Metabolic disorder during CAD

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Metabolic approach in management of CAD is now well known, so, in this topic I just gave a light on the metabolic disorder during myocardial ischemia which clarify the impotance of this approach in CAD

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Metabolic disorders during the myocardial ischemia:

Metabolic disorders during the myocardial ischemia BY Dr.Abdelsalam Sherif

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sarcomere glycogen membrane nucleus mitochondria The myocyte There is an abundance of mitochrondria in the heart (30% of cellular body)

The roles of mitochondria:

The roles of mitochondria The myocardium is typically aerobic The contractile process represents roughly 75% of the myocardium’s energy requirements The mitochondrion has two roles: ATP synthesis Maintenance of Ca ++ homeostasis

ATP synthesis:

ATP synthesis There are two pathways for ATP synthesis in the myocyte: the glucose pathway the free fatty acid pathway

ATP synthesis through the glucose pathway:

ATP synthesis through the glucose pathway glucose G-6-P pyruvate ADP ATP Krebs Cycle acetyl CoA ATP glycolysis Carbohydrate oxidation mitochondrion + O 2 pyruvate PDH lactate

ATP synthesis through the free fatty acid pathway:

ATP synthesis through the free fatty acid pathway FFA Acyl CoA Acyl CoA  oxidation ATP + O 2 ATP acetyl CoA CPT1 Krebs Cycle mitochondrion

Metabolic pathways:

GLYCOLYSIS GLUCOSE METABOLISM GLUCOSE OXIDATION FFA OXIDATION Metabolic pathways Glucose Free fatty acids Pyruvate Acyl CoA Contractile function Acetyl CoA ATP PDH Krebs cycle -OX 40 % 60 %

ATP synthesis:

ATP synthesis When the oxygen supply is normal, 2/3 of ATP is produced from the free fatty acid pathway that is the most expensive pathway in terms of O 2 consumption Metabolism 0 2 usage ATP production ATP/0 2 Comments Glucose oxidation 5.02 32 ATP 6.4 FFA oxidation 26.02 147 ATP 5.6 Anaerobic glycolysis 0 2 ATP acidosis

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions The oxidation of both fatty acids and glucose is limited by the lack of oxygen and there is a competition between the two pathways

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions Glucose Free fatty acids Pyruvate Acetyl CoA PDH Krebs cycle -OX Acyl CoA ATP Competition between the two pathways 

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions The oxidation of both fatty acids and glucose is limited by the lack of oxygen and there is a competition between the two pathways Glycolysis, which requires no oxygen, becomes more important and crucial for ATP production (20% - 40%):  glycolysis becomes further uncoupled from glucose oxidation, with the production of both lactate and H + , resulting in acidosis

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions Glucose Free fatty acids Pyruvate Acetyl CoA PDH Krebs cycle -OX Acyl CoA ATP lactate H + H + H + Ca ++ Ca ++ acidosis Ca ++ overload Uncoupling between glycolysis and glucose oxidation Glycolysis 

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions The oxidation of both fatty acids and carbohydrates is limited by the lack of oxygen and there is a competition between the two pathways Glycolysis, which requires no oxygen, becomes more important and crucial for ATP production (20% - 40%):  glycolysis becomes further uncoupled from glucose oxidation, with the production of both lactate and H + , resulting in acidosis The oxidation of free fatty acids still works (50% - 70%) but is less profitable and, moreover, worsens the uncoupling between glycolysis and glucose oxidation

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions Glucose Free fatty acids Pyruvate Acetyl CoA PDH Krebs cycle -OX Acyl CoA ATP lactate H + H + H + Ca ++ Ca ++ acidosis Ca ++ overload Uncoupling between glycolysis and glucose oxidation Glycolysis  The activity of -oxidation worsens the uncoupling between glycolysis and glucose oxidation Membrane damage

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions Glucose Free fatty acids Pyruvate Acetyl CoA PDH Krebs cycle -OX Acyl CoA ATP lactate H + H + H + Ca ++ Ca ++ acidosis Ca ++ overload Uncoupling between glycolysis and glucose oxidation Glycolysis  Membrane damage ATP partly used for the management of Ca ++ overload Contractile Dysfunction  ATP

Ischemic Conditions Summary:

Ischemic Conditions Summary Glucose Free fatty acids Pyruvate Acetyl CoA PDH Krebs cycle -OX Acyl CoA ATP lactate H + H + H + Ca ++ Ca ++ acidosis Ca ++ overload Uncoupling between glycolysis and glucose oxidation Glycolysis  Membrane damage ATP partly used for the management of Ca ++ overload Contractile dysfunction  ATP

Myocardial energy metabolism under ischemic conditions:

Myocardial energy metabolism under ischemic conditions Inhibiting FFA -oxidation and r estoring glucose oxidation, the most profitable pathway, represents a rationale approach for the management of myocardial ischemia

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Management of Stable Angina Guidelines European Society of Cardiology Management of stable angina pectoris. Recommendations of the task force of the European Society of Cardiology. Eur Heart J. 1997;18:394-413. American College of Cardiology and American Heart Association Guidelines for the management of patients with chronic stable angina. J Am Coll Cardiol. 1999;33:2092-2197 .

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To decrease the morbidity and mortality To decrease angina symptoms Two goals Management of Stable Angina Guidelines

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Management of Stable Angina Risk factors Lifestyle Medical treatment Revascularization Treatment strategy

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Risk Factors Management Hypertension Weight loss, low sodium intake, pharmacological treatment Diabetes Mellitus Diet, oral antidiabetics, insulin Estrogen Deficiency Hormone replacement therapy Smoking Smoking cessation program Overweight Mediterranean diet with vegetables, fruit, and fish Dyslipidemia Dietary modification, hypolipemic agents

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Lifestyle Physical activity Should be encouraged within the patient’s limitations, as it may increase exercise tolerance Stress control Stressful situations should be avoided; relaxation techniques can be advised; driving allowed except for public transport and heavy vehicles Sexual intercourse Nitroglycerin prior to intercourse

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Conventional Medical Treatment To decrease the morbidity and mortality Aspirin Lipid-lowering therapy Angiotensin-converting enzyme inhibitors (near future) To decrease the angina symptoms Hemodynamic treatments Metabolic therapy

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Antiplatelet agents Aspirin+++ 75-325 mg daily in the absence of contraindications SAPAT: 34% reduction in myocardial infarction and death in patients with stable angina pectoris Clopidogrel when aspirin is absolutely contraindicated no study in patients with stable angina To decrease morbidity and mortality (prevention of myocardial infarction and death)

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To decrease morbidity and mortality (prevention of MI and death) Lipid-lowering agents Statins+++ (simvastatin) Even in case of mild to moderate elevation of low-density lipoprotein cholesterol Target: low-density lipoprotein cholesterol <100 mg/dL 4S: 30% to 35% reduction in both mortality rate and major coronary events in patients with documented CAD (including stable angina)

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To decrease angina symptoms Hemodynamic treatments Symptomatic treatment of angina attack: NITROGLYCERIN : - sublingual - spray Long-term prophylactic treatment: 1860: Nitrates 1960:  -blockers 1970: Calcium antagonists 1980: Potassium channel activators

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What is the aim of the classic hemodynamic approach?  O 2 requirements Decrease in requirements via the limitation of cardiac work O 2 supplies Increase in supplies via dilation of the coronary arteries

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Hemodynamic drugs are effective BUT They are often difficult to handle: adverse effects contraindications drug interactions The hemodynamic approach is necessary but not sufficient

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The hemodynamic approach is necessary but not sufficient BUT Angina attacks still occur with the risk of: myocardial infarction arrhythmias sudden death Hemodynamic drugs are effective

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Effects of hemodynamic drugs on the prognosis of stable angina Nitrates Calcium antagonists  -blockers Failure of various studies concerning morbidity/mortality

Conclusion: Goals in the medical management of stable angina:

Conclusion: Goals in the medical management of stable angina To decrease mortality Modification of risk factors Aspirin Lipid-lowering therapy To decrease angina symptoms Hemodynamic treatments (efficient but not sufficient) Metabolic therapy 

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Why is metabolic therapy now recommended by the: European Society of Cardiology American College of Cardiology American Heart Association? Because ischemia also has metabolic consequences

LIMITATIONS OF COMBINED HEMODYNAMIC THERAPY:

In a recent meta-analysis, combined treatment of CCBs and B-blockers was shown to provide a 9% increase in efficacy..!! …Once the full hemodynamic effect has been achieved, additional benefit is unlikely to result by adding similarly acting agents. W. Klein, G. Jackson, L. Tavazzi. Coron Artery Dis.2002;13:427-436. LIMITATIONS OF COMBINED HEMODYNAMIC THERAPY

REALITY IN THE TREATMENT OF STABLE ANGINA:

REALITY IN THE TREATMENT OF STABLE ANGINA Despite almost all patients are treated, there is NO full control of angina symptoms After successful revascularization With hemodynamic combined therapy

After successful revascularization: a majority of patients remains symptomatic and treated:

After successful revascularization: a majority of patients remains symptomatic and treated Serruys et al. N Engl J Med. 2001;344:1117-1124.

THE NEED FOR IMPROVEMENT:

The Rationale for Metabolic Intervention THE NEED FOR IMPROVEMENT

NORMOXIC CONDITIONS:

GLUCOSE 1 O 2 6.3 ATP NORMOXIC CONDITIONS FATTY ACIDS 1 O 2 5.6 ATP AT LEAST 13 % MORE ENERGY PRODUCTION

ISCHEMIC CONDITIONS:

CALCIUM OVERLOAD CONTRACTILE DYSFUNCTION MEMBRANE DAMAGE ACIDOSIS ISCHEMIC CONDITIONS _

VASTAREL 20: 3-KAT Inhibitor MODE OF ACTION:

VASTAREL 20: 3-KAT Inhibitor MODE OF ACTION Reducesacidosis & Calcium overload Improved Cardiac Function Membrane Protection _ MORE PROFITABLE ENERGY REFERENCE Enhance Glucose Oxidation

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MYOCARDIAL ISCHEMIA HEMODYNAMIC DETERIORATION METABOLIC CHANGES Hemodynamic approach B-Blockers ,Ca-antagonists Nitrates, PTCA, CABG Metabolic approach VASTAREL 20 2 THERAPEUTIC TARGETS

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“The heart is an organ that needs energy from metabolism, thus, ischemic heart disease should be ideally treated by metabolic therapy” Opie – Lancet 1999

Metabolic Approach in Clinical Practice:

Metabolic Approach in Clinical Practice

VASTAREL 20: wholly additive efficacy in patients uncontrolled with a -blocker :

VASTAREL 20 : wholly additive efficacy in patients uncontrolled with a -blocker TRIMPOL II study Double-blind, randomized, placebo-controlled study in patients resistant to a monotherapy with metoprolol Eur Heart J. 2001;22:2267-2274.

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Baseline W12 Szwed H, Sadowski Z, Elikowski W, et al. Eur Heart J. 01;22:2267-2274. p<0.01 Angina attacks 3 2 0 4 5 1 NS Placebo Vastarel 20 VASTAREL 20 significantly reduces the number of angina attacks/week

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Baseline W12 360 390 420 450 480 510 NS P<0.05 Exercise duration (s) Placebo Vastarel 20 VASTAREL 20 increases exercise duration Szwed H, Sadowski Z, Elikowski W, et al. Eur Heart J. 01;22:2267-2274.

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Combination of VASTAREL 20 +  -blocker Vs Combination of L.A nitrate +  -blocker 2-month, double-blind, randomized study of Vastarel 20 mg tid vs ISDN 10 mg tid, in angina patients resistant to a monotherapy with propranolol Michaelides AP, Clin Drug Invest. 1997;13:8-14.

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Michaelides APClin Drug Invest. 1997;13:8-14. Effective symptom relief Mean weekly number of angina attacks (n) P<0.001 P<0.01 0 1 2 3 4 5 - 62% P<0.01 - 30% D0 D60 D0 D60 +ISDN +Vastarel 20 Propranolol VASTAREL 20 addition is twice more effective in reducing number of anginal attacks/week

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D0 D60 D0 D60 Exercise duration (S) P<0.001 NS P<0.001 0 400 800 +ISDN +Vastarel 20 Propranolol VASTAREL 20 prolongs exercise duration, whereas ISDN addition has no effect. Improvement in exercise test Michaelides APClin Drug Invest. 1997;13:8-14.

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Effects of VASTAREL 20 on ischemic left ventricular dysfunction in patients with coronary artery disease Prof S. Chierchia American Journal of Cardiology Sept 1998

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Placebo Vastarel 20 mg tid 15 days 15 days DET DET DET DET 15 patients Placebo Vastarel 20 mg tid Rest-stress echocardiography Am J Cardiol. 1998;82 . VASTAREL 20: Comparison with placebo

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VASTAREL 20: Effect on Regional Myocardial Function Placebo Vastarel 20 P =0.013 WMSI at rest 1,4 1,34 1,3 1,4 1,5 WMSI under dobutamine P =0.018 1,71 1,61 1,5 1,6 1,7 1,8 Am J Cardiol. 1998;82.

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P =0.003 Hg/kg/mn Dobutamine dose 22,7 28,7 20 25 30 Dobutamine time min P =0.019 15,3 17,9 10 14 18 Placebo Vastarel 20 Am J Cardiol. 1998;82. VASTAREL 20: Effect on Ischemic Threshold

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“combined hemodynamic and metabolic treatment is more effective than combined hemodynamic therapy and is well tolerated” W. Klein, G. Jackson, L. Tavazzi. Coron Artery Dis.2002;13:427-436.

Conclusion: Goals in the medical management of stable angina:

Conclusion: Goals in the medical management of stable angina To decrease mortality Modification of risk factors Aspirin Lipid-lowering therapy Betablockers (II ary prevention) ACEIs To decrease angina symptoms Hemodynamic treatments (efficient but not sufficient) Metabolic therapy

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Gibbons et al. 2002 ACC / AHA Practice Guidelines

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Gibbons et al. 2002 ACC / AHA Practice Guidelines

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Addresses the metabolic abnormality of IHD. Proven anti-anginal and anti-ischemic efficacy Totally additive effect Provides myocardial cyto-protection . NO modification of hemodynamic parameters. NO known contra- indication. NO drug-drug interaction. Simple dose to all patients . VASTAREL 20 3 tablets daily AS SOON AS MYOCARDIAL ISCHEMIA EXISTS

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Newly diagnosed angina patients Patients resistant to conventional therapy Patients not eligible for invasive intervention Treated patients suffering side-effects Patients with additional risks Elderly Diabetic LVD Optimizes cardiac metabolism Improves clinical status Has excellent tolerance AS SOON AS MYOCARDIAL ISCHEMIA EXISTS

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