1. MECHANICAL PROPERTIES OF THE HEART
Sandor Gyorke, Ph.D.
Office: DHLRI 507
Telephone: (614)

2. Learning Objectives
Compare and contrast cardiac and skeletal muscle cells in terms of mechanisms of contraction and relaxation, cross bridging, and ion transport.
Define the determinants of myocardial oxygen consumption
Relate cardiac muscle mechanics to ventricular function using LaPlace’s Law: define pressure and volume work
Describe the effects of parasympathetic and sympathetic stimulation on cardiac muscle cells.

3. Learning Resources
Pathophysiology of heart disease. Fifth Edition, Ed. L.S. Lilly, Lippincott Williams & Wilkins, Baltimore, MD, 2011 (pp ; 28-43; )
D.E. Mohrman & L.J. Heller. Cardiovascular Physiology, 8th edition, McGraw-Hill, New York

4. Lecture Topics Cardiac excitation-contraction coupling.
Modulation of myocyte calcium handling by parasympathetic and sympathetic influences.
Force-length relationships.
Myocardial oxygen consumption.

5. Introduction
Heart muscle has many properties in common with skeletal muscle. Both muscles are striated, and have similar contractile elements including sarcomeres that contain thick and thin filaments. The basic principles of muscle structure and function are covered in the Bone and Muscle block.
At the same time many important functional and morphological differences exist between cardiac and skeletal muscles, including differences in Ca2+ handling, connectivity, and energetics.
This eModule will focus on principles underlying the clinically relevant concepts of myocardial contractility and pressure-volume relationships as well as oxygen consumption.

6. Excitation-Contraction Coupling in Cardiac Muscle
Na+-Ca2+ exchange
Na+
Na+ channel
Sarcolemma
Ca2+
Na+
T-tubule
Ca2+
Ca2+
ATP
Troponin-C
Ca2+
Ca2+ channel
Sarcoplasmic
reticulum
Ryanodine
receptor

7. Sequence of Events in Cardiac Excitation-Contraction Coupling
Action potential (AP) propagates over the surface of the myocyte and into the myocyte along the T-tubule.
The AP in the T-tubule opens voltage dependent Ca2+ channels allowing the entry of Ca2+ from the extracellular fluid into the cell.
This rise in cytosolic [Ca2+] causes the release of a larger pool of Ca2+ stored in the sarcoplasmic reticulum (SR) through Ca2+ release channels called ryanodine receptors. This mechanism is known as Ca2+-induced Ca2+ release.
The released Ca2+ binds to troponin, which disinhibits actin and myosin interactions and results in force production.
Contraction ends when released [Ca2+] is pumped back to the SR by Ca2+ ATPase

8. Relation Between Tension and Cytosolic Calcium Concentration in Cardiac Muscle
peak of
100%
The rise in [Ca2+] in normal cardiomyocytes during a beat is only large enough to produce a fraction of the intrinsically available tension.
The strength of contraction can be increased by increments of [Ca2+] attained via inotropic interventions.
enhanced
contraction
peak of
normal
Relative force (%)
contraction
Diastole -7 -5 10 10
[Ca2+]i (molar)

9. Similarities Between Length-Tension and Volume-Pressure Relationships
200 60
120
180
Length (% resting)
100 50
Force (100% maximum)
peak
resting
Intraventricular
systolic pressure
Pressure (mm Hg)
100
Intraventricular
diastolic pressure
100
200
Diastolic volume (ml)
The intraventricular systolic pressure is similar in shape to the total force development measured in a muscle strip.
Peak and resting force produced by a stimulated and unstimulated, respectively, cardiac muscle strip.

10. Contractility Positive and Negative Inotropes
CONTRACTILITY (or INOTROPIC STATE) is defined as the strength of contraction at a constant initial muscle (sarcomere) length
Inotropic interventions that increase contractility are called
POSITIVE INOTROPES (noradrenaline, digoxin)
Inotropic interventions that decrease contractility are called
NEGATIVE INOTROPES (acetylcholine, Ca2+ channel blockers)

11. Positive and Negative Inotropic Effects on the Ventricular Volume-Pressure Curve
norepinephrine
(digoxin)
control
Ventricular pressure
(Ca-channel
blockers,
Heart failure)
acetylcholine
End-Diastolic volume

12. Molecular Mechanisms of Positive Inotropic Effects of NorepinephrineCa
Channel
Norepinephrine AC b -R Gs P
ATP
Phospholamban
cAMP C
PKA P
SR CaATPase R C
Myosin
ATP
Ca2+
Sarcoplasmic
reticulum

13. Molecular Mechanisms of Negative Inotropic Effects Of AchetylcholineCa
Channel
Ach AC
mAchR Gi
ATP
cAMP

14. Mode of Action of Digoxin in Increasing Intracellular
Cystolic Calcium Concentration [Ca2+]
Na+ -Ca2+
digoxin
exchange
(-)
3Na+
3Na+
(-)
2K+
Ca2+
(-)
[Ca2+]
[Na+] raises

15. Metabolism
High fatigue resistance due to a large number of mitochondria (oxidative phosphorylation) and a good blood supply, which provides nutrients and oxygen.
Most of energy comes from fatty acids and carbohydrates.
Only ~1% of energy is derived from anaerobic metabolism (through lactate production) at basal metabolic rates.
In ischemic conditions not enough ATP can be produced to sustain ventricular contractions.

16. Main Sources of ATP Production in Cardiac Muscle
ADP + Pi
Amino acids
and ketones
Lactic acid
ATP
Glycogen
(5%)
Glucose
Oxidative Phosphorylation
Glycolysis
Fatty acids
(35%)
(60%)
Oxygen

17. Major Determinants of Myocardial Oxygen Consumption
(MVO2)
Organ
MVO2 (ml O2/min per 100g)
Brain 3
Kidney 5
Skin
0.2
Resting muscle 1
Contracting muscle 50
Cardiac State
MVO2 (ml O2/min per 100g)
Arrested heart 2
Resting heart rate 8
Heavy exercise 70
Myocardial O2 consumption
Heart rate
Contractility
Wall tension
(T = Pr/2h, T-wall tension, P intraventricular pressure, r-radius, and h-wall thickness)
Coronary blood flow.
Vascular tone (adenosine and nitric oxide, etc)
Mechanical factors
(compression)

18. Summary
The Ca2+ which enters the cardiomyocyte during the action potential triggers Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR), causing contraction by sliding of thick and thin filaments.
The force of contraction is modulated by increasing or decreasing the amount of Ca2+ released from the SR and bound to troponin binding sites. Sympathetic stimulation, results in phosphorylation of Ca2+ channels and of the SR Ca2+ pump regulatory protein phospholamban, thereby increasing SR Ca2+ release and contractility (positive inotropy). Stimulation of the parasympathetic system reduces contractility by reducing phosphorylation of the same proteins (negative inotropy).
An increase in myocardial fiber length (as occurs with augmented ventricular filling) increases contractile strength due to a more optimal overlap between the thin and thick filaments (Frank-Starling relationship).
The heart relies almost entirely on aerobic metabolism for energy production. Carbohydrates and fatty acids used as energy sources, the energy of which is converted into ATP by oxidative metabolism in the mitochondria.
The Ca2+ which enters the cardiomyocyte during the action potential triggers Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR), causing contraction by sliding of thick and thin filaments.
The force of contraction is modulated by increasing or decreasing the amount of Ca2+ released from the SR and bound to troponin binding sites. Sympathetic stimulation, results in phosphorylation of Ca2+ channels and of the SR Ca2+ pump regulatory protein phospholamban, thereby increasing SR Ca2+ release and contractility (positive inotropy). Stimulation of the parasympathetic system reduces contractility by reducing phosphorylation of the same proteins (negative inotropy).
An increase in myocardial fiber length (as occurs with augmented ventricular filling) increases contractile strength due to a more optimal overlap between the thin and thick filaments (Frank-Starling relationship).
The heart relies almost entirely on aerobic metabolism for energy production. Carbohydrates and fatty acids used as energy sources, the energy of which is converted into ATP by oxidative metabolism in the mitochondria.

19. Mechanical Properties of the Heart Quiz

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