Objectives:

1.Describe the major properties of cardiac

muscle.
2.Discuss Frank-Starling law.
3.Describe how an action potential causes
contraction (cardiac excitation-contraction
coupling).
Contractility is the ability of the cardiac muscle
to contract.
The effect of various factors on contractility is
called inotropism; a positive (+ve) inotropic
effect means an increase in myocardial
contractility, whereas a negative (-ve)
inotropic effect means a decrease in myocardial
contractility.
  Excitation-Contraction coupling in the heart muscle:
As in skeletal muscles, the depolarization wave reaching via the T tubules
causes the opening of Ca+2 channels in the sarcoplasmic reticulum
adjacent to the T-tubules. The released Ca+2 from the cisternae of the
sarcoplasmic reticulum (activator Ca+2; aCa+2) binds to troponin C, leading
to cross bridge formation between actin and myosin, which results in
contraction.
In cardiac muscle, the amount of this activator Ca+2 is often insufficient to
initiate contraction, but it can be increased indirectly by the following
mechanism:
The depolarization wave in the T-tubules opens the long-lasting Ca+2
chann¬els in the T-tubule membrane, and sarcolemma, Ca+2 diffuses from
the ECF through these channels into the cardiac muscle fibre cell causing a
small increase in the cytosolic (fluid of the cytoplasm) calcium concentration
in the region of the T-tubules and adjacent sarcoplasmic reticulum. This
Ca+2 is called depolarizing Ca+2, and although its amount is normally very
small, yet it is important because it acts as a signal for the release of large
amount of activator Ca+2 from the cisternae of sarcoplasmic reticulum, it is
mainly this cytosolic Ca+2 that causes the contraction, i.e. once Ca+2 is in
the cytoplasm, it binds to troponin and stimulates contraction. As a result,
myocardial cells contract when they are depolarized. The force of
contraction is directly proportional to the amount of cytosolic Ca+2.
Contraction ends when the cytosolic Ca+2
concentration restored to its original level. In
other words, relaxation of the cardiac muscle
occurs as a result of release of the actin-myosin
combination, this is achieved by decreasing the
intracellular Ca+2 to its pre- contraction level,
which occurs by:
1- Active re uptake of Ca+2 into the
sarcoplasmic reticulum by Ca+2 pump (primary
active transport of Ca+2).
2- Active pumping of excess Ca+2 outside the
fibres by Na+- Ca+2 exchanger carrier protein
(secondary active transport ; counter transport).
The heart normally cannot be stimulated again
until after it has relaxed from its previous
contraction because myocardial cells have long
refractory periods that correspond the long
duration of their action potentials. Summation
of contractions and tetanus are thus prevented,
and the myocardium must relax at each
contraction to ensure the rhythmic pumping
action of the heart.


 Figure: (2) = slow calcium channel, dCa+2 =
depolarizing calcium, (3) = Ca+2-pump (active
transport), (4) = Na+-Ca+2 Exchanger, aCa+2 =
activator calcium.
Factors that affect cardiac contractility:

 Mechanical
 Cardiac
 Extra cardiac

Mechanical factors:

•Preload (venous return)

•Afterload
 The preload:
 The preload is the load that determines the
initial length of the resting muscle before
contraction. The level of the preload is
rep¬resented by the end-diastolic volume
(EDV) i.e., by the venous return (VR). It affects
the tension developed in the muscle. When
the venous return (EDV), increases, the
strength of ventricular contraction increases
too, leading to an increa¬se in the stroke
volume (Frank-Starling law).
 Frank-Starling's law of the heart
 This law describes the length-tension relationship in
muscles; it states that the force of contraction of the
ventricles depends on the initial length of ventricular
muscle fibers. In such a way, that the force of myocardial
contraction is directly proportional to the initial length of
the cardiac muscle fibres (i.e. to the preload (VR) or EDV).
This means that the greater the degree of stretching of the
myocardium before contraction, the greater the force of
contraction. In other words, Frank-Starling law reflects the
relationship between ventricular end-diastolic volume
(EDV) and stroke volume; when the blood returns to the
heart during the filling phase, this blood will distend the
ventricles so the ventricles will produce more powerful
contraction to pump the increased volume of the blood.
The Significance of Frank-Starling's law
The Starling's law allows autoregulation of myocardial contractility
(regulation of the contractility by changing the length of the muscle fibers),
in the following conditions:
(1) In normal hearts. Starling's law allows changes in the right ventricular
output to match changes in the venous return (VR), and maintains equal
outputs from both ventricles. For example, if the systemic VR increases,
the EDV of the right ventricle increases, leading to a forceful contraction
that increases its output to match the increased VR. At the same time, the
increased right ventricular output increases the pulmonary VR to the left
ventricle, which also increases its EDV, resulting in an increase of its output,
which balances the increased right ventricular output.
(2) In denervated hearts (e.g. transplanted hearts); autoregulation of
myocardial contractility becomes the main mechanism.
(3) In cases of rise of the arterial blood pressure: the stroke volume of the
left ventricle would decrease. However, the retained blood in the left
ventricle plus blood returning to it from the left atrium during the next
diastole increase the EDV. This leads to a forceful contraction, thus the
accumulated blood in the left ventricle will be ejected in spite of the
increased arterial blood pressure.
The Afterload:
The afterload is the load that the muscle faces
when it begins to contract. In the intact heart,
the afterload is produced by the aortic
impedance which is determined by:
•The aortic pressure (arterial systolic blood
pressure).
•The arterial wall rigidity (arteriosclerosis).
•Blood viscosity (polycythemia).
•The myocardial mass.
•The heart rate.
The myocardial mass:
A significant injury or loss of the functioning ventricular muscle
(e.g. due to ischemia or necrosis) decreases the force of myocardial
contractility. This also occurs in cases of heart failure.
The heart rate:
The force of cardiac contractility is affected by the frequency of
stimulation. An increase in the frequency of stimulation (i.e.
shortening the intervals between the stimuli) causes a proportional
increase in the force of contraction.
Accordingly, tachycardia causes a +ve inotropic effect while
bradycardia exerts a -ve inotropic action. The +ve inotropic effect
in tachycardia is due to the increase in the number of depolarization
(which increases the intracellular Ca+2 content and its availability to
the contractile proteins (troponin C)).
Extra cardiac factors:
These factors affect the cardiac inotropic state
and they include the following:

• Neural
• Physical
• Chemical
Neural factors:
Sympathetic stimulation and noradrenaline exert a
+ve inotropic eff¬ect by increasing;
•Cyclic-AMP in the cardiac muscle fibres (which
leads to activation of the Ca+2 channels and more
Ca+2 influx from the ECF).
•The heart rate.
Conversely, parasympathetic stimulation and
acetylcholine exert a -ve inotropic effect (by
opposite mechanism) but on the atrial muscle only
(since the vagi nerves don't supply the ventricles).
Physical factors:
A moderate rise of the body temperature
strengthens cardiac contractility (by increasing
the Ca+2 influx and ATP formation in the
muscle) while an excessive rise of the body
temperature (e.g. in fever) exhausts the
metabolic substrates in the cardiac muscle and
decreases its contractility. Hypothermia also
decreases cardiac contractility.
Chemical factors:
(A) Hormones:
Catecholamines (epinephrine, norepinephrine and dopamine),
glucagon and the thyroid hormones; all exert a +ve inotropic
effect.
(B) Blood gases:
Moderate hypoxia (O2 lack) and hypercapnia (CO2 excess)
increase the cardiac contractility, whereas severe hypoxia and
hyper¬capnia directly depress the cardiac muscle and
decrease its contractility.
(C) H + ion concentration (pH):
An increase of the blood [H+] i.e. drop of the blood pH
(acidosis) produces a -ve inotropic effect, whereas a
decrease of the blood [H+] i.e. rise of the blood pH (alkalosis)
produces a + ve inotropic effect
D) Inorganic ions:
•Sodium: Hypernatraemia favors Na+ influx and Ca+2 efflux by the
Na+-Ca+2 exchanger carrier, thus it has a -ve inotropic effect. On
the other
hand, hyponatraemia exerts a +ve inotropic effect by an opposite
mechanism.
•Potassium: Hyperkalaemia has a -ve inotropic effect (weakens the
myocardial contractility; flaccidity) and may stop the heart in
diastole. This is because the excess K+ in the ECF decreases the
resting membrane potential (more positive resting membrane
potential; closer to the threshold)) in the cardiac muscle fibers, so
the amplitude of the action potential is reduced leading to less
influx of the depolarizing Ca+2 and in turn less release of activator
Ca+2 from the sarcoplasmic reticulum. In addition, Hyperkalaemia
increases excitation and decreases conduction leading to ectopics
and dilated, flaccid heart. On the other hand, hypokalaemia
produces a +ve inotropic effect by an opposite mechanism.
•Calcium: Hypercalcaemia exerts a +ve inotropic effect as a result
of more cytosolic Ca+2. Whereas hypocalcaemia has a little (or no) -
ve inotropic effect, since lowering of the serum Ca+2 level causes
fatal tetany before affecting the heart. However, hypocalcaemia
causes cardiac flaccidity like Hyperkalaemia.
E) Toxins:
Several toxins (e.g. certain snake venoms and the toxin released by
the diphtheria microorganisms) produce a-ve inotropic effect
(mostly by a direct action on the contractile mechanism of the
cardiac muscle).
(F) Drugs:
•Cardiac glycosides (e.g. digitalis; Digoxin): These drugs inhibit the
Na+-K+ ATPase in the sarcolemma of the cardiac muscle fibres, so
the intracellular Na+ concentration increases. This decrease the
Na+ influx, thus Ca+2 efflux through the Na+-Ca+2 exchanger is
also decreased. Accordingly, the intra-cellular Ca+2 concentration
increases, producing a +ve inotropic effect. Digitalis also increases
the slow Ca+2 influx during the action potential.
•Xanthines (e.g., caffeine and theophylline; bronchodilator): They
exert a +ve inotropic effect.
•Ouinidine, barbiturates, procainamide (and other anesthetic drugs)
as well as Ca+2 blocker drugs all have a -ve inotropic effect by
decreasing Ca+2 influx into the cardiac muscle fibres.