.

4-Redox stress & injury-response to injury4-Redox stress & injury-response to injury

5-Myocyte hypertrophy & excessive collagen 5-Myocyte hypertrophy & excessive collagen deposition with fibrosis. deposition with fibrosis.

66-Activation of Renin-Angiotensin-Aldosteron -Activation of Renin-Angiotensin-Aldosteron system.system.

*All these changes will lead to*All these changes will lead to decrease in decrease in compliance & impaired relaxation as a result of compliance & impaired relaxation as a result of gradual disruption of the myofibrillar gradual disruption of the myofibrillar architecture,architecture, wherebywhereby the ventricle loses its the ventricle loses its ability to return to its normal resting state during ability to return to its normal resting state during diastole resulting impaired filling.diastole resulting impaired filling.

Treatment of metabolic syndrome:Treatment of metabolic syndrome: (I) Insulin resistance:(I) Insulin resistance: -T-There is no definite drug treatment for here is no definite drug treatment for

this.this.

- B- But the safest & most effective way is ut the safest & most effective way is to reduce insulin resistance is weight to reduce insulin resistance is weight loss & increased physical activity.loss & increased physical activity.

- C- Carefullyarefully choose antihypertesive drugs choose antihypertesive drugs because different agents have different because different agents have different effects on insulin resistance.effects on insulin resistance.

(II) Aggressive treatment of each (II) Aggressive treatment of each individual metabolic disorder individual metabolic disorder associated with MSassociated with MS::

=Dyslipidemia =Dyslipidemia

=Hypertension =Hypertension

= Clotting disorder= Clotting disorder

=Hyperglycemia or DM=Hyperglycemia or DM

These individual factors should be These individual factors should be agressively treated according to the agressively treated according to the standard guidelnes.standard guidelnes.

The The RAASRAAS acronym : for acronym : for prevention & treatment:prevention & treatment:

R= R= Reductase Inhibitor (HMG-CoA)Reductase Inhibitor (HMG-CoA)

A=A= ACEI—prils ,, ARBS-sartansACEI—prils ,, ARBS-sartans

Adrenergic (blockade) of proreninAdrenergic (blockade) of prorenin

A=A= Aggressive control of diabetes Aggressive control of diabetes

Aggressive control of hypertension Aggressive control of hypertension Aggressive control of homocysteineAggressive control of homocysteine

S=S= Statins Statins

*RAAS is a multifactorial & *RAAS is a multifactorial & global approachglobal approach to prevent & to prevent & slow the progression of islet , slow the progression of islet , intimal, renal neoronal,retinal & intimal, renal neoronal,retinal & myocardial redox stress which is myocardial redox stress which is directly implicated in the directly implicated in the development of multiple MS & development of multiple MS & diabetic-opathies & the vascular end diabetic-opathies & the vascular end stage on myocardium .stage on myocardium .

By using aggressive reducing the elevated

substrates producing the A-FLIGHT toxicities & ROS

&using the simple RAAS acronym we my be able to restore endogenous antioxidant & antioxidant

network specially eNO.

(IV) lowering the levels of (PAI-I):(IV) lowering the levels of (PAI-I): -Allow-Allow the myocardiumto be able to the myocardiumto be able to

undergo remodling , collateralization undergo remodling , collateralization arteriogenesis with collateral vessels arteriogenesis with collateral vessels formationformation

- Contribute- Contribute in awakening of hibernating in awakening of hibernating myocardium & improve myocardial myocardium & improve myocardial function.function.

ThisThis can be achieved by MMP-Inhibitor & can be achieved by MMP-Inhibitor & AntioxidantAntioxidant

(V) Ineresting point:(V) Ineresting point:The commonally used antibiotic The commonally used antibiotic

(Tetracycline)(Tetracycline) has a unique action has a unique action on MMPs independent of their on MMPs independent of their antibiotic action. It inhibits MMPs antibiotic action. It inhibits MMPs activity.activity.

So So this antibioticthis antibiotic may be introduced to may be introduced to ameliorate myocardial nitric oxide ameliorate myocardial nitric oxide dysfunction.dysfunction.

(V) Treatment paradigm for (V) Treatment paradigm for Endothelial dysfunctionEndothelial dysfunction::

1-Prevent 1-Prevent the competitive inhibition by the competitive inhibition by ADMA(Asymmetric DimethylarginineADMA(Asymmetric Dimethylarginine

2-prevent2-prevent hs-CRP from decreasing eNOS hs-CRP from decreasing eNOS & prevent glycation of eNOS enzyme& prevent glycation of eNOS enzyme

3-Add folic3-Add folic acid to lower Homocysteine & acid to lower Homocysteine & ADMA levels as well as restoring BH2 & ADMA levels as well as restoring BH2 & BH3BH3..

We are awaiting theWe are awaiting the availability of availability of new MMP-inhibitorsnew MMP-inhibitors ,& new ,& new antioxidantsmolecules such as :antioxidantsmolecules such as :

- SOD & catalase mimetics- SOD & catalase mimetics

- New probucole –like (phenolic - New probucole –like (phenolic

analog)AGI-1067analog)AGI-1067

Recently the use ofRecently the use of : :

- Thiazolodinedions- Thiazolodinedions

- Statins- Statins

- ACE-inhibitors- ACE-inhibitors

- ATI-blokers- ATI-blokers

Is a stronglyIs a strongly suggested,because suggested,because they are effective “they are effective “causal causal antioxidantsantioxidants””

The Empower of The Empower of RAASRAAS aat an earliar stage in the t an earliar stage in the

treatment of the paradigm treatment of the paradigm people may be able to live a people may be able to live a longer life with lesslonger life with less

morbidity , mortality & live tomorbidity , mortality & live to die die another day…….another day…….

THANK

YOU