Pathophysiology of Heart and
Circulatory System summary
1
,Lecture 1 | ECG and rhythm disorders 3
Practical 1 | ECG and rhythm disorders 6
Lecture 2 | Cardiac energetics 8
Lecture 3 | Cardiomyopathies 11
Lecture 4 | The vascular system and hypertension: focus on small arteries 14
Lecture 5 | Vascular pathology 17
Practical 2 | Cardiovascular re exes 22
Lecture 6 | Epidemiology and pathogenesis of type 2 diabetes mellitus 23
Lecture 7 | Lipoproteins 25
Keynote lecture | The increase of cardiac output in evolution 28
Lecture 8 | Angiogenesis 29
Lecture 9 | Permeability 33
Practical 3 | Macro- and microcirculation 36
Lecture 10 | Myocardial perfusion in health and disease 40
Practical 4 | Cardiopulmonary exercise test 43
2
fl
, Lecture 1 | ECG and rhythm disorders
NORMAL PHYSIOLOGY OF THE HEART
- The resting membrane potential of a ventricular cardiomyocyte is -90 mV
- Occurs when all ions reach their (electrochemical) equilibrium potential: the potential
di erence across the membrane required to maintain the concentration and electrical
gradient across the membrane (i.e. no net ow of ions)
- Is determined by: the concentrations of positively and negatively charged ions across the
cell membrane, the relative permeability of the cell membrane to these ions, and the ionic
pumps that transport ions across the cell membrane
- Na+, Ca2+ and K+ being the most important ions
- NB: di erent cell types within the heart have di erent resting potentials, depending on
equilibrium potentials, ionic conductances, and membrane potential
- In a cardiac cell, changes in membrane potential primarily result from changes in ionic
conductances
- The resting potential is near the equilibrium potential for K+ (-96 mV), because the
relative conductance for K+ is high in the resting cell, while the relative conductances
for Na+ and Ca2+ are low
- During a ventricular AP: the relative conductances for Na+ and Ca2+ increase and for
K+ decreases -> the membrane potential becomes more positive (i.e. depolarized)
- Excitation-contraction coupling: contraction of the heart following electrical stimulation of
cardiomyocytes
- Ensures that cardiomyocytes can coordinate their contraction: cells must be excited rst
before they contract
- Refractory period: period (immediately after the rst stimulus) in which cardiomyocytes
cannot be stimulated again (in-excitable due to Na-channels not being reset), ensuring that
the cells cannot be stimulated excessively, and that contraction is followed by relaxation of
the heart muscle (i.e. the heart can be lled with blood after each contraction)
- Absolute refractory period (ARP): the membrane cannot respond at all because Na+
channels are inactivated
- Relative refractory period (RRP): Na+ channels are closed but can open, and the
membrane will respond to a stronger-than-normal stimulus by initiating another AP
- Action potential: depends on the in ow of Na+ and Ca2+, and out ow of K+
1. Rapid depolarization: fast voltage-gated Na+ channels open (activated)
- Is followed by rapid inactivation (closing) of the fast Na-channels
2. Plateau: slow voltage-gated Ca2+ channels open
3. Repolarization: slow K+ channels open
- Ca2+ and contraction:
- Ca2+ enters the cardiomyocytes through voltage-gated Ca-channels during an AP
- Calcium induced calcium release (CICR): junctional SR with a Ca-reservoir, which
functions as amplifying system, causing much higher levels of Ca2+ to enter the cytosol
once triggered by Ca2+ entering the cell
- Accounts for 75-90% of Ca2+ inside the cytosol
- Ca2+ in the cytosol is needed for the cardiomyocytes to contract: Ca2+ binds to
myo laments, thereby initiating contraction
- One heartbeat at cellular level:
1. Electrical signal of neighboring cell (cardiomyocyte, SA node, conduction system)
2. Action potential (1. Na+ in ux; 2. Ca2+ in ux; 3. K+ e ux)
3. Ca2+ induced Ca2+ release
4. Ca2+ binds to myo laments
5. Power stroke: cell shortening, force development (=contraction)
6. Ca2+ released from myo laments
7. Ca2+ re-uptake in SR: relaxation
3
ff fi ff fi fi fl fl fi fl fl ff fi ffl fl fi
, ELECTROCARDIOGRAM (ECG)
- An ECG measures the spread of action potentials throughout the heart, and thereby re ects the
di erences between heart regions (i.e. that have and have not undergone an AP)
- SA node -> AV node -> AV bundle (aka bundle of His; at base of the ventricles) -> bundle
branches (inter-ventricular septum) -> Purkinje bers (in ventricular walls)
- SA node: pacemaker cells on top of the RA, which set the heart rhythm, and ensure
spreading of the AP throughout the atria
- Pacemaker (‘slow response’) APs: depolarization primarily by relatively slow
inward Ca2+ currents via voltage-gated Ca-channels
- Factors increasing the SA node ring rate: sympathetic stimulation, muscarinic
receptor antagonist, β-adenoreceptor agonists, circulating catecholamines,
hypokalemia, hyperthyroidism, hyperthermia
- Factors decreasing the SA node ring rate: parasympathetic stimulation,
muscarinic receptor agonists, β-blockers, ischemia/hypoxia, hyperkalemia, Na-
and Ca-channel blockers, hypothermia
- AV node: pacemaker cells in the inter-atrial septum, which act as a backup for the SA
node, and ensure spreading of the AP throughout the ventricles
- Delays the AP due to slow conduction, ensuring that the atria can completely
depolarize and contract prior to the ventricles
- AV bundle, bundle branches, and Purkinje bers: conduct AP from AV node to the
septum, downwards, and up to the ventricular walls
- Waves of the ECG:
- P-wave: spread of the depolarization wave through the atria (from the SA node)
- PR-interval: conduction through the AV node
- QRS-complex: spread of the depolarization wave through the ventricles
- T-wave: repolarization of the ventricles
- The appearance of the recorded ECG depends on: location of recording electrodes on the
body surface, conduction pathways and speed of conduction, and changes in muscle mass
- 12 lead ECG:
- Standard limb leads (Einthoven triangle):
- Lead I: right arm (-) to left arm (+)
- Lead II: right arm (-) to left leg (+)
- Lead III: left arm (-) to left leg (+)
- Augmented limb leads: aVL (left arm), aVR (right arm), aVF (left leg)
- Unipolar leads: all positive electrodes, with other limb leads used as negative
references
- Precordial leads: 6 electrodes (V1-V6) on the chest around the heart
- Unipolar leads: all positive electrodes
- Measure the electrical activity in a horizontal plane, which is perpendicular to the limb
leads’ frontal plane
- Interpretation of ECG:
- A wave of depolarization (instantaneous mean electrical vector) traveling toward a positive
electrode results in a positive de ection on the ECG trace
- A wave of depolarization traveling away from a positive electrode results in a negative
de ection
- A wave of repolarization traveling toward a positive electrode results in a negative
de ection
- A wave of repolarization traveling away from a positive electrode results in a positive
de ection
- A wave of depolarization or repolarization oriented perpendicular to an electrode axis
produces no net de ection
- The instantaneous amplitude of the measured potentials depends upon the orientation of
the positive electrode relative to the mean electrical vector
- Voltage amplitude (positive or negative) is directly related to the mass of tissue undergoing
depolarization or repolarization
4
fffl
fl fiflfi fi fi fl
Circulatory System summary
1
,Lecture 1 | ECG and rhythm disorders 3
Practical 1 | ECG and rhythm disorders 6
Lecture 2 | Cardiac energetics 8
Lecture 3 | Cardiomyopathies 11
Lecture 4 | The vascular system and hypertension: focus on small arteries 14
Lecture 5 | Vascular pathology 17
Practical 2 | Cardiovascular re exes 22
Lecture 6 | Epidemiology and pathogenesis of type 2 diabetes mellitus 23
Lecture 7 | Lipoproteins 25
Keynote lecture | The increase of cardiac output in evolution 28
Lecture 8 | Angiogenesis 29
Lecture 9 | Permeability 33
Practical 3 | Macro- and microcirculation 36
Lecture 10 | Myocardial perfusion in health and disease 40
Practical 4 | Cardiopulmonary exercise test 43
2
fl
, Lecture 1 | ECG and rhythm disorders
NORMAL PHYSIOLOGY OF THE HEART
- The resting membrane potential of a ventricular cardiomyocyte is -90 mV
- Occurs when all ions reach their (electrochemical) equilibrium potential: the potential
di erence across the membrane required to maintain the concentration and electrical
gradient across the membrane (i.e. no net ow of ions)
- Is determined by: the concentrations of positively and negatively charged ions across the
cell membrane, the relative permeability of the cell membrane to these ions, and the ionic
pumps that transport ions across the cell membrane
- Na+, Ca2+ and K+ being the most important ions
- NB: di erent cell types within the heart have di erent resting potentials, depending on
equilibrium potentials, ionic conductances, and membrane potential
- In a cardiac cell, changes in membrane potential primarily result from changes in ionic
conductances
- The resting potential is near the equilibrium potential for K+ (-96 mV), because the
relative conductance for K+ is high in the resting cell, while the relative conductances
for Na+ and Ca2+ are low
- During a ventricular AP: the relative conductances for Na+ and Ca2+ increase and for
K+ decreases -> the membrane potential becomes more positive (i.e. depolarized)
- Excitation-contraction coupling: contraction of the heart following electrical stimulation of
cardiomyocytes
- Ensures that cardiomyocytes can coordinate their contraction: cells must be excited rst
before they contract
- Refractory period: period (immediately after the rst stimulus) in which cardiomyocytes
cannot be stimulated again (in-excitable due to Na-channels not being reset), ensuring that
the cells cannot be stimulated excessively, and that contraction is followed by relaxation of
the heart muscle (i.e. the heart can be lled with blood after each contraction)
- Absolute refractory period (ARP): the membrane cannot respond at all because Na+
channels are inactivated
- Relative refractory period (RRP): Na+ channels are closed but can open, and the
membrane will respond to a stronger-than-normal stimulus by initiating another AP
- Action potential: depends on the in ow of Na+ and Ca2+, and out ow of K+
1. Rapid depolarization: fast voltage-gated Na+ channels open (activated)
- Is followed by rapid inactivation (closing) of the fast Na-channels
2. Plateau: slow voltage-gated Ca2+ channels open
3. Repolarization: slow K+ channels open
- Ca2+ and contraction:
- Ca2+ enters the cardiomyocytes through voltage-gated Ca-channels during an AP
- Calcium induced calcium release (CICR): junctional SR with a Ca-reservoir, which
functions as amplifying system, causing much higher levels of Ca2+ to enter the cytosol
once triggered by Ca2+ entering the cell
- Accounts for 75-90% of Ca2+ inside the cytosol
- Ca2+ in the cytosol is needed for the cardiomyocytes to contract: Ca2+ binds to
myo laments, thereby initiating contraction
- One heartbeat at cellular level:
1. Electrical signal of neighboring cell (cardiomyocyte, SA node, conduction system)
2. Action potential (1. Na+ in ux; 2. Ca2+ in ux; 3. K+ e ux)
3. Ca2+ induced Ca2+ release
4. Ca2+ binds to myo laments
5. Power stroke: cell shortening, force development (=contraction)
6. Ca2+ released from myo laments
7. Ca2+ re-uptake in SR: relaxation
3
ff fi ff fi fi fl fl fi fl fl ff fi ffl fl fi
, ELECTROCARDIOGRAM (ECG)
- An ECG measures the spread of action potentials throughout the heart, and thereby re ects the
di erences between heart regions (i.e. that have and have not undergone an AP)
- SA node -> AV node -> AV bundle (aka bundle of His; at base of the ventricles) -> bundle
branches (inter-ventricular septum) -> Purkinje bers (in ventricular walls)
- SA node: pacemaker cells on top of the RA, which set the heart rhythm, and ensure
spreading of the AP throughout the atria
- Pacemaker (‘slow response’) APs: depolarization primarily by relatively slow
inward Ca2+ currents via voltage-gated Ca-channels
- Factors increasing the SA node ring rate: sympathetic stimulation, muscarinic
receptor antagonist, β-adenoreceptor agonists, circulating catecholamines,
hypokalemia, hyperthyroidism, hyperthermia
- Factors decreasing the SA node ring rate: parasympathetic stimulation,
muscarinic receptor agonists, β-blockers, ischemia/hypoxia, hyperkalemia, Na-
and Ca-channel blockers, hypothermia
- AV node: pacemaker cells in the inter-atrial septum, which act as a backup for the SA
node, and ensure spreading of the AP throughout the ventricles
- Delays the AP due to slow conduction, ensuring that the atria can completely
depolarize and contract prior to the ventricles
- AV bundle, bundle branches, and Purkinje bers: conduct AP from AV node to the
septum, downwards, and up to the ventricular walls
- Waves of the ECG:
- P-wave: spread of the depolarization wave through the atria (from the SA node)
- PR-interval: conduction through the AV node
- QRS-complex: spread of the depolarization wave through the ventricles
- T-wave: repolarization of the ventricles
- The appearance of the recorded ECG depends on: location of recording electrodes on the
body surface, conduction pathways and speed of conduction, and changes in muscle mass
- 12 lead ECG:
- Standard limb leads (Einthoven triangle):
- Lead I: right arm (-) to left arm (+)
- Lead II: right arm (-) to left leg (+)
- Lead III: left arm (-) to left leg (+)
- Augmented limb leads: aVL (left arm), aVR (right arm), aVF (left leg)
- Unipolar leads: all positive electrodes, with other limb leads used as negative
references
- Precordial leads: 6 electrodes (V1-V6) on the chest around the heart
- Unipolar leads: all positive electrodes
- Measure the electrical activity in a horizontal plane, which is perpendicular to the limb
leads’ frontal plane
- Interpretation of ECG:
- A wave of depolarization (instantaneous mean electrical vector) traveling toward a positive
electrode results in a positive de ection on the ECG trace
- A wave of depolarization traveling away from a positive electrode results in a negative
de ection
- A wave of repolarization traveling toward a positive electrode results in a negative
de ection
- A wave of repolarization traveling away from a positive electrode results in a positive
de ection
- A wave of depolarization or repolarization oriented perpendicular to an electrode axis
produces no net de ection
- The instantaneous amplitude of the measured potentials depends upon the orientation of
the positive electrode relative to the mean electrical vector
- Voltage amplitude (positive or negative) is directly related to the mass of tissue undergoing
depolarization or repolarization
4
fffl
fl fiflfi fi fi fl
