Cardiovascular Disease - Basics
Based on Australian university lecture
- Created by: nCaitlyn
- Created on: 05-11-15 07:45
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- Cardio-vascular Disease
- Obesity
- Large number of factors that lead to obesity, involving individual's lifestyle, physiology, social factors, etc.
- Overweight => 25 while obesity =>30
- Increasing over time, developed males are most obese, while developing males are least
- Corelation between disadvantaged groups and obesity
- Leads to number of complications, i.e. T2 DIABETES
- high glucose demands leads to high insulin production, insulin resistance makes pancreas pump out more inslin until beta cells overworked and stressed to the point where they can no longer produce insulin
- insulin resisatance, metabolic overload and systemic inflammation along with genetic susceptibility of MODY1-5 genes lead to islet amyloidosis and fibrosis
- from cellular inflammatory stress, ER stress, oxidative stress, amyloid stress and stressed islet integreity
- genetics involve development and fnction of beta cells
- insulin resisatance, metabolic overload and systemic inflammation along with genetic susceptibility of MODY1-5 genes lead to islet amyloidosis and fibrosis
- Number of drugs for management and treatment
- metformin - mitochondria, reduces gluconeogenesis, weight loss
- sufonylureas acts on glucose sensing machinery to destabilie K channel and lower insulin threshold (caused hypoglycaemia and weight gain)
- acarbose caused severe flatulence
- thiazolidinediones acts on PPAR-gamma receptors creating partioning effect that increases insulin sensitivity
- SGLT2 inhibitors - prevents glucose reabsorption but increases UTI risk (weight loss)
- Incretin pathway
- GLP1 analogues to stimulate insulin release, and suppresses appetite
- DPP4 inhibitors to prevent inhibition of GLP1
- amylin analogue inhibits glucagon release and suppresses appetite
- bariatric procedures reduce food that can be eaten and therefore directly affects glucose absorption (also increases GLP1 of incretin)
- Incretin pathway
- GLP1 analogues to stimulate insulin release, and suppresses appetite
- DPP4 inhibitors to prevent inhibition of GLP1
- Incretin pathway
- incretin factor - gut secreted hormone that signals to pancreas to produce insulin - this is impaired in diabetes
- diabetic complications
- acute: hyperglycaemic hyperosmolar state (involves dehydration and loss of renal function)
- chronic: micro vs macrovascular diseases
- micro includes retinopathy, nephropathy and neuropathy through four different pathways that transform glucose into other toxic products (fructose, AGE etc)
- macro includes stroke, heart disease and peripheral vascular diseses
- high glucose demands leads to high insulin production, insulin resistance makes pancreas pump out more inslin until beta cells overworked and stressed to the point where they can no longer produce insulin
- Associated with variety of CVD, e.g. hypertension, but cannot lose weight or keep it off due to evolutionary and physiological mechanisms
- Lipid Metabolism
- Obesity
- Large number of factors that lead to obesity, involving individual's lifestyle, physiology, social factors, etc.
- Overweight => 25 while obesity =>30
- Increasing over time, developed males are most obese, while developing males are least
- Corelation between disadvantaged groups and obesity
- Leads to number of complications, i.e. T2 DIABETES
- high glucose demands leads to high insulin production, insulin resistance makes pancreas pump out more inslin until beta cells overworked and stressed to the point where they can no longer produce insulin
- insulin resisatance, metabolic overload and systemic inflammation along with genetic susceptibility of MODY1-5 genes lead to islet amyloidosis and fibrosis
- from cellular inflammatory stress, ER stress, oxidative stress, amyloid stress and stressed islet integreity
- genetics involve development and fnction of beta cells
- insulin resisatance, metabolic overload and systemic inflammation along with genetic susceptibility of MODY1-5 genes lead to islet amyloidosis and fibrosis
- Number of drugs for management and treatment
- metformin - mitochondria, reduces gluconeogenesis, weight loss
- sufonylureas acts on glucose sensing machinery to destabilie K channel and lower insulin threshold (caused hypoglycaemia and weight gain)
- acarbose caused severe flatulence
- thiazolidinediones acts on PPAR-gamma receptors creating partioning effect that increases insulin sensitivity
- SGLT2 inhibitors - prevents glucose reabsorption but increases UTI risk (weight loss)
- amylin analogue inhibits glucagon release and suppresses appetite
- bariatric procedures reduce food that can be eaten and therefore directly affects glucose absorption (also increases GLP1 of incretin)
- incretin factor - gut secreted hormone that signals to pancreas to produce insulin - this is impaired in diabetes
- diabetic complications
- acute: hyperglycaemic hyperosmolar state (involves dehydration and loss of renal function)
- chronic: micro vs macrovascular diseases
- micro includes retinopathy, nephropathy and neuropathy through four different pathways that transform glucose into other toxic products (fructose, AGE etc)
- macro includes stroke, heart disease and peripheral vascular diseses
- high glucose demands leads to high insulin production, insulin resistance makes pancreas pump out more inslin until beta cells overworked and stressed to the point where they can no longer produce insulin
- Associated with variety of CVD, e.g. hypertension, but cannot lose weight or keep it off due to evolutionary and physiological mechanisms
- Lipid Metabolism
- Hypercholesterolemia
- unregulated intake and production of cholesterol with limited efflux - turns cell into foam cell, preventing any further uptake of cholesterol so that there remains high cholesterol in blood
- statins can reduce by impairing HMG CoA reductase, therefore reducing cholesterol biosynthesis, upregulating cholesterol receptors and therefore reduce cholesterol in blood
- familial involves LDL receptor mutation so that there is no uptake of cholesterol
- Alzheimer's Disease
- production of amyloid A(b) proteins occurs on lipid rafts, therefore more lpids, more production
- Tangier's Disease
- Hypercholesterolemia
- unregulated intake and production of cholesterol with limited efflux - turns cell into foam cell, preventing any further uptake of cholesterol so that there remains high cholesterol in blood
- statins can reduce by impairing HMG CoA reductase, therefore reducing cholesterol biosynthesis, upregulating cholesterol receptors and therefore reduce cholesterol in blood
- familial involves LDL receptor mutation so that there is no uptake of cholesterol
- mutations in ABCA1 reduces HDL and impairs reverse cholesterol transport
- CETP inhibitors
- Hypercholesterolemia
- Atherosclerosis
- accumulation of LDL in macrophages, creating foam cells
- accumaltion of foam cells leads to recruitment and modification of SMC functions, and recruitment of ECM
- results in thickening of initima of blood vessels, leading to occlusion - 80% occlusion is when bad stuff happens
- Regular metabolism
- liver releases Apolipoproteins as VLDL
- IDL either returns to liver or becomes further modified (LDL) and taken up by cells
- reverse cholesterol transport involves ABCA1 transporter and conversion of LDL into HDL and return to liver
- triglycerides hydrolysed and bound with cholesterol as intermediate lipoprotein body (IDL)
- IDL either returns to liver or becomes further modified (LDL) and taken up by cells
- reverse cholesterol transport involves ABCA1 transporter and conversion of LDL into HDL and return to liver
- IDL either returns to liver or becomes further modified (LDL) and taken up by cells
- IDL either returns to liver or becomes further modified (LDL) and taken up by cells
- liver releases Apolipoproteins as VLDL
- Hypercholesterolemia
- Lipid Metabolism
- Alzheimer's Disease
- production of amyloid A(b) proteins occurs on lipid rafts, therefore more lpids, more production
- Tangier's Disease
- mutations in ABCA1 reduces HDL and impairs reverse cholesterol transport
- CETP inhibitors
- Atherosclerosis
- accumulation of LDL in macrophages, creating foam cells
- accumaltion of foam cells leads to recruitment and modification of SMC functions, and recruitment of ECM
- results in thickening of initima of blood vessels, leading to occlusion - 80% occlusion is when bad stuff happens
- Regular metabolism
- liver releases Apolipoproteins as VLDL
- triglycerides hydrolysed and bound with cholesterol as intermediate lipoprotein body (IDL)
- triglycerides hydrolysed and bound with cholesterol as intermediate lipoprotein body (IDL)
- liver releases Apolipoproteins as VLDL
- Obesity
- Lipid Metabolism
- Cardio-myopathy
- characterised by dilated, baggy global-shaped heart, as a result of high cycling of compensatory and decompensatory mechanisms for heart failure
- Results from secondary injury related remodelling, neurohormone activation and endothelium damage
- remodelling beings at cellular level when SERCA and PLB are reduced, therefore reducing Ca secretion and altering contractions (also associated with fibrosis
- neurohormone activation includes noradrenlain toxicity to cardaic myocytes, endothelin 1 (apparently involved in vasoconstriction) and TNF induced cardiac damage, natriuretic proteins VAMP/VMP can indicated degree of heart failure
- endothelium damage, associated with ROS
- Can lead to complications like mitral regurgitation, atrial fibrillation, and BBB
- mitral regurgitation involves dilation of the mitral valve annulus, therefore allow blood to flow back into the left ventricle from the aorta
- has impact on atrial shape, and pressure, so there is contractual dyssynchrony between atrium and ventricle
- atrial fibirilliation involves altered and uncoordinated electrical activation originating from atria, loss of signal to AV node, therefore atria can't pump properly and results in dizziness, reduced heart function, etc.
- has additive effects to already failing heart
- has relationship to lack of phospholambin,affecting both atria and ventricl
- BBB = bundle branch block, right is more potent than lett complete blockage of electrical signlal
- mitral regurgitation involves dilation of the mitral valve annulus, therefore allow blood to flow back into the left ventricle from the aorta
- treatments include heart transplant, artificial heart, current drugs and therapies, palliative care
- gene therapy currently being explored, with ideas to improve SERCA and phospholambin production
- delivery through either intra-coronary infusion or V-focus recirculation (more significant effect than intra
- gene therapy currently being explored, with ideas to improve SERCA and phospholambin production
- Chronic Kidney Disease
- strong association with CVD and hospitalisations
- leads to accumulation of serum phosphates, and therefore Ca and vitamin D reduction, ultimately causing secondary hyperparathyrodism
- high phosphate stimulates vascular smooth muscle cells to dedifferentiate into osteoblasts, to produce calcium and cause calcification of blood vessels, therefore impacting endothelial function
- less calcium also results in bone diseases
- less vitamin D impacts immune system responses
- FGF23 adds to detrimental effect by increasing excretion of phosphate into blood stream and reducing vitamin D levels
- high phosphate also has correlation with CVD
- strong association with CVD and hospitalisations
- in western society, phosphate issues partly due to high dietary intake, particularly of inorganic phosphates which are readily broken down and absorbed
- leads to accumulation of serum phosphates, and therefore Ca and vitamin D reduction, ultimately causing secondary hyperparathyrodism
- high phosphate stimulates vascular smooth muscle cells to dedifferentiate into osteoblasts, to produce calcium and cause calcification of blood vessels, therefore impacting endothelial function
- less calcium also results in bone diseases
- less vitamin D impacts immune system responses
- FGF23 adds to detrimental effect by increasing excretion of phosphate into blood stream and reducing vitamin D levels
- therefore, treatment and management focuses around reducing dietary intake of phosphate and perhaps choosing organic phosphates instead ofinorganic
- treatment and management may also include phosphate binders that prevent their absorption by the gut so they pass out intact
- leads to accumulation of serum phosphates, and therefore Ca and vitamin D reduction, ultimately causing secondary hyperparathyrodism
- Obesity
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