بسم الله الرحمن الرحيم

1. بسمالله الرحمن الرحيم (رب أوزعني أن أشكر نعمتك التيأنعمت علي وعلي والدي وأنأعمل صالحا ترضاه00000) صدق الله العظيم

2. Metabolic Syndrome By Ragab Abd El Salam (MD) Prof. of Cardiology

3. Introduction - MS Affectsapproximately 47 plus million Americans -Of them approximately 20% develop type II DM -The remaining 80% will be able to resist for a time by beta-cell expansion, hypertrophy & hyperplasia. -But this without pay :, the price will be a condition of hyperinsulinimia & hypermylinemia which place the patients at higher risk for hypertension & CAD.

4. *Metabolic syndrome –X Vs Cardiac syndrome –X: The other type of syndrome –X is cardiac: it is described as : - Typical Anginal pain - Positive ETT - Normal coronary angiography Metabolic syndrome –X is usualy associated with cardiac syndrome –X , while the reverse is not the case In some instances both syndromes are coincident

5. We try to live this day to die in another day:  Due to improved treatment of complication associated with HTN & CAD , more patients with this trio now live long enough for the clinical syndrome of heart failure . Currently ,we are at an intersection (crossroads) of the decreasing mortality curve from CAD-CHD and the increasing mortality curve from CHF

6. What is the metabolic syndrome? It is characterized by a group of risk factors in one person 1-Central obesity 2-Atherogenic dyslipidemia 3-Raised blood pressure 4-Insulin resistance 5-Prothrombetic sate 6-Proinflamatory state.

7. The underlying causes are: 1-Overweight/obesity 2-Physical inactivity 3-Genetic factors

8. People with MS are at increased risk of: 1-CAD 2-CHF 3-Type 2 DM, 4-HPN , 5-Cardiomyopathy. 6-Other diseases related to plaque buildups in artery walls (e.g: stroke & peripheral VD)

9. Who has MS ? 1-It is closely associated with insulin resistance 2-genetically predisposed people to insulin resistance 3-Acquired factors : -excess body fat -physical inactivity -central obesity NB:-any patient with family history of type 2 DM shuod be evaluated for glucose intolerance & blood pressure abnormalities.

10. *Obesity & metabolic syndrome: • It is directly related to MS & T2DM . • It is important to single out obesity as it plays an important role in the development of HTN ,CAD , & CHF; • Ther is a graded increase in the risk of CHF across categories of body mass index. • For each increment of 1 inch in the BMI there will an increase in CHF of 5% for men & 7% for women

11. *Obesity increases the prevalence of most of cardiovascular risk factors *Moreover obesity shifts the manifestation of these risk factors to younger age groups such that cardiac events become clinically overt prematurely. * For all of thesewe may find in the near future that the prevalence & incidence of cardiovascular events may be increasing in a younger age population.

12. 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.

13. hypertension Hyperglycemia IGT,IFG & T 2 DM microalbum& hyperurimia IR IR Obesity & dyslipidemia Hyperinsulinemia AMYLIN

14. *Clinical link of IS & MS 1-strong family history of DM. 2-High risk ethnic background 3-Obesity 4-Macrosomia 5-Multiparity 6-Gastational DM 7-Polysystic ovary syndrome 8-Impaired glucose intolerance 9-Impaired fasting glucose 10-Aging 11-Hypertenson 12-Dyslipidemia

15. Lookingat the “whole forest” instead of looking at individual trees:  This is a global MS approach of cardiovascular risk assessment & it is important to treat the whole disease not an individual factor. This true as each component of MS plays a role in CAD & also in the future development of cardiovascular events.

16. *Redox Homeostasis: -It the process of reduction & oxidation in order to re-pair unstable ,damaging ,reduced reactive oxygen species(ROS) which will include: OFR( superoxide & -OH-hydroxyl radical) , hydrogen peroxide& reactive nitrogen species. -This is the homeostasis balance between (ROS) & antioxidant capacity

17. *endothelial Nitric Oxide (eNO) The protective role of eNO 1-promotes vasodilatation 2-Counteract smooth muscle cell proliferation 3-Decrease the adhesiveness to WBCs 4-decreases platelets adhesivness 5-anti-iflammatory 6=anti-oxidant 7-anti-fibrotic

18. Pathophysiology: (I) The A-FLIGHT multiple metabolic toxisties: -It is the acronym of the toxic trio of MS -this results in an elevated tension of redox stress oxygen species(ROS)& activation of remodeling pathways in the cells & tissues. -Each of the metabolic toxicities play s a role in the pathogenesis prior the diagnosis of overt DM.

19. The A-FLIGHT toxicities: A -Amylin -Angiotensin II -Advanced glycation end product -Advanced lipoxidation end product -Absnce of antioxidant netwark -Aging -Atherosclerotic nephropathy

20. F=Free fatty acid toxicity L=lipotoxicity lipid triad: -FFA -ALE -Long chain acyl-COA I= Insulin toxicity Insulin resistance Insulin defienicy Inflammatory toxicity

21. G= Glucotoxicity H= Hypeertension toxicity Homocysteine toxicity T= Triglyceride toxicity Thrombotictoxicity Taurine(antioxidant) depletion

22. *Pathophysiologic Consequence 1-Excess (ROS) production 2- Inflammation begets inflammation 3- Cytotoxicity 4-Apoptosis 5-Atheroembolization

23. 6-Ischemia / injury 7-remodeling , systolic & diastolic dysfunction 8-decreased nitrous oxide (NO) 9 -Endothelial cell injury 10 -ROS begets ROS 11-Islets of Amyloid polypeptide deposition

24. (II) Redox stress: Redox imbalance –a contraction of reduction & oxidation: implies of loss of redox homeostasis resulting in an excess production of (ROS) via the process of reduction or oxidation . (III) Oxidative stress: Implies loss of redox homeostasis with an increase in (ROS) via sigular process of oxidation.

25. Origins of (ROS) 1-Excess oxygen ( oxygen therapy) 2-Absorption of radiant energy 3-exosure to toxins 4-Reduction-oxidation of normals 5-Ischemia-ischemia reperfusion inury 6-Inflammatory processes. 7-Autocatalytic reaction(ROS beget ROS)

26. *Role of (ROS): -elevated tension of redox stress. -tremendous local energy production -this will lead to damage of the surroundings -consume NO ONOO which also consumes & inactivate NO NB:It was known for a time that (ROS) are toxic via A) lipid peroxidation B) DNA damage leading to mutation& death ( apoptosis) C) Cross-linkage to stiff aged proteins -

27. “A thief in the night It points to Homocysteine: -As it consumes the endogenous antioxidant NO”& the antioxidant enzymes. -Not only ” a rubber “but also Hcy acts as an accelerant to a fire where the fire is ROS & redox stress -In addition to his Hcy allows other A-FLIGHT toxicities to take a greater toll & overwhelm the endogenous antioxidant mechanisms within myocardium..

28. How is the metabolic syndrome diagnosed? The metabolic syndrome is diagnosed by the presence of three or more of the following : 1- Central obesity(as measured by waist circumferance) -Men—greater than 40 inches -Women—greater than 35 inches 2-FB Triglyc. is more than 150 mg/dl 3-Blood HDL: -Men-less than 40 mg/dl -Women –less than 50mg/dl

29. 4-Blood pressure is equal to or greater than 130/85 mmHg 5-fasting blood glucose is equal to or greater than 110 mg/dl This diagnostic criteria are according to the Adult Treatment Panel- III (ATP) NB: ATP-III did not find evidence to recommend routine assessment of insulin resistance ( e.g. increased fasting insulin level) ,pro-thrombotic states & pro-inflammatory state

30. MS & Cardiomyopathy: Mechanisms: 1- Basement membrane thickening 2- Fibrosis (perivascular & interstitial) 3- PAS+hyaline staining of interstitium 4- Decreased Capillary density & capillary microangiopathy. 5- Endothelial cell proliferation 6- Myocardial-myocyte hypertrophy(Myocytolysis) 7- Accelerated atherosclerosis(atheroscleropathy) 8- Microangiopathy.

31. The trigger trios in MS includes: 1-the multiple metabolic A-FLIGHT toxicities 2-elevated tension of redox stress 3-Nitric oxide inhibition 4- Vascular paradox: Accelerated Angiogenesis( capillary vessel formation) & impaired arteriogenesis( collateral vessels formation) 5-Elevated plasminogen activator inhibitor-1(PA1-1) so , there is not only impaired fibrinolysis but also impaired remodeling & collateralization.

32. Atherosclerosis & MS: Atherosclerosis is accelerated in MS along several mechanisms: 1-Endothelial dysfunction with decreaese in NO 2-Metabolic A-FLIGHT toxicities 3-ROS with its bad effects 4-Homocysteine ( a theif in the night. 5-The eNOS gene, enzyme & eNOS reaction: -defect in the eNOS gene is associated with insulin resistance , hypertension & dyslipidemia. -The Glu-Asp gene polymorphism:

33. It is associated with increased incidence hypertension & spastic angina *Higher frequency of abnormal angiographic findings *Significant decrease in basal NO production * Not only this , but also this gene could iteract with other gene polymorphism and special environmental conditions as(smoking , obesity, & the A-FLIGHT toxicities of MS)

34. MS & Remodeling: It is defined as any change in an existence or native structure. - The trigger may be tear-down or degrade the existence -The matrix metalloproeinases(MMPs) are the degrading enzymes responsible for degradation of the existence structures - Normally these enzymes are present in an inactive latent zymogen ( proMMPs)

35. Types of Remodeling: A) Passive remodeling : occurs at the local site of ischemia & is related to myocyte necrosis & is also termed surragate fibrosis. B) Active remodeling:occurs at a site remote of injury or ischemia in non-infarcted area & is not associated with myocyte nerosis& also termed interstitial fibrosis

36. MMPs are activated in MS by several factors : e.g. ROS & plasminAdvanced glycation end products(AGE) - once MMPs are activated degradation of collagen starts first , followed by elastin & then stiffer matrix occurs with myocardial remodeling (decreasing vent. compliance , relaxation & filling).

37. MS & Diastolic Dysfunction(Dd): - Itmay be observed in about of 40 % of cases free of CAD & other factors cause Dd - The global systolic function is usually normal. - Other associated factors of MS increases the incidence of Dd in this syndrome.

38. * Mechanisms of Dd in MS: 1-Marked increased interstitial & perivascular fibrosis of ECM. 2-The presence of a concederable amount of Periodic Acid Schiff positive material( in the interstitium, arterial wall & basement membrane.) 3-Myocardial remodeling. 4-Redox stress & injury-response to injury 5-Myocyte hypertrophy & excessive collagen deposition with fibrosis.

39. 6-Activation of Renin-Angiotensin-Aldosteron system. *All these changes will lead to decrease in compliance & impaired relaxation as a result of gradual disruption of the myofibrillar architecture,whereby the ventricle loses its ability to return to its normal resting state during diastole resulting impaired filling.

40. Treatment of metabolic syndrome: (I) Insulin resistance: -There is no definite drug treatment for this. - But the safest & most effective way is to reduce insulin resistance is weight loss & increased physical activity. - Carefully choose antihypertesive drugs because different agents have different effects on insulin resistance.

41. (II) Aggressive treatment of each individual metabolic disorder associated with MS: =Dyslipidemia =Hypertension = Clotting disorder =Hyperglycemia or DM These individual factors should be agressively treated according to the standard guidelnes.

42. The RAAS acronym : for prevention & treatment: R= Reductase Inhibitor (HMG-CoA) A=ACEI—prils ,, ARBS-sartans Adrenergic (blockade) of prorenin A= Aggressive control of diabetes Aggressive control of hypertension Aggressive control of homocysteine S= Statins

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

44. 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.

45. (IV) lowering the levels of (PAI-I): -Allow the myocardiumto be able to undergo remodling , collateralization arteriogenesis with collateral vessels formation - Contribute in awakening of hibernating myocardium & improve myocardial function. This can be achieved by MMP-Inhibitor & Antioxidant

46. (V) Ineresting point: The commonally used antibiotic (Tetracycline) has a unique action on MMPs independent of their antibiotic action. It inhibits MMPs activity. So this antibiotic may be introduced to ameliorate myocardial nitric oxide dysfunction.

47. (V) Treatment paradigm for Endothelial dysfunction: 1-Prevent the competitive inhibition by ADMA(Asymmetric Dimethylarginine 2-prevent hs-CRP from decreasing eNOS & prevent glycation of eNOS enzyme 3-Add folic acid to lower Homocysteine & ADMA levels as well as restoring BH2 & BH3.

48. We are awaiting the availability of new MMP-inhibitors ,& new antioxidantsmolecules such as : - SOD & catalase mimetics - New probucole –like (phenolic analog)AGI-1067

49. Recently the use of : - Thiazolodinedions - Statins - ACE-inhibitors - ATI-blokers Is a strongly suggested,because they are effective “causal antioxidants”

50. The Empower of RAAS at an earliar stage in the treatment of the paradigm people may be able to live a longer life with less morbidity , mortality & live todie another day…….