Complete summary of the course Heart Failure and Therapy (AB_1211) from the minor Biomedical Topics in Health Care, given at VU Amsterdam. This summary contains all information needed for the exam, and includes all the material from the lectures. This summary was made during my third year of biomed...
,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
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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
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