MECHANICAL PROPERTIES OF THE HEART

Sandor Gyorke, Ph.D.

Office: DHLRI 507

Telephone: (614) 292-3969

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.

Learning Resources

Pathophysiology of heart disease. Fifth Edition, Ed. L.S. Lilly, Lippincott Williams & Wilkins, Baltimore, MD, 2011 (pp. 23-27; 28-43; 217-227)

D.E. Mohrman & L.J. Heller. Cardiovascular Physiology, 8th edition, McGraw-Hill, New York 2014.

Lecture Topics

• Cardiac excitation-contraction coupling.

• Modulation of myocyte calcium handling by parasympathetic and sympathetic influences.

• Force-length relationships.

• Myocardial oxygen consumption.

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.

Na+

T-tubule

Sarcolemma

Na+

Troponin-C

Ca2+

ATPCa2+

Ca2+

Na+ channel

Na+-Ca2+ exchange

Ca2+ channel

Ryanodine receptor

Sarcoplasmicreticulum

Ca2+

Excitation-Contraction Coupling in Cardiac Muscle

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

10 10-7 -5

[Ca2+]i (molar)

Re

lativ

e fo

rce

(%)

100%

Diastole

peak ofnormalcontraction

peak ofenhancedcontraction • 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.

Relation Between Tension and Cytosolic Calcium Concentration in Cardiac Muscle

Pre

ssur

e (m

m H

g)

0

100

200

Diastolic volume (ml)0 200100

Intraventriculardiastolic pressure

Intraventricularsystolic pressure

60 120 180Length (% resting)

100

50

0For

ce (

100%

max

imum

) peak

resting

Peak and resting force produced by a stimulated and unstimulated, respectively, cardiac muscle strip.

The intraventricular systolic pressure is similar in shape to the total force development measured in a muscle strip.

Similarities Between Length-Tension and Volume-Pressure Relationships

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)

Ve

ntri

cula

r p

ress

ure

End-Diastolic volume

norepinephrine

control

acetylcholine

(digoxin)

(Ca-channel blockers,Heart failure)

Positive and Negative Inotropic Effects on the Ventricular Volume-Pressure Curve

Gsb -R

Norepinephrine

cAMP

Ca Channel

AC

ATP

CR

PKAC

Sarcoplasmicreticulum

ATP

Ca2+

Phospholamban

P

P SR CaATPase

Myosin

Molecular Mechanisms of Positive Inotropic Effects of Norepinephrine

GimAchR

cAMP

Ca ChannelAC

ATP

Ach

Molecular Mechanisms of Negative Inotropic Effects Of Achetylcholine

Na+ -Ca2+exchange

3Na+

2K+

digoxin

[Na+] raises[Ca2+]

3Na+ (-)

(-)Ca2+

(-)

Mode of Action of Digoxin in Increasing Intracellular Cystolic Calcium Concentration [Ca2+]

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.

Oxygen

Glucose

Fatty acids

Glycolysis Oxidative Phosphorylation

ATP

ADP + Pi

Amino acidsand ketones

(60%)

(35%)

(5%)

Lactic acid

Glycogen

Main Sources of ATP Production in Cardiac Muscle

Major Determinants of Myocardial Oxygen Consumption

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)

Cardiac State MVO2

(ml O2/min per 100g)

Arrested heart 2

Resting heart rate 8

Heavy exercise 70

Organ MVO2

(ml O2/min per 100g)

Brain 3

Kidney 5

Skin 0.2

Resting muscle 1

Contracting muscle 50

(MVO2)

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.

Mechanical Properties of the Heart Quiz

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Questions? sandor.gyorke@osumc.edu

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