Metabolic, Cardiovascular Disease Flashcards
Atherosclerosis
Disease affecting the innermost layer of large and medium side arteries
Plaques or atheroma which are deposits of fibrous tissues and lipids
Tunica intima
Endothelial cells separated by tight junction, scattered myointimal cells
A basement membrane underlying ECs. Have tight junctions and a thin cytoplasm for gas exchange
Functions of tunica intima
Regulation of blood flow
Barrier function
Blood clotting
Inflammation and immune function
Angiogenesis
Regulate BP
Tunica Media
Smooth muscle cell layers
Regulate flow by contraction and stabilise EC by secreting ECM and activating TGF-B
Elastic lamina layers - assist continuous flow
Tunica externa
Connective tissue containing:
Fibroblasts
Leukocytes
Nerves
Lymphatics
Blood vessels
Arterioles
small branches within tissues
Muscular arteries
e.g coronary arteries
media largely of smooth muscle cells
few elastic fibres
separate internal/external elastic laminae
Large elastic arteries
Aorta and common carotid
Prominent elastic laminae in their media
Internal/external elastic laminae continuous
Exposed to high pulsatile pressures
Elastic recoil assists the continuous flow
Aetiology of atherosclerosis
Still not completely understood
Four major positive risk factors of atherosclerosis
Hyperlipidaemia
Cigarette smoking
Hypertension
Diabetes mellitus
Negative risk factors of atherosclerosis
High levels of circulating HDL
Moderate alcohol consumption
Cardiovascular fitness
Pathogenesis of atherosclerosis
Initiation may involve endothelial cell injury
Progression involves most cellular components of the vessel wall
Atherosclerosis is an example of chronic inflammation
Endothelial cell injury
Caused by haemodynamic force
Chemical insults
Cytokines
May lead to:
ALtered permeability
Adhesion of leukocytes
Activation of thrombosis
Endothelial progenitors are recruited
Leukocyte migration into plaque
Circulating monocytes adhere to endothelial cells and enter the atherosclerotic lesion.
Differentiate into macrophages and ingest large amounts of oxidised lipoproteins and are called foam cells
Die by necrosis or apoptosis and cytoplasmic contents escape into the extracellular space.
Smooth muscle cell activation and migration
Macrophages, platelets and endothelial cells produce growth factors that activate vascular smooth muscle cells.
Smooth muscles migrate and proliferate into the tunica intima through failures of IEL
Lipoprotein entry and oxidation
Oxidised lipoproteins attract monocytes and release cytokines and growth factors. Cause dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells
Aneurysm can be caused by…
Mural thrombosis
Embolization
Wall weakening
Occlusion by thrombus can be caused by…
Plaque rupture
Plaque erosion
Plaque hemorrhage
Mural thrombosis
Embolization
Critical stenosis can be caused by
Progressive plaque growth and ischemia
Consequences of atherosclerosis
Atheroma are often silent
Plaques become unstable/vulnerable
- thin fibrous cap at luminal aspect of plaque
- high lipid content of core
- inflammation
causes symptoms due to
- Rupture
-haemorrhage
-thrombosis
-dissection
Common clinical consequences of atherosclerosis
Myocardial infarction
Peripheral vascular disease
Cerebrovascular disease
Haemostasis
Haemostasis is the physiological response of a blood vessel to injury. Serves to prevent blood loss by plugging leaks in injured vessels. In healthy vessels, haemostasis is off to maintain the blood in a fluid state
Endothelial cells inhibit haemostasis by
Physically insulating tissues from blood
Producing enzymatic and chemical inhibitors of platelet activation
Nitric Oxide (NO)
Prostacyclins
Producing antithrombin on their surface which binds and inactivates the coagulation enzyme thrombin
Haemostasis is accomplished between
Endothelial cells
Platelets
Clotting cascade
Endothelial cells promoting haemostasis by…
Produce endothelin which causes vasoconstriction
Loss of endothelial barrier, activating platelets and coagulation cascade
Produce von Willebrand factor, promoting platelet adhesion to ECM exposed by vessel injury
Produce tissue factor = thromboplastin which activates coagulation cascade
Platelets
Produced by cytoplasmic fragmentation of megakaryocytes in bone marrow
Lifespan of 7 days
Chocolate chip structure - alpha and dense granules that contain chemical mediators of haemostasis
Platelets promote haemostasis by
They become activated by ECM proteins
Secrete chemical signals including Thromboxane A2, vasoactive amines and ADP
Signals promote combination of vasoconstriction and platelet aggregation
Reduced platelets
Purpura (bleeding from skin capillaries)
Major spontaneous haemorrhage
Coagulation cascade promoting haemostasis
Coagulation system is a cascade of proteolytic reactions
Zymogens are activated
Cascade is initiated by several stimuli including tissue factor
Activation of thrombin catalyses fibrinogen -> fibrin monomers
Fibrin polymerise into fibrin strands
Fibrin strands form a meshwork with fused platelets to form a stable plug
Counter-regulatory mechanisms limit haemostatic plug to the site of injury
Thrombosis
Thrombus - Mass formed from blood constituents with the circulation during life
Thrombi are made of fibrin, platelets and entrapped RBC and WBC
May form in arteries or veins
Obstruct lumen, or break off as an embolus
Blood clot
Formed in static blood
Clot is soft, jelly-like, unstructured and composed of a random mixture of blood cells suspended in serum proteins
Virchow’s Triad components
Endothelial injury
Abnormal blood flow
Hypercoagulability
Types of endothelial injury
Atherosclerosis
Hypoxia
Infection/inflammation
Physical damage - crushing veins and haemodynamic stress
Chemical damage
Formation of thrombi
Artificial surfaces can activate the intrinsic coagulation cascade, bind pro-inflammatory complement cascade proteins and bind other proteins that may activate platelets
Vascular implant patients must take anticoagulant drugs
Abnormal blood flow
Turbulence caused by narrowing, aneurysms, infarcted myocardium and abnormal cardiac rhythm
In veins, stasis (pooling of venous blood) causes this
- Failure of RHS of heart
- Immobilisation
- Compressed veins
- Varicose veins
- blood viscosity
Changes to blood cause
Platelets coming into contact with endothelium
Impaired removal of pro-coagulant factors
Impaired delivery of anti-coagulant factors
Directly cause injury or activation of endothelium
Atherosclerotic plaques which are pro-coagulant
Genetic causes of hypercoagulability
Deficiency of antithrombin III
Deficiency protein C
Acquired causes of hypercoagulability
Tissue damage
- acute phase response from liver
- pro inflam/pro coag/ complement
- cytokines causes platelet release
Post-operative
Malignancy
Cigarette smoke
Elevated blood lipids
Oral contraceptives
Mechanisms to limit coagulation
Antithrombins
Proteins C & S - vitamin K dependent
Tissue factor pathway inhibitor
Arterial thrombosis
Formation of thrombosis in arteries
Mural thrombosis
Form along wall of heart or blood vessel and are usually after infarctions
Venous thrombosis
Thrombosis formation in veins which can lead to embolization to lungs
Pulmonary Thromboembolus
Blood clot deep in deep veins of the leg
Emboli
Intravascular mass carried by blood flow from its point of origin to distant site
Types of emboli
Thrombus
Fat
Air
Atheromatous Debris
Bone marrow
Amniotic fluid
Effects of emboli
Stenosis - narrowing of vessels leading to occlusion
Emboli from leg veins will lodge in pulmonary artery (pulmonary embolus). Causes pulmonary infarction, reduced CO, right heart failure, in worst case death
Emboli from left side of heart or aorta will enter the systemic arterial system and may pass to the brain, spleen, kidney, gut, legs, etc
Ischaemia
Inadequate local blood supply to a tissue
Hypoxia
deficiency of oxygen which causes cell injury by reducing aerobic respiration
Anoxia
complete lack of oxygen
Infarction
necrosis of a tissue due to ischaemia
Causes of iscahemia
external occlusion - tumours
internal occlusion - atherosclerosis
Spasm
Capillary blockage
Shock
Increased demand
Venous obstruction
Susceptibility of different cells with increasing sensitivity to ischaemia
Fibroblasts and macrophages
Skeletal muscle
Myocardium
Renal proximal tubular epithelium
Neurons
Ischaemia
If doesn’t kill - reduces ATP and activation of signalling cascades
Ischaemia causes decreased ATP by
Decreased oxidative phosphorylation with down the line leads to ER swelling, cellular swelling, loss of microvilli, blebs, clumping of nuclear chromatin and lipid deposition
Apoptosis vs necrosis
apoptosis requires energy so not in ischemic cells
Neutrophils and ischaemia
Off the scale
Resistance to cell death is enhanced by hypoxia
O2 regulated gene expression
Anoxia causes increased HIF transcription system activity. This increases NFkB activity and pro-survival target RNAs
Effects of ischaemia at tissue level (increasing in damage)
Function defects due to sub-optimal tissue perfusion
- myocardial dysrhythmia
- renal insufficiency
Adaptation, atrophy and shutdown
Apoptosis
Infarction
Factors influencing outcome of vessel occlusion
Size
Speed
Duration
Reperfusion
Metabolic demands
Adequacy
Red infarcts
Haemorrhagic
Occur in tissues with a dual blood supply such as the lung and tissues where blood flow is reestablished after arterial occlusion
White infarcts
Anaemic
Occur in solid tissues supplied by a single artery, often wedge shaped
Usual pattern after infarction
Coagulative necrosis in solid organs
Ischaemic heart disease syndromes
Angina Pectoris
Chronic ischaemic heart disease with heart disease
Myocardial infarction
- Transmural infarction
- Subendocardial infarction
Cerebral ischaemic injury
Timing of infarction
<24 hours - neutrophils develop from viable margins
1-3 days macrophages and lymphocytes appear
Fibroblasts and endothelial cells are then recruited (organisation) to form granulation tissue
6-8 weeks the infarct is organised and replaced by a fibrous scar
Some tissues (e.g liver) may attempt regeneration
Treatment of myocardial infarction
Thrombolytic agents (streptokinase or tissue-type plasminogen activator)
Mechanical re-expansion of the occluded vessel or coronary artery bypass grafting
Problem of further damage by reperfusion injury
Complications of myocardial infarction
Mural thrombus
Dysrhythmias
Heart failure
Reperfusion injury
Effects of reperfusion
Short period of ischaemia followed by reperfusion may result in complete reversal of ischaemic cell injury
Longs periods of ischaemia followed by reperfusion may cause additional damage to cells
Reactive oxygen species
ROS are produced in cells after blood flow is reintroduced after long periods of ischaemia
Accumulation of ROS causes cell injury called oxidative stress
Reperfusion damage due to free radicals (ROS)
Attack double bonds in UFAs -> lipid peroxidation
Oxidase aa side changes -> enzyme damage
React with thymine -> DNA damage
Hypovolemic shock
A sudden decrease in circulating blood volume e.g vessel rupture and extensive haemorrhage
Cardiogenic shock
A dramatic decrease cardiac output e.g heart attack, arrhythmia
Circulating vasoconstrictor mediators and neural factors
Angiotensin II
Catecholamines
Thromboxane
Leukotrienes
Endothelin
a-adrenergic
Circulating vasodilator mediators and neural factors
Prostaglandins
Kinins
B-adrenergic
Systemic arterial hypertension
Systemic arteries
Pulmonary hypertension
Pulmonary vascular circuit
Portal hypertension
Hepatic portal veins and its tributaries
Smoking and damage to endothelial cells
Chemical insult from free radicals and oxidants. Create a pro-oxidative environment.
Superoxide anion reacts with NO to form peroxynitrite & leads to protein nitration. Damaged & dysfunction endothelial cells. Leads to increased deposition of oxidized lipids
Dysfunction endothelial cells
Increase expression of adhesion molecules provoking the development of a procoagulant and inflammatory environment
Diabetes mellitus and damage to endothelial cells
Hyperglycemia results in glycation of amino-acids. Advanced glycation end products
Damages function and structure of proteins. Damages endothelial and smooth muscle cells. Generates oxygen-free radicals and is pro-inflammatory
Perturbed lipid metabolism, elevating circulating free fatty acids increasing chances of atheroma formation
Hypertension BP
Over or equal to 140/90mmHg
Micro-angiopathy in hypertension
Sclerotic damage in small blood vessels of the glomerulus of kidney and the retina of the eye can result in kidney damage and blindness
Hypertension increases risk of
Myocardial infarction
Blindness and kidney disease
Cerebrovascular hemorrhage
Aortic dissection/aneurysm
Left ventricular hypertrophy
Cardiac failure
Left ventricular hypertrophy
Heart has to increase cardiac output. Pathological cardiac hypertrophy is a compensatory response to the increase peripheral vascular resistance in hypertension to minimise the stress on the myocardial left ventricle.
Pathological hypertrophy
Stimuli is the pressure overload in myocardium. Accompanied by the increase in the number of myocardial capillaries
Fibrosis occurs within hypertrophic myocardium.
Increased migration of fibroblasts into the myocardium these become activated into myofibroblasts.
Interstitial fibrosis
Deposition of excessive and inappropriate ECM
Heart failure
Fibrosis causes cardiac dysfunction
Weak contractile function
Impaired electrical conduction
Dilated heart failure
The fibres of the muscular wall become weakened & stretched - not typically directly hypertension related
Coronary artery disease
Ischaemia
Reparative fibrosis
Hypertrophy
Weakened ventricle wall & dilation
Heart failure
Infarction of heart
Detected as cardiac troponin release
Cardiomyocytes cannot be replaced by cell division
Functional tissue is replaced by collagen
Oedema
Abnormal and excessive accumulation of transudate fluid in the interstitial space of tissues
Transudate vs exudate
Clear and acellular vs cloudy, inflammatory cells and protein rich
Left sided heart failure
Decreased emptying of LV
Increased volume in LV and PV
Increased volume in pulmonary capillaries
Movement of fluid from capillaries into the alveoli
Rapid filling of the alveolar spaces = pulmonary oedema
Breathlessness
Right sided failure
Increased pressure in the pulmonary system will eventually lead to right-sided heart failure
Causes back pressure on systemic venous circulation
Observed as venous congestion of visceral organs
Lower legs oedema
Obesity
Increased accumulation of adipose tissue which arises when energy intake exceeds energy expenditure
Subcutaneous fat
Less dangerous health wise
Pear shaped
More fat around buttocks and legs
Greater hip circumference
More common in women
Intra-abdominal fat (visceral fat)
More dangerous health wise
Apple shape
Shows up as fat in gut
Greater waist circumference
More common in men
BMI
Height in m / (body weight in kg) ^2
Doesn’t asses which depot the fat is in
Circumferences and diameters at waist and hips
Give some idea of degree of obesity and relative amount of fat in visceral vs subcutaneous
Skinfold thickness
Idea of amount of subcutaneous fat
BMI for healthy people, overweight and obese
BMI of 18.5 -24.9 = healthy weight
25 - 29.9 = overweight
BMI > 30 = obesity
Hydrostatic weighting
Compares body weight inside and outside a tank of water since fat is lighter than lean tissues. Doesn’t tell you where the fat is located
Impedence
Can measure relative amounts of fat but lacks accuracy by electric currents
Ultrasound
Measure total amount of body fat. Gives only total level of fat
DEXA or CAT
Gives high degrees of accuracy is assessing total %. Downside is the cost.
NMR can identify the presence of biological molecules such as fat
Can identify the presence of biological molecules such as fat in tissues. Can accurately define how much fat is in the body and where it is, downside is cost
Women and men fat
Women have higher percentage of fat and also more lower body fat
Adipocytes in obesity
Consist up to 95% stored lipid as triglycerides
Insulin is an anabolic hormone and one of its major actions is stimulating lipid accumulation
Adrenergic receptors regulate lipid release from adipocytes
Can be over 100um
Specialized in storing triglycerides safely and triglyceride deposition in other cells is highly deleterious
Deleterious effects on glucose metabolism resistance that leads to Type-2 diabetes. Damaging spillover of lipid into other tissues such as liver .
Triglycerides being broken down process
Perilipin controls access of enzymes to lipid droplets
First fatty acid is removed by adipose tissue triglyceride lipase (ATGL)
The second fatty is removed by hormone sensitive lipase (HSL)
The third fatty acid is removed by monoglyceride lipase (MGL)
Adrenergic receptors activate…
Protein kinase A which phosphorylates perilipin and increases access of lipases to lipid droplets. PKA phosphorylates and increases the activity of HSL.
Insulin stimulates lipid accumulation by shutting down HSL
Causes of increase accumulation of fat
Environment factors - less exercise, warm, easily digestible foods, stimulating more insulin release
MC4R gene
Psychological factors
Fetal programming resulting changes to fetus
Illnesses affecting endocrine system such as hypothyroidism which can affect basal metabolic rate and reduces energy expenditure
Side effect of prescribed drugs
Signals regulating appetite
Integrated in hypothalamus and brainstem.
Hormonal signals to hypothalamus
Neuronal and hormonal signals to brain stem
Sensory mechanisms regulate appetite and metabolism
Signals from mouth and nose via nerve cells to modulate food intake and metabolism and prepare digestive system by secreting saliva and stomach acid.
Gut influence on food intake (Ghrelin)
Ghrelin and vagus nerve link stomach to brain to regulate appetite. Ghrelin is high in fasted state and promotes hunger. Falls rapidly after meal
Gut influence on food intake (CKK)
Cholecystokinin (CKK) induces sense of fullness in response to mechanical stretch of stomach and gut
Gut influence on food intake (L and K cells)
Secrete hormones that have powerful effects on appetite and energy expenditure. These include GLP1, GIP and GDF15.
Hormone influence on food intake
Insulin and leptin from fat acts in the hypothalamus to regulate appetite
Leptin
Receptors are mainly found in two sets of neurons in the arcuate nucleus of the hypothalamus
Leptin acts to shut down the production of the appetite promoting hormone AGRP
Alpha-MSH binds to melanocortin 4 receptors (MC4R) in nearby neurons
Together they suppress appeptite
Consequences of obesity
CBF reading allat
Treating obesity
Diet, exercise and behaviour modification
Recombinant leptin in ppl with genetic leptin deficiency
GLP1 agonists reduce appetite and SGLT2 inhibitors increases glucose loss into urine
Gut bypass surgery
How does diabetes arise
Beta cells are destroyed so insulin cant be made (Type 1)
Insulin cant act on its target tissues. Beta cells make more insulin to compensate and loss of insulin action becomes evident
Hypoglycemia
brain starts to malfunction
Hyperglycemia
Glucose spills into the urine so energy is lost.
Glucose is a chemically reactive species so at high blood glucose, proteins in circulation and blood vessels become glycated and are damaged.
How does insulin control blood glucose
Food is absorbed from gut, levels of blood glucose rise above 5mM
Triggers insulin release
Triggers uptake of glucose into liver, muscle and fat. Lowers BGL
If BGL fall below 5mM, glucagon is released
How does insulin leave the pancreas
Portal vein and reaches the 3 main targets which have the highest cell surface levels of the insulin receptor at their cell surface
Glucagon + adrenaline
Stimulate releases of glucose from glycogen
Other way of producing glucose
Certain amino acids can be converted to glucose via gluconeogenesis
Increasing rate of glucose transport into cells
Liver has GLUT4. Insulin causes GLUT4 molecules to move from intracellular sites to plasma membrane It can transport more glucose and during exercise it can be translocated to PM using a different signalling pathway
Impacts of diabetes
Hyperglycemia, damages proteins in the body leading to diabetic complications
Tiredness
Polyuria and polydipsia
Muscle wasting
Ketoacidosis
What happens when there is no insulin?
Wasting of tissues
Acidification of blood
Dangers of high levels of blood glucose
Damage to retina (retinopathy)
Infections and gangrene due to damage to small blood vessels
Neuropathy
Nephropathy
Atherosclerosis
High sugar causing damage
Results in high sorbitol
Causes osmolar imbalance and water accumulates in cells and cell swells and dies. Particularly affects tissues where aldose reductase is expressed such as nerves, retina and kidneys
Causes glycation
HbA1c
When blood glucose are high, glucose is added to proteins by non-enzymatic mechanism. Haemoglobin becomes glycated.
Monitoring HbA1c allows an estimate of longer term exposure to glucose.
HbA1c levels correlate with risk of diabetic complications
Different types of diabetes
Type 1
Type 2
Monogenic (Maturity onset diabetes of the young)
Maternally inherited diabetes and deafness (MIDD)
Gestational diabetes
Malnutrition induced diabetes
Type 1 diabetes
Absence of insulin due to loss of function beta cells
Usually seen in younger subjects
0.3%
HLA genes that control autoimmune response
Auto antibodies against B-cells can be detected in blood
Viral infections, cancer and immune checkpoint inhibitor therapy for cancer can cause type-1 diabetes
Type-2 Diabetes
5-10%
Obesity is major risk factor
Progressive diseases and mainly affects older people
Beta cells lose ability to secrete insulin or die
Do not have islet cell antibodies
What causes Type-2 diabetes
Insulin resistance - becomes less effective
BGL cant be controlled
Obesity is major driver
- release of IL-6 interferes with insulin receptor signalling
- Increases levels of lipids in circulation also interfering with insulin receptor signalling
Variants in TCF7L2 gene links increases risk of b-cell failure
Gestational diabetes
Abnormal regulation of glucose metabolism during pregnancy
Low insulin secretory capacity in women results in increases in circulating glucose levels that reach the definition of diabetes
Symptoms disappear after birth but 60% of these women develop diabetes in later life suggest pre-disposition
Type 2 diabetes drugs - Metformin
Reduces BGL by increasing use of glucose in cells of gut
Type 2 diabetes drugs - Sulfonylurea
Force b-cells to release more insulin to compensate for insulin resistance
Type 2 diabetes drugs - modulate GLP-1 signalling
improve insulin sensitivity
Type 2 diabetes drugs - SGLT2 inhibitors
Block re-uptake of glucose in kidney, so it lost in urine
