1. Mechanisms of Myocardial Contraction Dr. B. Tuana

2. Heart Structure Heart Consists of 2 Independent parallel pumps The Right Side is Responsible for Pulmonary Circulation The Left Side is Responsible for Systemic Circulation

3. Cardiac Phases There are 2 Principle Phases in the Cardiac Cycle Systolic Phase (lasting ~0.3 sec) is the phase of contraction of the heart. This requires the most energy. Diastolic Phase (lasting ~0.5 sec) is a phase of relaxation and filling of the heart. During the diastolic phase, the cardiocyte`s supply of nutrients replenished

4. ATP The energy that myocytes need to contract during the systolic phase comes from ATP ATP Can be generated from either oxidative phosphorylation or glycolysis

5. ATP From Oxidative Phosphorylation Under normal conditions (when adequate O 2 is present), the oxidative phosphorylation pathway predominates. Occurs entirely within the mitochondria (abundant in heart)-differs from skeletal muscle (fatigue?) Both fats and CHO enter the mitochondria as 2- carbon fragments which are then oxidized to CO2 and H2O

6. ATP From Oxidative Phosphorylation Free Fatty Acids bound to albumin in plasma are taken into myocyte Plasma TG's are hydrolyzed by lipase to FFA's. Lipase activity is regulated by hormones.

7. Myocardial Oxygen Consumption (MV0 2 ) Cardiocytes require large amounts of oxygen to generate ATP from Aerobic metabolism. ~75% of MV0 2 is for contraction of myocytes. ~25% of MV0 2 is for other cellular processes (ion transport) Disease states increase MV0 2 to a point where myocytes become ischemic. (eg Coronary Artery Disease).

8. ATP From Glycolysis Glycolysis is essential for aerobic carbohydrate breakdown Allows ATP to be generated under Anaerobic Conditions

9. Substrates Used for ATP Production ~% oxygen utilized. ~Normal Conditions: (100%) O2, free fatty acids (70%), glucose (15%) and lactate (15%). ~Hypoxia: mainly glucose (from glycogen, anaerobic) ~Hyperlipidemia: triglycerides (~50%), FFA (~30%) ~CHO loading: glucose (~70%), lactate (~30%) ~Diabetics, Starvation: ketones (~70%), FFA (30%) ~Exercise: lactate (~60%), glucose (~15%), FFA (20%)

10. Carbohydrate Breakdown

11. Fatty Acid Breakdown

12. ATP PRODUCTION IS TIGHTLY COUPLED TO MECHANICAL ACTIVITY: Hormones (epi, norepi) increase mechanical work Hormones also increase ATP production via...increased glycolysis, glycogen mobilization and FFA production ADP concentration can control rate of ATP synthesis by oxidative phosphorylation Increased cardiac activity, increases ATP breakdown to ADP...which stimulates oxidative phosphorylation pathways to make more ATP. A Decrease cardiac activity leads to excess ATP...which inhibits further ATP synthesis

13. Excitation Contraction Coupling in Cardiac Muscle Action potential propagated along muscle cell membrane (sarcolemma) Sarcolemma possesses deep invaginations referred to as T-tubules Calcium induced calcium release Intercalated discs-gap junctions, force transmission

14. Excitation-contraction in cardiomyocytes

15. Excitation Contraction Coupling in Cardiac Muscle Propagating action potential opens Voltage gated Ca 2+ channels The intracellular concentration of Ca 2+ rises which triggers further release of Ca 2+ from the sarcoplasmic reticulum (SR)-contraction Inotropy (inotropic agents + or -) Ca 2+ ATPase in SR (Ca 2+ uptake)- relaxation

16. Stimulation of contraction by adrenergic stimulation in heart cells

17. Stimulation of Contraction by adrenergic stimulation

19. Excitation Contraction Coupling in Cardiac Muscle Involves Interaction between actin and Myosin Thick filaments (Myosin) utilize ATP to slide over thin (actin) filaments Involves the activity of several regulatory proteins (ie troponin, tropomyosin)

20. Excitation Contraction Coupling in Cardiac Muscle – Actin and Myosin Principle proteins of muscle contraction Actin has a binding site for myosin Myosin has a ATP hydrolysing domain, and an actin binding site The regulatory proteins troponin and tropomyosin are associated with actin

21. Excitation Contraction Coupling in Cardiac Muscle – Troponin and Tropomyosin Tropomyosin is a long protein associated with actin that covers the actin binding site in the resting state Troponin lies at regular intervals along the actin filament. Troponin mediates the activity of tropomyosin Troponin is sensitive to levels of Ca 2+

23. Excitation Contraction Coupling in Cardiac Muscle As the intracellular concentration of Ca+2 rises troponin is activated. The activated troponin triggers tropomyosin to undergo a conformational change. This conformational change exposes the myosin binding site on actin

24. The Contractile Process ATP

27. Power Stroke