It Takes Heart: What Makes the Heart Powerful

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It Takes Heart What Makes the Heart Powerful?

• Kerry S. McDonald and Todd J. Herron

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Overview

• Main Idea
• Background information
• Cardiac Cycle
• Calcium regulation of force
• Calcium regulation of myocyte-loaded shortening
  rates
• Covalent modulation of myofibrillar proteins
• Myosin heavy chain
• Summary

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Main Idea

• The pumping action of the heart varies
  considerably on a beat-to-beat basis and is
  ultimately determined by the extent of
  ventricular myocyte shortening during systole

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Background information

• The hearts job is to pump blood for the
  transport of gases, nutrients, and water to cells
  throughout the body.
• During strenuous exercise such as running,
  cardiac output increases from 5 l/min to upwards
  of 35 l/min
• 3 fold increase in heart rate
• 2 fold increase in stroke volume
• What causes this drastic change in cardiac output?

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Cardiac Cycle

• Phase 1
• Ventricular filling
• Pressure in the atria exceeds pressure in the
  ventricles and blood enters the ventricles
  through the atrioventricular (AV) valves.
• Myoplasmic calcium levels are low and
  force-generating interactions are at a minimal.

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Cardiac Cycle continued

• Phase 2
• Isovolumic contraction
• Electrical excitation of the ventricles
• Myoplasmic calcium increases initiating
  force-generating transitions between actin and
  myosin
• Raise in ventricular pressure causes the AV
  valves to close
• Pressures in pulmonary artery and aorta are
  greater than ventricular pressures, so both
  semilunar valves are closed
• Pressure rises with no change in volume

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Cardiac Cycle continued

• Phase 3
• Ventricular contraction
• Pressure in the ventricles exceeds pressures in
  the pulmonary artery and aorta, semilunar valves
  open
• Blood is ejected as individual myocytes perform
  work by shortening against a load

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Cardiac Cycle continued

• Phase 4
• Isovolumic relaxation
• Pressures in the pulmonary artery and aorta
  exceeds pressure in the respective ventricles
• Semilunar valves close
• Cardiac cycle is complete

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Calcium regulation of force

• 3 factors that regulate force production in
  cardiac myocytes
• Calcium levels (changes on a beat-to-beat basis)
• Rises from diastolic level of 10-7 M to systolic
  levels ranging from 10-6 to 10-5 M
• Thin filament regulatory proteins (3 phases)
• Absence of calcium blocked state
• When calcium binds to troponin closed state
• Cross-bridge attachment to actin open state
• Myosin cross bridges

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Calcium regulation of force cont.

• Calcium levels change in response to
• Intrinsic signals such as stretch
• Extrinsic signals such as sympathetic neural
  stimulation of a- and ß-adrenergic receptor
  systems
• Autocrine/paracrine signals
• Angiotensin II
• Endothelin
• Nitric oxide

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Calcium regulation of force cont.

• Changes in myoplasmic calcium levels may affect
  stroke volume by modulating several aspects of
  the cardiac cycle.
• Increased calcium accelerates the rate of
  pressure development in intact hearts
• Calcium regulates the rate of force-generating
  transitions between myosin and actin.
• Faster rates of force development due to greater
  myoplasmic calcium tend to

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Calcium regulation of myocyte-loaded shortening
rates

• Greater myoplasmic calcium also augments
  power-generating capacity of myocytes by
  increasing shortening rates during loaded
  contractions
• Velocity of very lightly loaded shortening
  progressively increased as a function of
  extracellular calcium
• Peak absolute power output increased more than 5
  fold as calcium activation levels increased from
  30-100

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Calcium regulation of myocyte-loaded shortening
rates cont.

• As calcium increases, the fraction of thin
  filaments in the open state increases in response
  to cooperative activation by strongly binding
  myosin cross bridges
• Greater number of cycling cross bridges are able
  to bear a given load, so each cross bridge bears
  less force and can cycle faster in accordance
  with its force-velocity characteristics
• Thus calcium may vary loaded shortening by
  modulating the number of cycling cross bridges
  working against a load.

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Covalent modulation of myofibrillar proteins

• ß-adrenergic stimulation cAMP dependent protein
  kinase (PKA) is activated and phosphorylates 2
  myofibrillar proteins
• Myosin binding protein C (MyBP-C) on the thick
  filament
• PKA-induced phosphorylation of MyBP-C has an
  inotropic response which has been interpreted as
  an extension of myosin cross bridges toward the
  thin filaments.
• This increases the effective myosin concentration
  thus increasing force production.
• Troponin I on the thin filament
• phosphorylation of these sites is known to reduce
  the calcium affinity of troponin C and accelerate
  relaxation.

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Myosin Heavy Chain

• Myosin is a hexamer consisting of
• Two myosin heavy chains (MHC)
• Four myosin light chains (MLC)
• There are two cardiac MHC isoforms
• a-MHC
• ß-MHC

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Myosin Heavy Chain continued

• Failing human hearts appear to express ßMHC
  exclusively
• Myocardial preparations expressing aMHC exhibit
  2 fold faster rates of force development the
  ßMHC preparations
• Loaded shortening velocities are significantly
  faster at all loads and peak power output is 3
  fold faster in aMHC when compared to ß-MHC

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Summary

• Any factor that increases cardiac myocyte work or
  power will increase stroke volume and ultimately
  cardiac output.
• Greater myocyte work may occur by simply
  extending the fraction of time during systole
  used for ejection.
• Faster myofibrillar force-development rates which
  tend to shorten phase 2 and provide more
  fractional time for ejection are
• Increased calcium
• PKA induced phosphorylation of myofibrillar
  proteins
• Expression of a-MHC

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Summary continued

• Greater force during ejection would speed myocyte
  shortening and increase power output since and
  given afterload would become less of a relative
  load.
• Any factor that increases force during phase 3
  and/or directly speeds loaded cross bridge
  cycling rates would increase myocardial power
  during ejection and yield greater stroke volume.

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THE END---------------QUESTIONS??