cardiopulmonary disease Flashcards
Name neural, hormonal, local (things that come from the vessels themselves) in both vasoconstriction and vasodilation
Vasoconstrictor
neural= Sympathetic nerves
hormonal=Local Angiotensin II, Noradrenaline
local= Endothelin-1
Vasodilator
neural=Nitric oxide from nerves
hormonal=Adrenaline
local= Metabolites, Nitric oxide from endothelium
Explain Ventilation Perfusion Matching
Blood ejected from the right side of the heart goes to the lungs to pick up as much oxygen as is possible.
The best transfer of oxygen will occur if the blood is directed to areas where there is the best ventilation and highest oxygen concentration
There is no point in sending lots of blood through areas with poor ventilation and a low oxygen concentration
In order to achieve this vasoconstriction occurs in areas with low oxygen concentration in the lungs
When we get the right amount of blood going to well ventilated high oxygen areas and little going to poorly ventilated low oxygen areas this is called ventilation perfusion matching .
Describe ventilation Perfusion Mismatch
A mismatch occurs when we get insufficient blood going to areas of good ventilation and high oxygen concentration
And/or
We get too much blood going to areas where there is poor ventilation and a low oxygen concentration
Hypoxic Pulmonary Vasoconstriction - Mechanism
Describe what is supposed to happen versus when in hypoxia
This is the most favoured hypotheses:
Located in the cell membrane of the vascular smooth muscle cells in the pulmonary tree is a potassium channel called Kv1.5
Under normal conditions reactive oxygen species (ROS) are produced by the electron transport chain in the mitochondria
These ROS keep the potassium channel open, allowing the exit of potassium ions. This causes hyperpolarisation (cell membrane pd more negative)
This inhibits the calcium channels in the cell membrane.
Smooth muscle cell contraction can be initiated by calcium entry, So less calcium coming in means less contraction
DURING HYPOXIA
A decrease in oxygen will decrease the activity of the electron transport chain
This will decrease ROS production
This will inhibit the potassium channel
This will cause depolarisation (cell membrane pd more positive)
This stimulates the calcium channel
This allows greater calcium entry that then triggers contraction
Pulmonary hypertension
What is this characterised by?
What prevents this in normal conditions?
Haemodynamic abnormality common to a variety of conditions, characterised by increased right ventricular afterload = increased pressure.
pulmonary arterial hypertension developed depends on amount of vascular tree that is compromised.
Normally pulmonary circulation not predisposed to become hypertensive. and is prevented by;
-Low pressure system
-High capacity – large reserve
-Thin walled (not many smooth muscle cells)
Name some respiratory conditions that cause PAH?
PAH, mean pulmonary arterial pressure of 25mmHg at rest/ Normal 15mmHg.
COPD most common cause
Sleep apnoea
Cystic fibrosis
Occupational lung disorders
Interstitial lung disease
Pulmonary embolism - RV failure
High altitude, cor pulmonale
Alveolar hypoventilation, drive, physical impediments
Global HPV
What is normally the problem when you have Pulmonary venous hypertension?
Normally there is mitral valve, LV dysfunction
What are some of the risk factors for pulmonary arterial hypertension disease?
*Definite
Fenfluramine
Toxic rapeseed oil
Aminorex
Dexfenfluramine
*Likely
Ampthetamines
Methamphetamines
*Possible
Cocaine
Phenylpropanolamine
St Johns wort
SSRI
Chemotherapy
*Unlikely
Oral contraceptives
Oestrogen
Cigarette smoking
What are some symptoms of pulmonary arterial hypertension?
Dyspnoea (difficulty in breathing)
Fatigue
Dizziness
Syncope (fainting)
Chest pain
Palpitations
Orthopnoea (difficulty breathing lying down)
Cough
Hoarseness
What is the pathogenesis of pulmonary arterial hypertension?
What does it start with?
What are the 3 things it leads to which will eventually cause pulmonary hypertension
Always starts with chronic lung disease which leads to;
1. hypoxia which will lead to polycythemia (a reaction caused by drop of O2. It is the production of more red blood cells.)
2. hypercapnia (too much CO2)
3. acidosis restricted pulmonary vascular bed
These will lead to pulmonary hypertension and the end product is failure of the right ventricle.
What is Familial PAH
What are the possible effects of these mutations?
What are the transformed growth factors called?
FPAH – autosomal dominant
mutations = 10-20 % chance of PAH
The effects of those mutation cause effects of vascular homeostasis and embryologic development
Transforming growth factors
-Bone morphogenic protein receptor 2 (75%, exon)
-Activin receptor kinase type 1
-Endoglin (EC glycoprotein)
What are the knock on effects of mutations on proteins;
-Bone morphogenic protein receptor 2 (75%, exon)
-Activin receptor kinase type 1
-Endoglin (EC glycoprotein)
They lead to activation of the SMAD proteins, things combine to give SMAD4, which will enter into the nucleus where it controls gene expression in smooth muscle cells and endothelial cells. The Trouble is if you have a mutation you still get the SMADS but they have a different effect. They still move into the nucleus but instead of regulation of gene expression you get unregulated gene expression. This leads to smooth muscle cells changing from being contractile to becoming synthetic which means the start making lots of things such as extracellular matrix. They also change endothelial cells and make them activated.
Postulated pathobiology in pulmonary arterial hypertension
Give one of the hypothesis that says 3 things will lead to plexogenic and thrombotic pulmonary arteriopathy
the combination of genetic predisposition and vascular injury can lead to 3 things
1. coagulation abnormalities (conditions that affect the blood clotting process) leading to thrombosis in situ
2. vascular smooth muscle hypertrophy
3.vasodilator/vasoconstrictor imbalance leading to pulmonary vasoconstriction.
These 3 things will lead to plexogenic and thrombotic pulmonary arteriopathy
Vascular (plexogenic) lesions in pulmonary arterial hypertension.
What does a normal artery look like in comparison to a PAH artery?
describe plexogenic lesions and how they have developed
Normal artery from outside to inside has a
media, interstitium, endothelium
The first thing that happens is hyperplasia of endothelium which means more endothelial cells and hypertrophy of smooth muscle cells so cells grew bigger. The lumen becomes restricted. This increase in hypertrophy (muscularisation) starts to block off small precapillary arteries in the pulmonary tree so this is already beginning to block off chances of ventilation
There is then the movement of inflammatory mediators such as T-cell B- cells and antibodies into the arteries giving inflammation. This combination of medial hypertrophy (growth) and endothelial dysfunction and inflammation will give plexiform lesion.
There is then that imbalance between coagulation and anticoagulation will result in a blood clot.
Thrombosis and PAH
Describe what the vascular endothelial cells have
Describe the sequence of events that cause a blood clot
Vascular endothelial cells have both anti-thrombotic and pro-thrombotic properties (differential expression of proteins and enzymes on the cell membrane)
Damage to the endothelial lining increases their expression of pro-thrombotic properties
In particular a protein called tissue factor is exposed at the cell membrane
When tissue factor comes into contact with clotting factor X (in the circulating blood) this triggers the clotting pathway
Upon contact with tissue factor clotting factor X becomes factor Xa
Factor Xa converts pro-thrombin into thrombin
Thrombin converts soluble fibrinogen into insoluble fibrin
Fibrin forms a meshwork which traps red blood cells
Thrombin also activates platelets
The combination of activated platelets with the fibrin meshwork and trapped red blood cells gives you a clot
