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Samenvatting Heart Failure and Therapy
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PHYSIOLOGY OF THECARDIOVASCULAR SYSTEM
The function of the heart is to pump deoxygenated blood to the lungs and
pump oxygenated blood to all organs in the body. Together with the blood
vessels, it provides adequate perfusion of all organs and tissues of the body.
The contraction and relaxation of the heart determine cardiac output.
Cells need to be stimulated first, before they can contract. This is known as
excitation-contraction coupling. It happens independent of the CNS, the
heart can do it on its own. Pacemaker cells reside in the top-right atrium (SA-
node). The only conduction connection between atria and ventricles
happens via the AV-node. This conduction is slowed down, so the atria and
ventricles don’t contract at the same time. This to ensure proper filling of the
ventricles. AV-node is the slowest point in the conduction system.
Conduction in the heart
The pacemaker cells have a rhythm of themselves. This is because of a special type of action potentials.
The inside of pacemaker cells is more negatively charged than the outside. This results in a negative
membrane potential. The pacemaker cells change this potential by opening and closing the ion channels
(sodium, calcium, potassium). Sodium and calcium always have a higher concentration extracellularly,
whereas the potassium concentration is always higher inside the cell. The initial part is the slow opening
of sodium channels. When the threshold is reached, the calcium channels also open. When the charge of
the cells become positive, the potassium channels open to get the cell back to negativity. All channels are
voltage-gated, so they respond to a change in membrane potential. The sodium channels determine the
rhythm, because it brings cardiomyocytes to the threshold. Ventricular cardiomyocytes don’t have
sodium channels, so they can’t initiate contraction.
The fight-or-flight response increases the heart rate. There goes more blood to the muscles to run away.
This happens under the influence of (nor)adrenaline. In rest, there is an acetylcholine response, which
slows down the heart rate. Noradrenaline causes further opening of sodium channel and they also open
sooner. So, the threshold is reached sooner. Acetylcholine opens potassium channels more, so there is
hyperpolarization. This causes a longer path of contraction, because there is more sodium needed to
reach the threshold. When receiving a donor heart, the heart rate becomes lower. Normally, its 100
beats per minute without influence of the nervous system. When taking the heart out, the nerves are not
able to be reconnected. These people lose influence of parasympathetic nerves, so the heart rate is not
decreased that much. They still have an adrenal gland, so there is release of adrenaline, but this route
works slower.
Sympathetic stimulation (NA) Parasympathetic stimulation (Ach)
The heart rate is determined by the pacemaker cells, through the resting membrane potential of SA node
cells and the velocity of depolarization. =Ventricular cells work in the same way as pacemaker cells, but
the sodium channel is a different one. These only open when there is a change in membrane potential in
a neighboring cell. There is also a longer action potential duration. Action potentials are linked to
contraction via calcium. The SR is filled with calcium. It is used as storage and amplifier system for muscle
, cells. To contract, the only thing necessary is the
increase of calcium in the cytosol. Calcium enters
the cells during an action potential, but this is not
enough. So, there is an amplification system. This
is called calcium-induced calcium release (CICR).
Binding of calcium to the SR causes the stored
calcium to be released from the SR. When the
calcium concentration is high enough, contraction
happens. If the calcium remains in the cell,
contraction keeps happening. For the
cardiomyocytes, calcium is immediately pumped
back to the SR via SERCA, to ensure relaxation.
To contract, the thick and thin filaments of the contractile proteins
interact with each other. The thick filament can pull the thin filament
and the cell shortens. This only happens when myosin (thick filament)
interacts with the actin (thin filament) and only when Ca2+ is present.
When Ca2+ comes in, it binds to proteins on the thin filament, causing a
structural change that moves the tropomyosin filament out of the way.
Now, myosin can bind and hydrolysis of ATP happens. Then, the
myosin is released and ADP is replaced with ATP. The force depends on
the amount of Ca2+ that is released. So, more Ca2+ leads to more force.
But also the Ca2+-sensitivity of the contractile apparatus is important.
Blood flow in the heart
Blood flow through the heart is completely determined by pressure differences. The pressure in the LV is
lower than the pressure is the LA, which allows filling of the ventricle by the atrium. To eject blood into
the aorta, the LV needs a pressure of 80mm. To be filled, the LV needs to have a pressure of about 5 mm.
This is known as the compliance of the ventricle. The phases in between are the isovolumetric phases.
Isovolumetric means that there is no change in volume during this phase, only change in pressure.
• Passive filling → Nothing is contracted and there is no force produced. Most of filling happens
passive. The AV valves are open and the aortic/pulmonary valves are closed.
• Atrial kick → Atria contract and last bit of blood is pushed into ventricles. AV valves (tricuspid on
the right and mitral on the left) are still open and aortic/pulmonary valves still closed.
• Isovolumetric contraction → Ventricles start contracting to build up pressure. This closes the AV
valves (1st heart sound), because the pressure inside the ventricles needs to exceed the pressure
inside the atria. This pressure is not high enough to open valves in aorta. So, all valves are closed
during this phase.
• Ejection → There is enough pressure built up to open valves in aorta. Blood is being ejected as
long as this pressure is high enough.
• Isovolumetric relaxation → The pressure not high enough anymore and aortic valves close (2nd
heart sound). However, the pressure needs to drop below 5 mm for the AV valves to open again
and permit passive filling. This drop in pressure happens during this phase.
Isovolumetric Isovolumetric
Passive filling Atrial kick Ejection
contraction relaxation
The end-diastolic volume is the amount of blood that is in the heart after filling. End-systolic volume is
amount of blood that is left in the heart after ejection. The difference between these is the stroke
volume. It is the amount of blood that is ejected every heartbeat. Normally, this is 120 - 40 = 80 ml. The
,ejection fraction is the stroke volume divided by the end-diastolic volume. This gives the percentage of
blood (from total volume) that has been pumped out from the ventricles during a contraction. Normally,
it is 120 - = 67%. This is used a lot, because it is easier to calculate with and volumes are hard to
measure with imaging. The ejection fraction can also be measured from a 2D image. In cases of heart
failure, the ejection fraction is lower than 45%, which indicates systolic dysfunction.
The cardiac output (ml/min) is the stroke volume times the heart rate. In a healthy person, this is 80 ml x
75 bpm = 6 L/min. During exercise, this can increase up to 100 ml x 150 bpm = 15 L/min. In exercise, both
stroke volume and heart rate are increased. So, the cardiac output can easily be tripled.
Regulation stroke volume
The stroke volume can be increased by adrenaline or the preload and afterload:
• End-diastolic volume (preload) → The preload is the amount of blood that the ventricles are
filled with. If more blood is pumped into the ventricles, more force is created. This stresses the
cardiomyocytes to produce more force. When starting to exercise, the venous return from the
legs increases (muscles in leg work as pump), which increases the stroke volume. When the
venous return changes a lot, the filling pressure increases, which leads to an increased stroke
volume. This is known as the Frank-Starling mechanism.
• Contractility sympathetic system (NA) → Noradrenaline/adrenaline binds to an adrenergic
receptor and activates an intracellular kinase. The amount of calcium that is being released is
increased, so there is more myosin-actin interaction and thus more force. An increased calcium
release and re-uptake increases contractility and relaxation. A decreased calcium sensitivity
accelerates relaxation.
• Peripheral adjustments (afterload) → The afterload is the blood pressure in the aorta or the
pulmonary artery. It is the pressure that is needed to open the valves. The afterload increases
when peripheral vessels vasoconstrict. When they vasodilate, the afterload decreases. When the
afterload is increased, there is a higher pressure needed to open the valve. This leaves less time
for ejection, because it takes longer to build enough pressure. When the afterload is decreased,
there is a lower pressure needed and ejection is achieved sooner.
These are all short-term regulations. A long-term high demand of blood causes hypertrophy of the
ventricles, for example in myocardial infarction (same amount of work, less muscle) or in hypertension
(increased afterload). However, it also happens during exercise or pregnancy, but this is seen as healthy
hypertrophy. Cardiomyocytes can’t divide, so the existing ones need to grow in order to provide higher
amounts of blood.
HYPERTROPHIC
CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) is characterized by sudden
cardiac death. It is a disease of the sarcomere. HCM is an autosomal
dominant disease, but not everyone with the disease gets sick. It
causes asymmetric cardiac hypertrophy. The prevalence of HCM is
1:500. Over 1500 mutations can result in HCM, but MYH7 and MYBPC3
mutations are most common (80%). This mutation causes changes in
histopathology of the heart, such as myocyte hypertrophy and
disarray, fibrosis and small vessel disease. This leads to changes in
physiopathology, such as LVH, diastolic dysfunction, left ventricular
outflow tract (LVOT) obstruction and arrhythmias. Symptoms of HCM are dyspnea, chest pain, syncope,
palpitations and sudden cardiac death.
, Pathophysiology of genotype positive HCM
Hypertrophy occurs in the septum between the right and left ventricle. This
results in diastolic dysfunction, and when it keeps growing, it will also lead to
systolic dysfunction. When this area reaches into the atria, this causes left atria
problems. The aortic channel (left ventricular outflow tract) gets smaller and
blood is difficult to get out. The valve of atria gets sucked into the HCM area and
blood doesn’t flow anymore.
HCM is very hard to predict and there is no preventive/curative therapy.
When someone has the sarcomere mutant protein, there will be inefficient
sarcomere function. In early ages, the mutant protein is balanced out by the
healthy protein, but when the disease progresses, this balance will shift and the mutant protein will
outperform the healthy one. Without any signs of disease, there is already a lower cardiac function.
Every HCM mutation carrier has the same inefficiency as people that have HCM. This sarcomere mutation
is critical to energy deficiency (mutant protein consumes more energy and takes longer to relax), which
leads to a disturbed metabolism and mitochondrial dysfunction. In turn, this leads to diastolic
dysfunction, which causes reduced cardiac perfusion. The gene-specific increase in tension cost was more
severe in MYH7 than in MYBPC3. When the mutated protein was replaced with the wildtype protein, the
tension cost almost went back to normal.
The myocardial efficiency decreases when the disease
advances. With metabolic imaging, the myocardial oxygen
consumption (MVO2) can be measured. Someone is
injected with acetate and a radioactive label it put on it.
The amount of acetate going through the heart and how
much radioactive CO2 is exhaled, can be measured. So, this measures how much oxygen is produced by
the myocardium.
The myocardial external work can also be measured. This is done best with a catheter, but this is rather
invasive. Catheterization results in a pressure-volume loop (left ventricle). The
external work done in the heart is the area of the PV-loop. A less invasive
manner is by calculating the mean arterial pressure (MAP) and the stroke
volume. This is an estimation of external work, by usage of over- and
underestimations (EW = SV x MAP). So, the myocardial efficiency can be
measured with 2 scans (PET for MVO2 and CMR for stroke volume). The MVO2
is the input energy and the myocardial external work is the output energy.
People with HOCM have such a high grade of thickening, that is obstructs the outflow. There is an
increase in use of oxygen in the clinical course, but when the disease gets very severe, it lowers again to
the same level as the control group, because the heart shifts the ratio of fat/glucose as fuel from 70/30 to
60/40, because glucose needs less oxygen to burn. This can’t be used as treatment, because it is toxic to
the liver.
Timing of diagnosis
A problem in diagnosing HCM is that the same diagnostic criteria is used for everyone, but some have a
natural bigger septum than others. The symptoms in women are different from men and cardiovascular
research has been predominantly done with white males. The diagnosis of HCM is confirmed with the
presence of a left ventricular wall thickness of ≥15 mm that is otherwise unexplained by abnormal
loading conditions (e.g., hypertension, valvular, congenital disease) or infiltrative cardiomyopathies.
Females have a smaller heart compared to males, so they take longer to get to the point where they get a
myectomy. So, women do worse because they have to wait longer to receive the appropriate care.
A myectomy (Morrow procedure) is a procedure where the thickened septum is cut-off. This doesn’t cure
the heart, but it can function better. On average, women get these when they are 50, while the male is
average 43 years. However, this allows for more progression in females, so all in measures of diastolic
dysfunction (filling patterns, filling pressure, flowing back of blood), women scored worse and their
septum was bigger. There is also more fibrosis and compliant titin in woman. This gives problems with
scar tissue and it is more difficult for the atrium to fill the ventricle. Female specific risk enhancers for
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