CHF What The Big Picture

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CHF What The Big Picture

  1. 1. Case conference “Heart Failure” From clinical to Basic Research 96/4/6 R 林軒名 / VS 陳業鵬
  2. 2. Pathophysiological Mechanisms Important in the Syndrome of Heart Failure N Engl J Med 2003;348:2007-18
  3. 3. N Engl J Med 2003;348:2007-18
  4. 4. N Engl J Med 2003;348:2007-18
  5. 5. ACC/AHA 2005 Guideline
  6. 6. N Engl J Med 2003;348:2007-18
  7. 7. Heart failure imbalance of energy and load
  8. 8. Ischemia Infarction Myopathy Hypertension Vulvular disease Myopathy Failing Heart Neurohormonal activation: Renin-Angioensin system, Adrenergic system, cytokine, etc. Peripheral alteration kidney, lung, muscel… Peripheral vascular resistence Journal of physiology 2003:055 Energy matabolism in heart failure Energy Loading
  9. 9. Medical Progress The Failing heart : An engine out of fuel N Engl J Med 2003;348:2007-18
  10. 10. <ul><li>30 to 40% of patients die from heart failure within 1 year after receiving the diagnos </li></ul><ul><li>Treatment of chronic heart failure with angiotensin-converting–enzyme (ACE) inhibitors, aldosterone antagonists, beta-receptor blockers, and resynchronization therapy. </li></ul><ul><li>The modulation of cardiac metabolism has promise as a new approach to the treatment of heart failure. </li></ul>
  11. 11. Cardiac energy metabolism <ul><li>Fuel form food: substrate utilization </li></ul><ul><ul><li>Glucose or free fatty acid breakdown </li></ul></ul><ul><ul><li>Beta-oxidation and glycolysis, Kerb’s cycle. </li></ul></ul><ul><ul><li>Mainly energy is from </li></ul></ul><ul><li>Energy production: </li></ul><ul><ul><li>Oxidative phosphorylation. </li></ul></ul><ul><ul><li>Mitochondria respiratory chain </li></ul></ul><ul><li>Transport of energy and consumption by the engine: ATP transfer and utilization. </li></ul>
  12. 13. Assesment of cardiac energy system <ul><li>Phosphorus-31 magnetic resonace </li></ul><ul><li>In vivo turnover rate of glucose and free fatty acid </li></ul><ul><li>Rate of oxidative phosphorylation and ATP transfer. </li></ul>
  13. 14. Phosphorus-31 magnetic resonace
  14. 15. Derangement of “Substrate Utilization” <ul><li>Free fatty acid: </li></ul><ul><ul><li>unchange or sligh ▲ uptake in early HF, </li></ul></ul><ul><ul><li>▼ uptake in advanced HF. </li></ul></ul><ul><li>Glucose </li></ul><ul><ul><li>▲ uptake in early HF </li></ul></ul><ul><ul><li>▼ uptake in advanced HF: insulin resistance develops in the myocardium </li></ul></ul><ul><li>In late HF, substantial increases in the concentrations of plasma free fatty acids, glucose, and insulin that are common. </li></ul>
  15. 17. Derangement of “Oxidative phosphorylation” <ul><li>Cardiac mitochondria have structural abnormalitie and are probably increased in number. </li></ul><ul><li>The activity of electron transport–chain complexes and ATP synthase capacity are reduced </li></ul><ul><li>The regulation of oxidative phosphorylation by the phosphate acceptors ADP, AMP, and creatine is impaired </li></ul><ul><li>The levels of uncoupling proteins may be increased. </li></ul><ul><li>Result in a substantial reduction of oxygen consumption and energy production in the failing myocardium. </li></ul>
  16. 18. Change in ATP transfer and utilization <ul><li>ATP transfer ▽ </li></ul><ul><li>Cr  pCr ▽ </li></ul><ul><li>ADP  ATP ▽ </li></ul><ul><li>Free ADP △ </li></ul><ul><li>Contractile work is not affected due to remaining ATP in early HF. </li></ul>
  17. 19. Derangement of “high-energy phosphate metabolism” <ul><li>phosphocreatine and total creatine levels decrease </li></ul><ul><li>Down-regulation of the creatine transporter function contributes to the reduced total creatine , and thus phosphocreatine levels. </li></ul><ul><li>The losses of high-energy phosphates and creatine kinase activity cause a severe decline in ATP transfer. </li></ul><ul><li>Reduction in energy delivery to the myofibrils by up to 71%. </li></ul><ul><li>Loss of inotropic reserve.  dyspnea on exertion. </li></ul>
  18. 20. Derangement of “high-energy phosphate metabolism” <ul><li>The ratio of phosphocreatine to ATP : powerful index of the energetic state of the heart </li></ul><ul><li>The total creatine level falls, and this reduction further decreases the phosphocreatine:ATP ratio. </li></ul><ul><li>pCr:ATP ratio correlate with NYHA fc and with indexes of systolic and diastolic function. </li></ul>
  19. 21. Changes in Cardiac energy system in HF
  20. 22. Energy production ↓ O2 and nutrient ↓ Mitochondria ↓ Mi-CK Energy transfer ↓ Cytosolic CK ↓ AK ↓ Creatine Energy utilization ↓ ATPase ↓ Bound CK ↓ Organella interaction ↓ ATPase synthesis ↓ PCr synthesis ↓ Phosphate: potential ↓ pCr/ATP ratio ↓ slowing of pCr shuffle ↓ calcium uptake ↓contractile kinetics ↓ Ion pump Journal of physiology 2003:055 Energy matabolism in heart failure
  21. 23. Molecular Regulators of Energy Metabolism <ul><li>Proliferator–activated receptor (PPAR) : </li></ul><ul><ul><li>PARα </li></ul></ul><ul><ul><li>PPARβ </li></ul></ul><ul><ul><li>PPARγ( PGC-1 ) </li></ul></ul><ul><li>Also see Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-/PGC-1 Gene Regulatory Pathway Circulation . 2007;115:909-917. </li></ul>
  22. 24. PPARα <ul><li>PPARα controls the expression of enzymes directly involved in fatty acid oxidation </li></ul><ul><li>In cardiac Hypertrophy, the expression of PPARα is decreased in proportion to the depression of fatty acid utilization. </li></ul><ul><li>The down-regulation of PPARα is thought to be the main mechanism underlying the switch in substrate utilization from fatty acids to glucose. This switch is typical of the hypertrophied heart. </li></ul>
  23. 25. PPARγ <ul><li>PPARγ coactivator-1 (also known as PCG-1α ), is a master regulator of metabolic function in mitochondria. </li></ul><ul><li>Activates multiple genes : </li></ul><ul><ul><li>PPARα and PPARβ and nuclear respiratory factors 1,2 </li></ul></ul><ul><ul><li>For fatty acid uptake and oxidation and for oxidative phosphorylation. </li></ul></ul><ul><li>Inhibition of PCG-1α probably as a direct consequence of high plasma catecholamine levels, leads to down-regulation of mitochondrial gene expression. </li></ul>
  24. 26. Mouse Gene-Knockout Models and Human Inborn Errors of Metabolism and Their Cardiac Phenotypes.
  25. 27. Mouse Gene-Knockout Models and Human Inborn Errors of Metabolism and Their Cardiac Phenotypes.
  26. 28. Modulation of Substrate Utilization <ul><li>Hint: </li></ul><ul><ul><li>intracoronary infusion of pyruvate </li></ul></ul><ul><ul><li>glucagon-like peptide 1 </li></ul></ul><ul><ul><li>transgenic overexpression of glucose transporter 1 </li></ul></ul><ul><li>Partial inhibition of fatty acid oxidation: trimetazidine, perhexiline </li></ul><ul><li>Carnitine palmitoyl transferase 1 inhibitor: etoxomir </li></ul>
  27. 29. Modulation of Oxidative Phosphorylation <ul><li>Direct stimulation of oxidative phosphorylation is not available </li></ul><ul><li>Possible way : increasing PCG-1α activity as a means of up-regulating oxidative phosphorylation enzymes </li></ul>
  28. 30. Manipulation of High-Energy Phosphate Metabolites <ul><li>Creatine and phosphocreatine levels can be augmented by increasing the creatine transporter function ( not effective) </li></ul><ul><li>Improve the myofibrillar efficiency of ATP utilization with new calcium-sensitizing or myosin activator compounds. </li></ul>
  29. 31. What is the big picture ? <ul><li>Truth of cardiac energy metabolism? </li></ul><ul><li>Metabolic therapy of heart failure? </li></ul><ul><li>Energy metabolism of other organ? </li></ul>
  30. 32. N Engl J Med 2003;348:2007-18
  31. 33. ACC/AHA 2005 Guideline

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