Heart Failure and Therapy
summary
1
,Physiology of the Cardiovascular System 3
Diabetes and Microangiopathy 5
General Background on Heart Failure 10
Translational Studies in Cardiomyopathies 13
Gene Regulation in the Cardiovascular System 16
Bench to Bedside Research in Hypertrophic Cardiomyopathy: ENGINE and
ENERGY 20
Animal Models of Cardiomyopathy 23
Pulmonary Arterial Hypertension: Clinical Aspects 26
Inherited Cardiomyopathies: Clinical Perspective 30
The Hoorn Studies: Diabetes and its Vascular Complications 33
Aging 37
Journal Club: Nitrosative Stress Drives HFpEF 41
Proteostasis Derailment as Root Cause of Electropathology in Atrial
Fibrillation: New Targets for Anti-arrhythmic Therapies 44
2
,Physiology of the Cardiovascular System
EXCITATION-CONTRACTION COUPLING
- Function of the heart:
- Pumping deoxygenated blood to the lungs
- Pumping oxygenated blood to all the organs in the body
- Together with blood vessels: providing adequate perfusion of all organs and tissues of the
body
- Contraction and relaxation of the heart determine cardiac output
- How they can be sustained: coordination of contraction and relaxation of 2-3 billion
cardiomyocytes
- Automation of the heart: the heart can beat independent of hormonal or neuronal input
- Automation is caused by spontaneously active pacemaker cells
- The heart has an inherent rate of ~100 bpm, but heart rate is normally reduced to 60-90
bpm by input from the CNS
- Heart rate is determined by:
- Resting membrane potential of SA node cells
- Velocity of depolarization: slope of the pre-potential
- The pre-potential (i.e. starting point) can be regulated, whereas the threshold value
cannot; threshold can be reached earlier with a higher pre-potential
- Action potentials in cardiomyocytes:
- [Na+] and [Ca2+] are high outside and low inside the cell; [K+] is high inside and low
outside the cell
- Relative ion permeability of the cell changes over time, due to the Na-/Ca-/K-
channels being voltage-gated
- 1) Rapid depolarization: fast Na-channels open, leading to in ux of Na+ into the cell
- 2) Plateau: slow Ca-channels open, leading to in ux of Ca2+ into the cell
- 3) Repolarization: slow K-channels open, leading to e ux of K+ out of the cell
- Note: cardiomyocytes only undergo an action potential when a neighboring cell undergoes
an action potential
- The neighboring cell can be a pacemaker cell, or a cell from the conduction system
- Increasing heart rate:
- Stimulation of the sympathetic NS ( ght/ ight)
- Release of noradrenaline can increase the heart rate by opening Na-channels via
intracellular signaling, thereby reducing repolarization
- Decreasing heart rate:
- Stimulation of the parasympathetic NS (rest/digest)
- Release of acetylcholine can decrease the heart rate by opening K-channels, thereby
leading to hyperpolarization (i.e. more negative pre-potential, therefore taking longer to
reach the threshold)
- Excitation-contraction coupling: contraction of the heart following electrical stimulation
of cardiomyocytes
- I.e. action potentials in cardiomyocytes result in contraction of the heart
- Contraction following excitation occurs via Ca2+ cycling (i.e. release and reuptake) in the
heart
- Calcium-induced calcium release (CICR): Ca2+ in ux activates RyR (=receptor) on
the SR membrane, thereby causing Ca2+ release into the cytosol
- SERCA pumps intracellular Ca2+ back into the SR
- Ca2+ and contraction:
- Tropomyosin-troponin is bound to actin, thereby preventing actin-myosin binding
- Once Ca2+ enters the cell, it binds to troponin, thereby inducing a conformational
change that exposes the binding sites for myosin
- Once myosin is bound to actin, contraction occurs via an ATP-mediated process
- Relaxation occurs once the Ca2+ is removed, thereby breaking the actin-myosin bonds
3
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, THE CARDIAC CYCLE
- Conduction system: sinoatrial (SA) node — atrioventricular (AV) node — AV bundle (aka
bundle of His) — bundle branches — Purkinje bers
- The AV node is the only way for the conduction to go through the heart, due to an isolating
layer between the atria and ventricles
- Cardiac cycle:
1. Atrial kick
- Atrial systole (aka contraction); ventricular diastole (aka relaxation)
- AV valves: open
- Aortic/pulmonary valves: closed
2. Isovolumetric contraction
- Ventricular systole; atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: closed
3. Ejection
- Ventricular systole; atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: open
4. Isovolumetric relaxation
- Ventricular and atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: closed
5. Passive lling
- Ventricular and atrial diastole
- AV valves: open
- Aortic/pulmonary valves: closed
- Most time of the cardiac cycle is spent in this phase
- Pressure:
- Passive lling: LV pressure is below LA pressure
- Isovolumetric contraction: all valves are closed to build up pressure inside the ventricles, in
order to exceed arterial (i.e. aortic and pulmonary arterial) pressure, thereby opening the
aortic/pulmonary valves for ejection
- Note: RV pressure is lower than LV pressure, due to the pulmonary arterial pressure
being lower than aortic pressure, therefore a lower pressure di erence has to be
exceeded by the RV
- This is also why the RV has less muscle tissue than the LV
- After ejection, the ventricular pressure falls down below arterial pressure, thereby closing
the aortic/pulmonary valves
- Volume:
- End diastolic volume: blood volume in the LV at the end of diastole
- End systolic volume: blood volume in the LV at the end of systole
- During ejection, the blood volume in the LV quickly decreases
- During passive lling, the blood volume in the LV slowly increases
- Stroke volume = end diastolic volume - end systolic volume
- E.g. SV = 130 - 50 = 80 mL/beat
- Stroke volume has to be the same in the RV vs. the LV; otherwise, pooling of blood occurs
- Input = output
- Ejection fraction = (EDV-ESV / EDV) * 100%
- E.g. EF = (130-) * 100% = ~62%
- Heart failure: EF <45% (systolic dysfunction)
- Cardiac output (mL/min) = stroke volume (mL) * heart rate (/min)
- Increased demand for blood: during exercise, demand for blood in skeletal muscle
increases by 12x, while total cardiac output increases by only 3.5x
- Rest: CO = 80 mL/beat * 63 bpm = 5 L/min
- Exercise (untrained) = CO = 100 mL/beat * 180 bpm = 18 L/min
4
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summary
1
,Physiology of the Cardiovascular System 3
Diabetes and Microangiopathy 5
General Background on Heart Failure 10
Translational Studies in Cardiomyopathies 13
Gene Regulation in the Cardiovascular System 16
Bench to Bedside Research in Hypertrophic Cardiomyopathy: ENGINE and
ENERGY 20
Animal Models of Cardiomyopathy 23
Pulmonary Arterial Hypertension: Clinical Aspects 26
Inherited Cardiomyopathies: Clinical Perspective 30
The Hoorn Studies: Diabetes and its Vascular Complications 33
Aging 37
Journal Club: Nitrosative Stress Drives HFpEF 41
Proteostasis Derailment as Root Cause of Electropathology in Atrial
Fibrillation: New Targets for Anti-arrhythmic Therapies 44
2
,Physiology of the Cardiovascular System
EXCITATION-CONTRACTION COUPLING
- Function of the heart:
- Pumping deoxygenated blood to the lungs
- Pumping oxygenated blood to all the organs in the body
- Together with blood vessels: providing adequate perfusion of all organs and tissues of the
body
- Contraction and relaxation of the heart determine cardiac output
- How they can be sustained: coordination of contraction and relaxation of 2-3 billion
cardiomyocytes
- Automation of the heart: the heart can beat independent of hormonal or neuronal input
- Automation is caused by spontaneously active pacemaker cells
- The heart has an inherent rate of ~100 bpm, but heart rate is normally reduced to 60-90
bpm by input from the CNS
- Heart rate is determined by:
- Resting membrane potential of SA node cells
- Velocity of depolarization: slope of the pre-potential
- The pre-potential (i.e. starting point) can be regulated, whereas the threshold value
cannot; threshold can be reached earlier with a higher pre-potential
- Action potentials in cardiomyocytes:
- [Na+] and [Ca2+] are high outside and low inside the cell; [K+] is high inside and low
outside the cell
- Relative ion permeability of the cell changes over time, due to the Na-/Ca-/K-
channels being voltage-gated
- 1) Rapid depolarization: fast Na-channels open, leading to in ux of Na+ into the cell
- 2) Plateau: slow Ca-channels open, leading to in ux of Ca2+ into the cell
- 3) Repolarization: slow K-channels open, leading to e ux of K+ out of the cell
- Note: cardiomyocytes only undergo an action potential when a neighboring cell undergoes
an action potential
- The neighboring cell can be a pacemaker cell, or a cell from the conduction system
- Increasing heart rate:
- Stimulation of the sympathetic NS ( ght/ ight)
- Release of noradrenaline can increase the heart rate by opening Na-channels via
intracellular signaling, thereby reducing repolarization
- Decreasing heart rate:
- Stimulation of the parasympathetic NS (rest/digest)
- Release of acetylcholine can decrease the heart rate by opening K-channels, thereby
leading to hyperpolarization (i.e. more negative pre-potential, therefore taking longer to
reach the threshold)
- Excitation-contraction coupling: contraction of the heart following electrical stimulation
of cardiomyocytes
- I.e. action potentials in cardiomyocytes result in contraction of the heart
- Contraction following excitation occurs via Ca2+ cycling (i.e. release and reuptake) in the
heart
- Calcium-induced calcium release (CICR): Ca2+ in ux activates RyR (=receptor) on
the SR membrane, thereby causing Ca2+ release into the cytosol
- SERCA pumps intracellular Ca2+ back into the SR
- Ca2+ and contraction:
- Tropomyosin-troponin is bound to actin, thereby preventing actin-myosin binding
- Once Ca2+ enters the cell, it binds to troponin, thereby inducing a conformational
change that exposes the binding sites for myosin
- Once myosin is bound to actin, contraction occurs via an ATP-mediated process
- Relaxation occurs once the Ca2+ is removed, thereby breaking the actin-myosin bonds
3
fi fl fl flffl fl
, THE CARDIAC CYCLE
- Conduction system: sinoatrial (SA) node — atrioventricular (AV) node — AV bundle (aka
bundle of His) — bundle branches — Purkinje bers
- The AV node is the only way for the conduction to go through the heart, due to an isolating
layer between the atria and ventricles
- Cardiac cycle:
1. Atrial kick
- Atrial systole (aka contraction); ventricular diastole (aka relaxation)
- AV valves: open
- Aortic/pulmonary valves: closed
2. Isovolumetric contraction
- Ventricular systole; atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: closed
3. Ejection
- Ventricular systole; atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: open
4. Isovolumetric relaxation
- Ventricular and atrial diastole
- AV valves: closed
- Aortic/pulmonary valves: closed
5. Passive lling
- Ventricular and atrial diastole
- AV valves: open
- Aortic/pulmonary valves: closed
- Most time of the cardiac cycle is spent in this phase
- Pressure:
- Passive lling: LV pressure is below LA pressure
- Isovolumetric contraction: all valves are closed to build up pressure inside the ventricles, in
order to exceed arterial (i.e. aortic and pulmonary arterial) pressure, thereby opening the
aortic/pulmonary valves for ejection
- Note: RV pressure is lower than LV pressure, due to the pulmonary arterial pressure
being lower than aortic pressure, therefore a lower pressure di erence has to be
exceeded by the RV
- This is also why the RV has less muscle tissue than the LV
- After ejection, the ventricular pressure falls down below arterial pressure, thereby closing
the aortic/pulmonary valves
- Volume:
- End diastolic volume: blood volume in the LV at the end of diastole
- End systolic volume: blood volume in the LV at the end of systole
- During ejection, the blood volume in the LV quickly decreases
- During passive lling, the blood volume in the LV slowly increases
- Stroke volume = end diastolic volume - end systolic volume
- E.g. SV = 130 - 50 = 80 mL/beat
- Stroke volume has to be the same in the RV vs. the LV; otherwise, pooling of blood occurs
- Input = output
- Ejection fraction = (EDV-ESV / EDV) * 100%
- E.g. EF = (130-) * 100% = ~62%
- Heart failure: EF <45% (systolic dysfunction)
- Cardiac output (mL/min) = stroke volume (mL) * heart rate (/min)
- Increased demand for blood: during exercise, demand for blood in skeletal muscle
increases by 12x, while total cardiac output increases by only 3.5x
- Rest: CO = 80 mL/beat * 63 bpm = 5 L/min
- Exercise (untrained) = CO = 100 mL/beat * 180 bpm = 18 L/min
4
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