Definitions

a. Chronotropic effects
• produce changes in heart rate.
b. Dromotropic effects
• produce changes in conduction
velocity primarily in the AV node.
c. Inotropic effects:
• is the intrinsic ability of cardiac muscle to develop force (contraction) at a given muscle length.
d. Bathmotropic effect:
• The response of muscle to stimulation (excitability)
e. Lusitropic effect:
• is myocardial relaxation.
All of the following definitions are accompanied by Positive (increase) and Negative (decrease)
Effects of autonomic nervous system stimulation:
Activation of sympathetic efferent nerves to the heart increases (positive chronotropy, inotropy, lusitropy and
dromotrope).Parasympathetic effects are opposite.
Parasympathetic effects on inotropy are weak in the ventricle, but relatively strong in the atria.
When the body activates the sympathetic system, it generally down regulates parasympathetic activity, and
vice versa, so that the activities of these two branches of the autonomic nervous system respond
reciprocally‫متعاكس‬.
‫) وذلك بسبب قلت وجوده في البطين‬inotropic & lusitropic ( ‫) على ال‬parasympathetic(‫سبب قلت تأثيرالبار‬
Chronotropic effects
Heart rate depend on the firing rate of the SA node
Normal heart rate (60 to 100 bpm), >100 bpm: tachycardia, <60 bpm: Bradycardia
Maximal heart rate is decrease with increase in age according to the formula
The rate at which pacemaker cells initiate impulses is a function of
 the maximum diastolic potential (MDP) (Normally is -60mV) does it become more negative
(hyperpolarize)-70mV or become less negative (depolarize) -50mV
the magnitude of the threshold potential (Normally is -40mV), so the difference between maximum
diastolic potential and threshold potential (20mV) doses it increases (30mV) or decrease 10mV)
the rate of phase 4 depolarization per min is it going to increase or decrease
The slop of the pre-potential is it going to decrease approaching 0 degree or increase
(1) Parasympathetic stimulation or Acetylcholine released at the nerve endings mediated by M2
muscarinic receptors will causes either:
 increases the K conductance of nodal tissue,
 Decrease cAMP in the cells, ►slows the opening of the Ca channels.
There will be decrease in heart rate due to
 The maximum diastolic potential increase (becomes hyperpolarized from -60mV to-70mV
The difference between maximum diastolic potential and threshold potential will increase from
20mV to 30mV
The slop of the pre-potential is decreased ‫الزاوية تصبح اقل‬
The rate of phase 4 depolarization decrease‫عدد المرات ب الدقيقة يصبح اقل‬
(2) Sympathetic stimulation or Nor-epinephrine secreted by the sympathetic ending binding
to β1 receptor, and the resulting:
increase in intra-cellular cAMP.
facilitates the opening of L type calcium channels,
increase ICa and the rapidity of the depolarization phase of the impulse.
There will be increase in heart rate due to
 The maximum diastolic potential decrease (becomes more depolarized from -60mV to
-50mV
The difference between maximum diastolic potential and threshold potential will idecrease
from 20mV to 10mV
The slop of the pre-potential is increased ‫الزاوية تصبح اكثر‬
The rate of phase 4 depolarization increased ‫عدد المرات ب الدقيقة يصبح اكثر‬
Factors affecting heart rate:
With increase in heart rate there is decrease in the total cardiac, systolic and diastolic time.
The shorting is due mainly to a decrease in the duration of systolic ejection.
The duration of systole is much fixed than that of diastole, and when the heart rate is increased, diastole
is shorten to a much greater degree. This fact has important physiological and clinical implication.
 it is during diastole that the heart muscle rests.
the coronary blood flow to the sub-endo-cardium portions of the left ventricle occurs during diastole.
most of the ventricular filling occurs in diastole.
At heart rate up to about 180, filling is adequate as long as there is ample ‫وافر‬venous return and
cardiac output per minute is increased by an increase in rate. However, at very high rates, filling may be
compromised to such a degree that cardiac output per minute falls and symptoms of heart failure
develop. The highest rate at which the ventricle can contract is theoretically about 400/min, but in adult
the AV node will not conduct more than about 230 impulses/min because of its long refractory period.
Dromotropic effect (Conduction Velocity)
Conduction velocity reflects the time required for excitation to spread throughout cardiac tissue (it takes
about 225 msec from SA node to last cell in ventricle).
Conduction velocity is altered by:
a. Sympathetic stimulation (increase)
b. Vagal stimulation (decrease)
c. Ischemia/ hypoxia (decrease)
d. Drugs: adrenergic (increase), cholinergic (decrease)
Changes in conducting velocity could affect:
A. nodal tissue

Sympathetic stimulation (positive dromotropic effect) increases conduction velocity through the AV
node, (reduce AV nodal delay)  speeding the conduction of action potentials from the atria to the
ventricles reducing the time between atrial and ventricular contraction and decreasing the PR
interval.
Parasympathetic stimulation (negative dromotropic effect) will do the reverse effect of sympathetic
stimulation.
Changes in SA node caused by autonomic stimulation is similar to that seen in AV node.
Drugs such as digitalis, increase vagal activity to the heart, are sometimes used to reduce AV nodal
conduction in patients that have atrial flutter or fibrillation.
Calcium channel blocker (such as verapamil or diltiazem) block L-type calcium channels so reduces
the conduction velocity of impulses through the AV node and can produce AV block.
B. non-nodal tissue
In non-nodal cardiac tissue, cellular hypoxia (or ischemia) leads to,

inhibition of fast Na+ channels,

a decrease in action potential amplitude (less negative the membrane potential at the beginning
of phase 0 depolarization,
a decrease in the rate (or slope) of phase 0 depolarization (measured as the change in voltage
per unit of time [dV/dt]: Vmax: mV/sec).

These membrane changes result in a decrease in speed by which action potentials are conducted
within the heart.
This can have a number of consequences.
First, activation of the heart will be delayed, and in some cases, the sequence of activation will be
altered. This can seriously impair ventricular pressure development.
Second damage to the conducting system can precipitate tachy-arrhythmias by reentry mechanisms
Class IA anti-arrhythmic drugs such as quinidine that block fast sodium channels cause a decrease
in conduction velocity in non-nodal tissue.
Inotropic effects:
Inotropic effect is the intrinsic ability of cardiac muscle to develop force (contraction) at a given
muscle length, which is also called inotropism.
Ejection fraction is often used as a clinical index to evaluate the inotropic status of the heart.
A. Effect of autonomic nervous system
1. Sympathetic stimulation causes increases contraction
of the heart (Positive inotropic effect) via:
a. Sympathetic stimulation → Gs → increase AC
(adenyl cyclase) and cAMP → increase opening L-type
Ca Channel during Phase 2 →increase contraction
(Positive inotropic effect)
Positive inotropic agents Catecholamine (i.e.,
Dopamine, Epnephrine (adrenaline), Norepinephrien
(noradrenaline), Dobutamine, and Digoxine)
b. Parasympathetic stimulation or acetylcholine via
muscarinic receptors causes decreases the force of
contraction in the atria (Negative inotropic effect) via:
 Decrease calcium influxe during the plateau
 Increase potassium efflux ►hyperpolarization
B. Effect of Cardiac hypertrophy
Cardiac hypertrophy will cause increases contraction of the heart (Positive inotropic effect) due to:
a. Physiological Cardiac hypertrophy as in exercise treining after prolonge time
b. Pathological Cardiac hypertrophy as after prolonge time of hypertension or aoric stenosis
Cardiac glycosides (digitalis)
increase the force of contraction by inhibiting Na+- K+-ATPase in the myocardial cell membrane as a result
of this inhibition, the intracellular [Na+] increases, diminishing the Na+ gradient across the cell membrane.
Na+- Ca2+ exchange (a mechanism that extrudes Ca2+ from the cell) depends on the size of the Na+
gradient and thus is diminished, producing an increase in intracellular [Ca2+].
Negative inotropic agents produce a decrease in contractility (examples Beta blockers, Calcium channel
blockers), also Hypoxia (↓ O2) and hypercapnia (↑ CO2) , acidosis(↓pH) depresses myocardial contractility.
Increased heart rate increases the force of contraction (positive inotropism).
This is called Positive staircase‫سلم‬, or Bowditch staircase (or Treppe phenomenon: in a stepwise fashion
The Bowditch effect is an autoregulation method by which myocardial tension increases with an increase in heart rate
Increase heart rate

Decrease diastolic time

Decrease the effect of Na/K-ATPase (due to decrease time availability to remove Na)

Decrease the effect of 3Na+/Ca++ exchanger which allows 3 Na to flow down its gradient in exchange for 1 Ca++ ion to
flow out of the cell

This results in an accumulation of calcium in the myocardial cell; and leads to a greater state of inotropism, a
mechanism which is also seen with cardiac glycosides.
D. Lusitropic effect:
Positive lusitropic effect means increase relaxation
Note:
Un-phosphorylated phospholamban inhibit sarcoplasmic reticulum
Ca2+-ATPase ►decrease Calcium reuptake→↑ cytoplasmic
calcium → prevent relaxation, so to stimulate relaxation we have
to phosphorylated phospholamban.
beta-adrenergic agonist or Sympathetic stimulation→ Gs→
increase AC (adenyl cyclase) and cAMP → increase cAMP-
dependent protein kinase→ phosphorylated phospholamban →
there will be no inhibition of sarcoplasmic reticulum Ca2+-ATPase
→ increase Calcium reuptake → decrease cytoplasmic calcium
→ stimulate relaxation.
The overall effect of Un-phosphorylated phospholamban is
antagonist of sarcoplasmic reticulum Ca2+-ATPase → increase
cytoplasmic calcium→ increase contractility (i.e., decrease
relaxation) →decrease ventricular filling and end diastolic volume
→decreasing stroke volume.
Negative lusitropic effect means decrease relaxation (as in
alkalosis)
E. Bathmotropic effect:
The bathmotropic effect means modifying the heart muscle membrane excitability, and thus the ease
of generating an action potential.
The ease ‫يسهل‬of generating an action potential is related to
 the magnitude of the resting membrane potential
 the activation state of membrane sodium channels
Positive Bathmotropic effects increase the response of muscle to stimulation (degree of
excitability, or threshold of excitation).
Norepinephrine and sympathetic stimulation in general raise the resting membrane potential
Digitalis: Converts the normal Purkinje action potential of heart muscle to the automaticity type,
which increases myocardial irritability
Hypocalcemia:
Calcium → blocks sodium channels → prevents depolarization
↓ Calcium→↑ sodium passage →↓ threshold for depolarization.
 Mild to Moderate Hyperkalemia: causes a partial depolarization of the resting membrane
potential
 Mild hypoxia or ischemia causes a marked depolarization of the resting membrane potential
Negative Bathmotropic effects decrease muscle degree of excitability.
 Acetylcholine and Parasympathetic stimulation (decreases excitability only of atrial muscle cells)
 Quinidine and other Class A Antiarrhythmic Agents: block the voltage gated sodium channels
 Hypercalcemia: decreases permeability to sodium, hyperpolarizes membrane
 Hypokalemia: hyperpolarization of the resting membrane potential
 Marked Hypoxia: partial depolarization of the muscle membrane
Heart sounds:
Slapping of the valves leaflets is not enough to generate a heart sound.
First heart sound:
The cause of the first heart sound:
During systole the AV valves are closed, and blood tries to flow back to the atrium back bulging the AV valve. But the taut chorda
tendinae stop the back and causes the blood to flow forward. This will cause vibration of the valves, blood and the walls of
the ventricles which is presented as the first heart sound.
It is a low, slightly prolonged sound (duration of about 0.15 sec and a frequency of 25 to 45 Hz).
Second heart sound:
During diastole, blood in the blood vessels tried to flow back to
the ventricles this will causes the semilunar vales to bulge. But the
elastic recoil of arteries causes the blood to bounce forward which will vibrate
the valves, blood and the walls of the ventricles.
The second sound lasts about 0.12 sec with a frequency of 50 Hz. It is loud
and sharp.
The interval between aortic and pulmonary valves closure during inspiration is
frequently long enough for the second sound to be re-duplicated
(Physiological splitting of second sound) occurs when the A2 sound precedes
P2 by a great enough distance to allow both sounds to be heard separately.
This happens during inspiration when
increased venous return to the right side of the heart delays the closure of the pulmonic valve or
 the diastolic arterial pressure on the left is 80 mmHg is higher than only 10 mmHg on the right. This higher closing pressure
leads to earlier closure of the aortic valve.
Splitting can occur in various diseases.
Third heart sound:
Third heart sound is soft, low-pitched sound, has duration of 0.1 sec.
Third heart sound is heard about one-third of the way through diastole
Third heart sound can be normal in normal young individuals but may be pathologic
Third heart sound coincides ‫يتزامن‬with the period of rapid ventricular filling and
Third heart sound is probably due to vibration set up by the inrush of blood.
Third heart cannot be heard by stethoscope in normal conditions but can be heard by microphone.
Fourth heart sound:
Fourth heart sound is an inaudible only by phonocardiogram, become audible in pathological conditions.
Fourth heart sound can sometime be heard immediately just after atrial contraction at the end of diastole and
immediately before the first sound.
Fourth heart sound is caused by vibration of the ventricular wall during forcible atrial contraction in the presence of
decreased ventricular compliance ("stiff" ventricle) as occurs in
ventricular hypertrophy.
Murmurs:
Murmurs, or bruits, are abnormal sound heard in various parts of
the vascular system. The two terms are used interchangeably,
through "murmur" is more commonly used to denote noise heard
over the heart than over blood vessels.
The major, but certainly not the only, cause of cardiac murmurs is
disease of the heart valves.
When the orifice of the valve is narrow (stenosis), blood flow
through it in the normal direction is accelerated and turbulent.
When a valve is incompetent, blood flows backward through it
(regurgitation or insufficiency), again through a narrow orifice that
is accelerated and turbulent.
The flow of blood in straight blood vessels, like the flow of liquid in narrow rigid tubes, is normally
(laminar). Within the blood vessels, an infinitely thin layer of blood in contact with wall of the vessel
dose not moves. The next layer within the vessel has a low velocity, the next a higher velocity, and
so forth, velocity being greater in the center of the stream (parabolic velocity).
Laminar flow occurs at velocity up to a certain (critical velocity). At or above this velocity, flow is
(turbulent). Turbulent flow creates sound.
The probability of turbulence is also related to the diameter of the vessel and the viscosity of the
blood.

Where: Re: Reynolds number, ρ (rho): is the density of the blood, D: is the diameter of the vessel, V:
is the velocity of flow, and η (eta): is the viscosity of blood.
Reynolds number more than 3000 turbulence is almost always present.
Blood will have a high speed when passes through narrow orifice, this is why sound is going to be
created why it passes through stenotic or regurgitated valve, where it is going to have high Reynolds
number and a murmur is heard.
The timing (systolic or diastolic) of a murmur due to stenosis or insufficiency of any particular valve
can be predicted from a knowledge of the mechanical events of the cardiac cycle.
Methods of measurement of cardiac output:
1. Direct Fick method:
Fick principle: state that
the amount of a substance taken up by an organ (or the whole body) per unit of time is
equal to
the arterial level of the substance minus the venous level (A - V difference) times the blood flow.
This principle can be applied to an organ, but if we want to applied this principle to measure the cardiac for
the body, then: CO X ( Ca-Cv)= VO2
‫) للجسم ك كل‬cardiac output(‫هذه المعادلة لحساب ال‬