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Mechanisms of Myocardial Contraction Dr. B. Tuana 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 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 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 ATP From Oxidative Phosphorylation • Under normal conditions (when adequate O2 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 2carbon fragments which are then oxidized to CO2 and H2O 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. Myocardial Oxygen Consumption (MV02) • Cardiocytes require large amounts of oxygen to generate ATP from Aerobic metabolism. • ~75% of MV02 is for contraction of myocytes. • ~25% of MV02 is for other cellular processes (ion transport) • Disease states increase MV02 to a point where myocytes become ischemic. (eg Coronary Artery Disease). ATP From Glycolysis • Glycolysis is essential for aerobic carbohydrate breakdown • Allows ATP to be generated under Anaerobic Conditions 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%) Carbohydrate Breakdown Fatty Acid Breakdown 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 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 Excitation-contraction in cardiomyocytes Excitation Contraction Coupling in Cardiac Muscle • Propagating action potential opens Voltage gated Ca2+ channels • The intracellular concentration of Ca2+ rises which triggers further release of Ca2+ from the sarcoplasmic reticulum (SR)-contraction • Inotropy (inotropic agents + or -) • Ca2+ ATPase in SR (Ca2+ uptake)relaxation Stimulation of contraction by adrenergic stimulation in heart cells Stimulation of Contraction by adrenergic stimulation Stimulation of Contraction by adrenergic stimulation 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) 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 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 Ca2+ 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 The Contractile Process ATP Power Stroke