Heart Failure & Therapy
Lecture 1: Physiology of The Cardiovascular System
- Function of the heart:
o Pumping oxygenated blood to other body parts.
o Pumping hormones and other vital substances to different parts of the body.
o Receiving deoxygenated blood and carrying metabolic waste products from the body and
pumping it to the lungs for oxygenation.
o Maintaining blood pressure (cardiac output) by coordination of contraction and relaxation.
o Together with blood vessels, it provides adequate perfusion of all organs and tissues.
- Excitation-contraction coupling:
o Excitation-contraction coupling refers to the series of events that link the muscle cell
membrane's action potential (excitation) (sarcolemma) to muscular contraction.
▪ Contraction of the heart following electrical stimulation of cardiomyocytes.
o The excitation-contraction coupling in cardiac myocytes is mediated by an electrical stimulus.
Calcium encounters a receptor and when bound together, calcium ions (Ca2+) enter the cell
cytoplasm. This triggers calcium-induced calcium release (CICR) from the sarcoplasmic
reticulum. Calcium is removed from the cytoplasm of the cell by a pump.
- Automation of the heart: The heart can beat independently of hormonal or neuronal input. Automation
is spontaneous and active and happens because of pacemaker cells.
- Conduction of the heart:
o The SA-node, in the top of the right atrium, starts the
sequence by causing the atrial muscles to contract
(pacemaker cells).
o The signal travels to the AV node, through the bundle of
HIS, down the bundle branches, and through the
Purkinje fibres, causing the ventricles to contract.
o The AV node is the only conduction connection between
atria and ventricles. Here, the signal slows down, so the
atria and ventricle don’t contract simultaneously. After
the ventricles, the electrical stimulus is very fast conducted.
- The four heart valves:
o Heart valves open and close to let blood flow and ensure that blood moves at the right time
and in the right direction. Between chambers, the valves are made of thin but strong flaps of
tissue, called leaflets or cusps.
o The tricuspid valve (3 leaflets) allows blood to flow from
the right atrium to the right ventricle and prevents blood
from flowing backward.
o The pulmonary valve (3 leaflets) allows blood to pump
from the right ventricle to the pulmonary artery. This artery
leads to the lungs, where the blood picks up oxygen.
o The mitral valve (2 leaflets) allows blood to flow from the
lungs into the left atrium and prevents backward flow from
the left ventricle to the left atrium.
o The aortic valve (3 leaflets) opens to let blood flow from the
left ventricle to the aorta and prevents backward flow from the aorta into the left ventricle.
- Pacemaker cells and their action potential:
o Pacemaker cells are highly specialized myocardial cells whose intrinsic ability to rhythmically
depolarise and initiate an action potential is responsible for the basal heart rate.
▪ Heart rate is determined by (1) resting membrane potential of SA-node cells and (2)
velocity of depolarisation (slope of the prepotential).
o Three ions are of importance: sodium (Na+) and calcium (Ca2+) are high extracellularly,
potassium (K+) intracellularly.
o The cells are more negatively charged inside than outside, causing a negative membrane
potential. The membrane potential can be changed by the opening or closing of ion channels.
, ▪ Channels are voltage-gated, meaning they respond to membrane potentials.
o Phase zero is the phase of depolarization. It starts when the membrane potential reaches
-40mV (threshold potential); calcium channels open, causing the influx of calcium ions which
results in an upstroke in membrane potential from -40mV to +10mV.
o Phase three is the phase of repolarization. The calcium channels close, blocking the flow of
calcium ions. Voltage-gated potassium channels open, allowing for efflux of potassium ions
which contributes to a rapid decrease of membrane potential from +10mV to -60mV.
o Phase four is a phase of gradual depolarization that occurs via pacemaker current due to a
slow influx of sodium ions. This causes membrane potential to change from -60mV to reach a
threshold potential of -40mV.
- Maintenance of blood supply and heart rate:
o When a person is scared, more blood is
needed to the muscles. The fight-or-flight
response causes norepinephrine to be
released from the sympathetic system,
therefore increasing the heart rate.
▪ When (nor)adrenaline is released and
binds to your cells, sodium channels
are opened more.
o In a person at rest, the parasympathetic system releases acetylcholine which slows down the
heart rate. The potassium channel opens more, and the sodium channel opens less; you are
further away from threshold, resulting in fewer heartbeats.
o Normally, you have a heart rate below 100 bpm. Someone who has received a donor’s heart
loses control of parasympathetic nerves, so when they are scared, their heart rate does
increase but takes a few seconds longer.
- Action potential of a ventricle cell:
o Ventricle cells do the same thing as pacemaker cells, but the sodium channel is different; it’s
closed until there is a signal in the neighbouring cell.
o The beginning part is different, and the length of the action potential is different (longer).
o During phase one (rapid depolarization), sodium channels open, resulting in a rapid influx of
sodium ions and a change in membrane potential from -70mV to +50mV.
o During phase two, calcium influx occurs through an
opening of calcium channels, balancing the potassium
efflux and creating a plateau (+50mV) → initiating
muscle contraction.
o Repolarization follows in phase three, involving
potassium efflux through potassium channels and
closing of calcium channels.
,- Calcium cycling in the heart:
o Calcium-induced calcium release is defined as calcium release by the action of calcium
alone without the simultaneous action of other activating processes.
▪ It activates ryanodine-sensitive receptors (RyR) in the sarcoplasmic reticulum to open
and release calcium, which stimulates contraction.
o When calcium binds to troponin proteins, conformational change occurs allowing myosin to
bind to actin.
- Different phases of the cardiac cycle:
o The cardiac cycle is a sequence of
alternating contraction and relaxation of
the atria and ventricles to
pump blood throughout the body. It starts at
the beginning of one heartbeat and ends at
the beginning of another.
o Atrial filling and contraction (1): as the
atria contract, ventricular pressure becomes
less than atrial pressure, and the
atrioventricular valves open. This results in
filling of the ventricles with blood. Aorta and
pulmonary valves are closed.
▪ The total volume of blood present
in ventricle at the end of diastole is
called end-diastolic
volume or preload.
o Isovolumetric contraction (2): as ventricle begins to contract, the pressure exceeds that of
the atrium, resulting in closure of atrioventricular and semilunar valves. There is no change in
the overall volume of the ventricle.
o Ejection (3): as the ventricular pressure exceeds pressure in the outflow tract, the semilunar
valves open, allowing blood to leave the ventricle. The aorta/pulmonary valve is also open.
▪ Amount of blood left in ventricle at the end of systole is known as end-systolic
volume (afterload). The amount of blood ejected from ventricle is known as stroke
volume output (EDV – ESV = 80ml/beat).
▪ The ratio of stroke volume output to the end-diastolic volume is called ejection
fraction and usually amounts to around 67%.
o Isovolumetric relaxation (4): the intraventricular pressure falls and atria continue to fill. The
AV-valves, and aortic and pulmonic valves close, causing the atrial pressure to rise again.
o Passive filling (5): pressure in the left ventricle is lower than in the atrium so the AV valves
open and the aorta/pulmonary valve remains
closed. The atria contract and more blood is
pumped into the ventricle (10-20% of filling).
- The main normal heart sounds:
o The first heart sound (systole) results from the
closing of the mitral and tricuspid valves. There is
low pressure and low frequency.
o The second heart sound (diastole) is produced by
closure of the aortic and pulmonic valves. There is
high pressure and high frequency.
, - Pressure in the heart:
o In the left ventricle, the pressure is lower than in the atrium.
o Veins are high-volume but low-pressure, and arteries are high-pressure systems.
o To eject blood into the aorta, you need at least 70mV pressure. To fill, you need to be so
relaxed that your blood pressure is 5mV.
- Differences between the LV and RV?:
o The stroke volume is equal.
o The pressure is higher in the LV than in RV, because the aorta has higher pressure than the
pulmonary artery; we need low pressure for gas exchange.
o RV is thinner than LV.
- Cardiac output:
o Cardiac output (ml/min) = stroke volume (ml) x heart rate (min-1) → the number of litres of
blood your heart pumps in one minute.
o Athletes have a high stroke volume and therefore have a low resting heart rate.
o Adrenaline and thyroid hormones influence the heart rate.
o Increasing stroke volume by either adrenaline or preload/afterload.
▪ Preload is how much blood you fill your atria with, and afterload is blood pressure in
aorta or pulmonary artery; the force needed to open the valves. The afterload
increases when peripheral blood vessels vasoconstrict and decreases when peripheral
blood vessels vasodilate.
▪ Frank-Starling mechanism: if you increase filling pressure, it produces more force
and increases stroke volume.
- Adrenergic stimulation:
o Adrenergic drugs stimulate nerves in your body's sympathetic nervous system (SNS). This
system helps regulate your body's reaction to stress or emergency.
o Activation of β-adrenergic receptor pathway by catecholamines triggers a cascade of events
that increases cAMP, which in turn activates PKA.
o The types of sympathetic or adrenergic receptors are alpha, beta-1, and beta-2. Alpha-
receptors are located in arteries. When the alpha receptor is stimulated by epinephrine, the
arteries constrict. This increases the blood pressure and the blood flow returning to the heart.
- Long term adjustments:
o Long-term high demand for blood: hypertrophy of the ventricles.
o For example: myocardial infarction (same amount of work, less muscle), chronic hypertension.
o But also: exercise, pregnancy.
Lecture 2: Introduction to Heart Failure
- Commotio cordis:
o Commotio cordis is an extremely rare condition that is the consequence of blunt force trauma
to the chest over the heart during a critical time during a heartbeat.
o The sudden focal distortion of the myocardium results in ventricular fibrillation, causing sudden
cardiac arrest in an otherwise structurally normal heart.
o Ventricular fibrillation is a complete loss of coordination of electrical signals.
o Individual cells are contracting but not at the same time, so it doesn’t produce enough pressure
to let blood flow out. This leads to a rapid increase in intracavitary pressure, focal ventricular
depolarization (20ms window), and
amplified dispersion of
repolarization.
o For victims of commotio
cordis, early cardiopulmonary
resuscitation (CPR) and rapid
defibrillation can significantly
increase the chances of survival.
Use an AED to shock the heart
back into normal rhythm.