Samenvatting Minor - Heart and Blood Vessels

Minor Heart and Blood Vessels week
Week 1-3
1-9 Lectures___________________________________________________________________3
Lecture 1: introduction to the course__________________________________________3
Lecture 2: vascular endothelium_______________________________________________3
2-9 Lectures__________________________________________________________________12
Lecture 1: development of the heart_________________________________________12
Lecture 2: development of the vessels_______________________________________17
Lecture 3: vascular regeneration_____________________________________________20
3-9 Lectures__________________________________________________________________24
Lecture 1: from DNA to protein (and RNA)____________________________________24
Lecture 2: an introduction to the RNAissance_________________________________27
Lecture 3: an introduction to PCR_____________________________________________30
4-9 Lectures__________________________________________________________________31
Lecture 1: Mouse models in CVD_____________________________________________31
Lecture 2: MicroRNA-126 protects against renal ischemia reperfusion injury by
promoting vascular integrity_________________________________________________33
7-9 Lectures__________________________________________________________________36
Lecture 1: introduction case report___________________________________________36
Lecture 2: physiology and control of the cardiovascular system_______________36
8-9 Lectures__________________________________________________________________46
Lecture 1: Electrophysiology of the heart_____________________________________46
Lecture 2: physiology of the heart and vessels: the ECG______________________48
Lecture 3: Narrow QRS-complex tachycardia’s________________________________51
9-9 Lectures__________________________________________________________________54
Lecture 1: Mechanisms of blood pressure regulation__________________________54
Lecture 2: Cardiovascular complications and treatment of hypertension______55
11-9 Lectures_________________________________________________________________57
Lecture 1: experimental approaches to treat hypertension____________________57
Lecture 2: gene therapy for cardiac diseases background_____________________58
Lecture 3: gene therapy for cardiac diseases – (pre) clinical application_______60
14-9 Lectures_________________________________________________________________63
Lecture 1: Primary haemostasis and its disorders_____________________________63
Lecture 2: Secondary haemostasis and fibrinolysis___________________________69
Lecture 3: Disorders of Secondary Hemostasis________________________________72
15-9 Lectures_________________________________________________________________74
Lecture 1: Imaging diagnosis in thrombosis and clinical decision rules________74
Lecture 2: Laboratory diagnosis of Coagulation Disorders_____________________76
16-9 Lectures_________________________________________________________________78
Lecture 1: Prohemostatics____________________________________________________78
Lecture 2: Anticoagulants and profibrinolytic treatment_______________________80
17-9 Lectures_________________________________________________________________82
Lecture 1: HIT, TTP/aHUS, DIC________________________________________________82
Lecture 2: New oral anticoagulants___________________________________________88
Lecture 3: novel hemostatis biologicals_______________________________________89

,1-9 Lectures
Lecture 1: introduction to the course

It is not about the number of genes, but about the size of the genome.
When an organism is more complex, the size of the genome is larger.

80% of the non-coding DNA is transcribed into non-coding RNA. These
facilitate an exponential increase in the complexity of post-transcriptional
regulation.
 Super-regulators. Regulation of cellular response to stress
 Increasingly appreciated in treatments
 Holds great promise for diagnosis and therapy

Alternative splicing: entry and expansion of introns, evolution of the
spliceosome and relaxation of intronic RNA sequences. Helped to make
multicellular organisms.

Non-coding RNA (ncRNA): a functional RNA molecule that is not
translated into a protein.
 MicroRNAs: they do not code for a protein. It functions in RNA
silencing and post-transcriptional regulation of gene expression.
 Long non-coding RNAs: non-protein coding transcripts longer than
200 nucleotides.
 Super regulators: regulation of cellular response to stress
 tRNA, rRNA, etc


Lecture 2: vascular endothelium

Endothelium is the largest organ in our body. It is a single cell deep
monolayer.
 Vasomotor tone
 Selective permeability
 Leukocyte trafficking
 Immunity
 Haemostasis / blood fluidity
 Vascular homeostasis



L-Arginine is transformed
into NO by the NOS
enzyme (derived from the
eNOS gene). This
happens in an endothelial
cell. The NO produced by



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,this endothelial cell is then transported to a smooth muscle cell and
causes relaxation.

NO is given to people with angina pectoris; it dilates the arteries for more
oxygenation during exercise.

Fenestrated capillaries are important in the pituary or kidneys. The liver
has discontinuous capillaries  liver sinusoids.




The shear stress in the venules is very low. The endothelial cells have
therefore a different shape. A venule is important for plasma leakage and
leukocyte trafficking.

Pericytes stabilize capillaries:




Hemangioblast  Endothelial progenitor cell  Artery/Vein/Capillary



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,Capillary in Heart: PDGF receptor attracts myocytes. Differs from brain and
kidney capillaries:




Endothelial cells imput signals:
 Mechanical stress (shear, stress)
 Vasoactive agents (Acetylcholine, Histamine..)
 Inflammatory mediators (TNF, LPS, Thrombin)
 Stress by radicals (UV, radiation, superoxide)
 Hypoxia
 Angiogenic factors (VEGF, Angiopoietins)
 Metabolic stress (Diabetes, Hypercholesterolemia)

Vasomotor tone is caused by:
 Blood pressure (output x vascular resistance)
o Shear stress, neurotransmitters, histamine
 Response to trauma (vasospasm)
 Regulation of tissue perfusion (glucose, O2, heat)
o Insulin

Vasomotor tone is regulated by eNOS gene  shear stress induces eNOS.
By activation of the eNOS gene the endothelial cells will produce more NO.

Macrovasculaire permeability is a selective barrier. Transcellulair
transport is energy dependent, paracellulair transport is not.

Microvascular permeability regulates molecules:
Increasing permeability


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,• Inflammatory mediators (Histamine, thrombin, bradykinin, LPS, TNF-α)
• VEGF (induces fenestra, junctional remodeling and vesiculo- vacuolar
organelles)
• Angiopoietin-2 (junctional remodelling)
Barrier stabilization
• FGF, S1P, Angiopoietin-1(pericyte derived)




Tight junctions are regulated by protein kinases.

By inflammation there is induction of EC genes:
 Leukocyte adhesion molecules (VCAM-1, E-selectin, ICAM-1, P-
selectin)
 Chemokines (MCP-1)  attract more molecules
 Cytokines (IL-6, IL-8)
 Hemostasis (TF, PAI-1, TM lowered)
 Angiogenesis, matrix remodelling (MMPs, plasminogen activators)

The endothelium in hemostasis: An anti-coagulant surface
Anti-coagulant factors
 Antithrombin III binding proteoglycans
 Thrombomodulin
 Tissue factor pathway inhibitor
Inhibition of platelet activation
 Proteoglycan surface
 NO and prostacyclin production
 ADAMTS-13 and ADAMTS-18
Pro-fibrinolytic factors
 Synthesis of plasminogen activators
 Receptors for u-PA, Plg and t-PA


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,Heparin binds to antithrombin III and makes the trombo-inhibitor active.




Hemostasis: a process that causes the bleeding to stop.
1. Vascular spasm
2. Platelet plug formation
a. Weibel-Palade bodies secrete vWF and P-selectin
3. Blood coagulation
a. Fibrinogen  fibrin

Angiogenesis in tissue damage:




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, Lecture 3

Casus
Man, 46 jaar
Presenteert zich met hoofdpijn en wazig zien
Bloeddruk: 210/130 mmHg
Laboratorium: Creatinin 600 umol/L
LDH increased
Platelet count decreased

Serious hypertension witch is damaging the endothelia of the capillaries.
Thrombotic microagiopathy.

Casus
Man, 54 jaar
Presenteert zich met acute pijn op de borst uitstralend naar de kaak
Bloeddruk: 180/100 mmHg
Laboratorium: verhoogd troponine

Because of the increased troponin you can conclude that cardiac tissue is
damaged. Myocardial infarct.
Endothelial dysfunction




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