CARDIOVASCULAR PATHOPHYSIOLOGY
CARDIAC PHYSIOLOGY
GENERAL CONCEPTS
HEART CONTRACTION
The heart does not have the capacity to regenerate, and stem cells are not present. Therefore, once a
cardiomyocyte is damaged, it will be never replaced. There is no turnover throughout life. Since the
entire cell cannot be replaced, its protein level is controlled.
The protein turnover is based on the balance between
protein synthesis and protein degradation. The protein
degradation is performed by the ubiquitin-proteasome
system and lysosomes.
The heart is a pump that is divided into four chambers. It
beats about 100,000 per day and it pumps about 7,500L of
blood daily. To have an efficiency contraction and pumping
of blood the cardiomyocytes are properly organised. Indeed,
if all areas of a chamber of the heart contract
simultaneously, the result will be an increased pressure in
the areas without an outlet (i. e. apex of ventricle).
Therefore, the heart of higher organisms has been
developed to avoid the maintenance of blood in chamber.
The contraction is started at the level of the apex, and then
it propagates towards the base, in which the aortic and
pulmonary valves are localised. In this way, all blood is pumped away from the chamber. Moreover,
the cardiomyocytes are organised in a specific way, so that once they contract, they slightly twist the
chamber, thereby increasing the proper ejection.
CONDUCTION SYSTEM
The contraction of the heart is mediated by the conduction system, which is made of specialised
cardiomyocytes capable of creating an autonomous action potential. The signal is generated by
pacemaker cells of the sinoatrial node, or Keith-Flack node. Then, it
is transferred to the atrioventricular node, or Ashoff-Tawara node via
the intra-atrial fibres (i. e. anterior, medial, posterior). The AV node
allows the contraction of atria and propagates the signal to the bundle
of His. The bundle of His has the function to lower the conduction
velocity, thus allowing atria to finish their systole before that
ventricles begin their own. Finally, Purkinje fibres cause the
ventricular contraction.
HEART REGULATION
The regulation of the heart is primarily determined by intrinsic mechanisms, but in some cases also
the nervous system may play important roles. In general, the heart is regulated via two systems, which
are:
• Frank-Sterling law: it is a law that states that the stroke
volume of the left ventricle will increase as the left
ventricular volume increases due to cardiomyocyte
stretch, causing a more forceful systole; therefore, when
there is more blood in the chamber, the
cardiomyocytes are more stretched, and this induces a
greater and stronger systole, which results in an
increased stroke volume; if there is a decrease in the
venous return, less blood fills the ventricle, which result
, in a decrease ejection fraction; note that this law is valid up to a certain threshold; indeed,
once the tension-length relationship of contractile fibres is overcome, the cardiomyocyte is
unable to contract properly, and this result in a decrease SV.
• Neurohormonal control: it is an extracardiac regulator of the heart function, which is
determined by two components, which are:
Systemic nervous system (SNS): it acts
on the conduction system or on
cardiomyocytes to decrease
(parasympathetic, Ach) or increase
(sympathetic, Ep, Nor) both the
conduction velocity and the
cardiomyocyte contraction.
Hormonal regulation: it is primarily
mediated by epinephrine and
norepinephrine released by the
adrenal medulla; they increase heart contractility and HR.
CONTRACTILE APPARATUS
FOUR SYSTEMS OF THE HEART
The heart is considered a mechanical engine, and it can be divided into four functional components,
which require to work together to allow the correct functioning of the heart; they are:
• Contractile myocardium: it is the
specialised muscular tissue that is
involved in the heart contraction.
• Conduction system: it is the main
regulator of cardiomyocyte
contraction; in case of dysfunction of
it (e. g. genetic causes, acquired
causes), each cell of the conduction
system begins to work independently
from the SA node; this results in
fibrillation (e. g. atrial fibrillation).
• Valvular apparatus: they are
important to maintain the
unidirectionality of blood flow; alterations of them may compromise the cardiac
haemodynamic; the possible alterations may be either stenosis (i. e. narrowing) and
prolapse/non-closure; for instance, in case of not closure of the aortic valve, the blood flows
back in the left ventricle (i. e. aortic regurgitation), resulting in an increase diastolic volume;
moreover, the organism will be less perfused.
• Coronary vessels: they are essential to irrorate and vascularise the heart itself; diseases
affecting them (e. g. atherosclerosis) may cause ischemic cardiomyopathy and myocardial
infarction.
All these systems cooperate to allow the correct functioning of the heart, and if one of them is
compromised, even the heart will be.
COMPONENTS OF THE CONTRACTILE APPARATUS
The correct contractile function of the working myocardium is determined by the structural and the
functional integrity of the cardiomyocytes. The correct contractile function requires three main
elements, which are:
• Contractile apparatus.
• Cytoskeleton.
, • Intracellular signals regulating contraction.
Alterations of these elements can be either congenital alterations (primary) or acquired alterations
(secondary).
The contractile apparatus is formed by the muscular functional
units, called sarcomeres; the sarcomere is the structure in which
there is the interaction between actin and myosin filaments.
When ATP and calcium are present, the globular head of myosin
can interact with the actin filaments, thereby causing the
shortening of the
sarcomere (power stroke,
about 10nm). The calcium
acts on the troponin-
tropomyosin complex
(troponin T, I, and C), which has the function of inhibiting the
actin-myosin binding. Since the troponin-tropomyosin complex
is displaced, the myosin can bind actin causing the shortening
of the sarcomere.
ALTERATIONS OF THE CONTRACTILE APPARATUS
The cardiomyopathies are diseases of the heart that are caused by alterations of the contractile
apparatus, the cytoskeletal elements, or the proteins involved in intracellular signalling regulation.
The alterations of the contractile apparatus causing
cardiomyopathies can be of two types, which are:
• Congenital alterations: they occur in myosin,
M-bp C, actin, troponin I, and tropomyosin
genes; they are the most common cause of
cardiomyopathy in Italy; since the
contraction of the sarcomere is reduced, to
allow a proper contraction of the entire heart,
the myocardium undergoes hypertrophy,
resulting in hypertrophic cardiomyopathy.
• Acquired dysfunctions: they occur in myosin,
troponin I, and troponin C; they are caused
by signals that alter the functionality of these
proteins; the outcomes will be hypertrophic cardiomyopathy and heart failure.
CALCIUM SIGNALLING
The calcium is an important ion required for cardiomyocyte contraction, and in general for muscular
contraction. It must be maintained at low concentration within the cell, and only once it is required (i.
e. contraction) its concentration should be
increased. When the action potential of a
cardiomyocytes is started, the voltage
dependent Ca2+ channels (VDCC) are
opened, and they slightly increase the
cytosolic [Ca2+]. This small increase triggers
the opening of the ryanodine receptors
(RyR) of the sarcoplasmic reticulum (SR),
which is the primary organelle involved in
calcium storage. Once the RyR are opened
all the calcium stored in the SR is moved in
CARDIAC PHYSIOLOGY
GENERAL CONCEPTS
HEART CONTRACTION
The heart does not have the capacity to regenerate, and stem cells are not present. Therefore, once a
cardiomyocyte is damaged, it will be never replaced. There is no turnover throughout life. Since the
entire cell cannot be replaced, its protein level is controlled.
The protein turnover is based on the balance between
protein synthesis and protein degradation. The protein
degradation is performed by the ubiquitin-proteasome
system and lysosomes.
The heart is a pump that is divided into four chambers. It
beats about 100,000 per day and it pumps about 7,500L of
blood daily. To have an efficiency contraction and pumping
of blood the cardiomyocytes are properly organised. Indeed,
if all areas of a chamber of the heart contract
simultaneously, the result will be an increased pressure in
the areas without an outlet (i. e. apex of ventricle).
Therefore, the heart of higher organisms has been
developed to avoid the maintenance of blood in chamber.
The contraction is started at the level of the apex, and then
it propagates towards the base, in which the aortic and
pulmonary valves are localised. In this way, all blood is pumped away from the chamber. Moreover,
the cardiomyocytes are organised in a specific way, so that once they contract, they slightly twist the
chamber, thereby increasing the proper ejection.
CONDUCTION SYSTEM
The contraction of the heart is mediated by the conduction system, which is made of specialised
cardiomyocytes capable of creating an autonomous action potential. The signal is generated by
pacemaker cells of the sinoatrial node, or Keith-Flack node. Then, it
is transferred to the atrioventricular node, or Ashoff-Tawara node via
the intra-atrial fibres (i. e. anterior, medial, posterior). The AV node
allows the contraction of atria and propagates the signal to the bundle
of His. The bundle of His has the function to lower the conduction
velocity, thus allowing atria to finish their systole before that
ventricles begin their own. Finally, Purkinje fibres cause the
ventricular contraction.
HEART REGULATION
The regulation of the heart is primarily determined by intrinsic mechanisms, but in some cases also
the nervous system may play important roles. In general, the heart is regulated via two systems, which
are:
• Frank-Sterling law: it is a law that states that the stroke
volume of the left ventricle will increase as the left
ventricular volume increases due to cardiomyocyte
stretch, causing a more forceful systole; therefore, when
there is more blood in the chamber, the
cardiomyocytes are more stretched, and this induces a
greater and stronger systole, which results in an
increased stroke volume; if there is a decrease in the
venous return, less blood fills the ventricle, which result
, in a decrease ejection fraction; note that this law is valid up to a certain threshold; indeed,
once the tension-length relationship of contractile fibres is overcome, the cardiomyocyte is
unable to contract properly, and this result in a decrease SV.
• Neurohormonal control: it is an extracardiac regulator of the heart function, which is
determined by two components, which are:
Systemic nervous system (SNS): it acts
on the conduction system or on
cardiomyocytes to decrease
(parasympathetic, Ach) or increase
(sympathetic, Ep, Nor) both the
conduction velocity and the
cardiomyocyte contraction.
Hormonal regulation: it is primarily
mediated by epinephrine and
norepinephrine released by the
adrenal medulla; they increase heart contractility and HR.
CONTRACTILE APPARATUS
FOUR SYSTEMS OF THE HEART
The heart is considered a mechanical engine, and it can be divided into four functional components,
which require to work together to allow the correct functioning of the heart; they are:
• Contractile myocardium: it is the
specialised muscular tissue that is
involved in the heart contraction.
• Conduction system: it is the main
regulator of cardiomyocyte
contraction; in case of dysfunction of
it (e. g. genetic causes, acquired
causes), each cell of the conduction
system begins to work independently
from the SA node; this results in
fibrillation (e. g. atrial fibrillation).
• Valvular apparatus: they are
important to maintain the
unidirectionality of blood flow; alterations of them may compromise the cardiac
haemodynamic; the possible alterations may be either stenosis (i. e. narrowing) and
prolapse/non-closure; for instance, in case of not closure of the aortic valve, the blood flows
back in the left ventricle (i. e. aortic regurgitation), resulting in an increase diastolic volume;
moreover, the organism will be less perfused.
• Coronary vessels: they are essential to irrorate and vascularise the heart itself; diseases
affecting them (e. g. atherosclerosis) may cause ischemic cardiomyopathy and myocardial
infarction.
All these systems cooperate to allow the correct functioning of the heart, and if one of them is
compromised, even the heart will be.
COMPONENTS OF THE CONTRACTILE APPARATUS
The correct contractile function of the working myocardium is determined by the structural and the
functional integrity of the cardiomyocytes. The correct contractile function requires three main
elements, which are:
• Contractile apparatus.
• Cytoskeleton.
, • Intracellular signals regulating contraction.
Alterations of these elements can be either congenital alterations (primary) or acquired alterations
(secondary).
The contractile apparatus is formed by the muscular functional
units, called sarcomeres; the sarcomere is the structure in which
there is the interaction between actin and myosin filaments.
When ATP and calcium are present, the globular head of myosin
can interact with the actin filaments, thereby causing the
shortening of the
sarcomere (power stroke,
about 10nm). The calcium
acts on the troponin-
tropomyosin complex
(troponin T, I, and C), which has the function of inhibiting the
actin-myosin binding. Since the troponin-tropomyosin complex
is displaced, the myosin can bind actin causing the shortening
of the sarcomere.
ALTERATIONS OF THE CONTRACTILE APPARATUS
The cardiomyopathies are diseases of the heart that are caused by alterations of the contractile
apparatus, the cytoskeletal elements, or the proteins involved in intracellular signalling regulation.
The alterations of the contractile apparatus causing
cardiomyopathies can be of two types, which are:
• Congenital alterations: they occur in myosin,
M-bp C, actin, troponin I, and tropomyosin
genes; they are the most common cause of
cardiomyopathy in Italy; since the
contraction of the sarcomere is reduced, to
allow a proper contraction of the entire heart,
the myocardium undergoes hypertrophy,
resulting in hypertrophic cardiomyopathy.
• Acquired dysfunctions: they occur in myosin,
troponin I, and troponin C; they are caused
by signals that alter the functionality of these
proteins; the outcomes will be hypertrophic cardiomyopathy and heart failure.
CALCIUM SIGNALLING
The calcium is an important ion required for cardiomyocyte contraction, and in general for muscular
contraction. It must be maintained at low concentration within the cell, and only once it is required (i.
e. contraction) its concentration should be
increased. When the action potential of a
cardiomyocytes is started, the voltage
dependent Ca2+ channels (VDCC) are
opened, and they slightly increase the
cytosolic [Ca2+]. This small increase triggers
the opening of the ryanodine receptors
(RyR) of the sarcoplasmic reticulum (SR),
which is the primary organelle involved in
calcium storage. Once the RyR are opened
all the calcium stored in the SR is moved in
