PBL 3 - MI

• How can we manage symptoms associated with the menopause?

  If symptoms are severe,HRTcan be offered

  This involves taking exogenous oestrogen alone or in combination with progesterone

  
• What are some risks associated with taking HRT?

  - Inc risk of DVT

  
  

  - Inc risk of breast cancer

  
  

  - Potential adverse drug interactions
• How can HRT inc risk of a DVT?

  Oestrogeninc productionofclotting factorsby the liver anddec productionofanticoagulation factorslike protein S and antithrombin --> hypercoagulatory state (1 of Virchow's triangle) --> inc risk of thrombosis - blood flow much slower in veins...

  
• How can HRT inc risk of breast cancer?

  Oestrogenpromotes growthand proliferation of breast tissue inc risk of mutations occurring
• How can menopause inc the risk of CVD such as coronary and peripheral artery disease?

  Dec in oestrogen --> reduced elasticity and vasodilation of bvs --> inc in TPR --> inc bp

  Also

  Dec oestrogen --> inc visceral adipose tissue --> inc levels of adipokines --> insulin resistance --> hyperinsulemia and hyperglycaemia --> vascular dysfunction

  Also

  Dec oestrogen --> inc SNS activity --> inc HR and vasoconstriction --> inc bp

  Hypertension--> inc stress and injury of endothelium --> inc permeability --> infiltration of LDL -->athersclerotic plaque...

  
• What is peripheral artery disease?

  Progressive narrowing and degeneration of thearteriesof theupper and lower extremities, usually as a result of atherosclerosis

  
• How does peripheral artery disease present?

  - Cold periphery

  - Intermittent pain,crampinganddiscomfortin the muscles of thelower extremitiesduring physical activity due to insufficient blood flow= intermittent claudication

  - Numbness and tinglingof lower exteremities due to nerve damage resulting from poor blood flow to the affected limbs

  
• What are some risk factors for developing PAD besides menopause?

  Factors that inc risk of athersclerosis including:

  
  

  Hypertension, smoking, hyperlipidemia, and diabetes --> endothelial injury or dysfunction --> inc permeability

  
  

  *same as coronary artery disease
• How can drugs such as HRT and anti-hypertensives reduce the risk of developing IHD or PAD?

  Inc oestrogen —> inc elasticity and vasodilation of bvs due to reduced SNS activity —> dec TPR —> dec bp

  
  

  Inc oestrogen —> dec visceral AT —> dec level of adipokines —> dec insulin resistance —> reduced risk of hyperglycaemia

  
  

  --> dec endothelial damage --> dec permeability --> dec risk of athersclerosis

  
• Describe the arterial supply of the myocardium

  Supplied by coronary arteries on surface of epicardium BUT most are within myocardium = intramural arterioles

  
• What ensures that the cardiac myocytes have the right amount of oxygen needed to enable the heart to keep pumping during any eventuality?

  Regulation of coronary blood flow towards high myocardial demand
• Why does the myocardium have a high metabolic demand?

  Due to its high ATP demand for its ATPases pumps including its Na+K+ATPases and SERCA, as well as crossbridge cycling for contraction

  
  

  This high ATP demand is satisfied by tightly regulated coronary perfusion (5x higher than other tissues) and high mitochondrial density
• What is the heart's main substrate for ATP production?

  Fatty acids
• When is bloodflow to the myocardium highest?

  Duringdiastole- the intramural coronary arteries become compressed during ventricular systole due to their position within the myocardial wall

  
• Why is coronary bloodflow reduced during ventricular systole?

  As ventricular pressure > arterial pressure

  
  

  This pressure difference is required to eject blood into systemic circulation BUT causes the inramural arterioles to compress due to them being within the myocardial wall

  
  

  Flow is only achieved when ventricular pressure falls below arterial pressure

  
• What physical factors can affect coronary blood flow?

  - Change in diastolic filling time

  
  

  - Change in diastolic arterial pressure

  
  

  - Change in LV end diastolic pressure
• How would a change in diastolic filling time affect coronary blood flow?

  Dec diastolic filling time decreases the time available for blood to flow into the coronary arteries --> dec cornary perfusion
• What could cause diastolic filling time to shorten?

  Several factors can lead to a reduction in diastolic filling time includingtachycardiaand otherarrhythmias

  In tachycardia the heart beats faster than normal, reducing the time available for ventricular relaxation and filling
• How could a change in diastolic arterial pressure affect coronary blood flow?

  If diastolic arterial pressure is decreased then coronary blood flow will decrease as the driving force for coronary perfusion during diastole is also reduced

  
  

  So basically is pressure in the aorta and other vessels is decreased during diastole there is less force to push blood through aortic sinus to fill coronary arteries
• What determines diastolic arterial pressure?

  Pressure in arteries during diastole is determined by vascular resistance, blood volume, and cardiac function
• What could cause diastolic arterial pressure to reduce?

  Several factors can lead to decreased end-diastolic arterial pressure:

  1. Blood volume

  Hypovolemia, from dehydration or bleeding --> reduced preload and venous return --> reduced CO and diastolic pressure

  2. Vessel compliance

  Increased compliance of the aorta and its branches --> lower diastolic pressure

  3. HR

  Tachycardia --> shortened diastole --> less time for heart to relax and refill with blood --> dec arterial diastolic pressure as there is a decrease in the amount of blood being pumped into the arteries during each cycle --> dec coronary perfusion

  4. Medications

  Vasodilators, antihypertensives, and diuretics can lower diastolic arterial pressure by reducing systemic vascular resistance (afterload) or blood volume

  5. Cardiac pathologies

  Conditions like aortic regurgitation can cause backflow during diastole, leading to decreased diastolic volume and pressure

  Other conditions such as a cardiac tamponade can restrict the expansion of the ventricles during diastole --> reduced CO and diastolic pressure
• How could a change in LV end diastolic pressure affect coronary blood flow?

  If end LV diastolic pressure inc, cornary blood flow would decrease- the lower the pressure in the ventricles, the less the intramural arteries are compressed!
• What could cause LV end diastolic pressure to inc? What can be another consequence of this?

  Elevated pressure within the left ventricle at the end of diastole can be caused by:

  - High blood volumee.g. from excessiev fluid retention from kidney failure

  - Volume overload- conditions that increase the volume of blood that fills the LV during diastole e.g. mitral regurgitation

  Mitral regurgitation --> blood leaking into LA during systole --> inc LV filling during diastole as blood from pulmonary veins AND regurgitant blood

  Aortic regurgitation does the same

  
  

  - Left ventricular dysfunction- Impaired contraction of the left ventricle --> inadequate emptying of the ventricle during systole --> elevated LVEDP

  Heart failure with reduced ehection fraction as well as hypertension resulting in LV hypertrophy and stiffness can result in this

  - Aortic stenosis- Narrowing of the aortic valve obstructs blood flow out of the left ventricle, causing pressure to rise within the ventricle during diastole

  The increase in LVEDP can lead to left ventricular dilation and hypertrophy over time, which can eventually result in heart failure if left untreated
• What 4 physiological mechanisms help regulate coronary blood flow?

  - Metabolic hyperaemia (predominant mechanism)

  
  

  - Autoregulation

  
  

  - Catecholamines

  
  

  - NO
• What is metabolic hyperaemia and how does it affect coronary blood flow?

  Inc in perfusion of a tissue due to inc metabolic activity - allows coronary blood flow to match the metabolic demands of the myocardium

  
  

  Inc metabolic activity --> inc conc of vasoactive metabolic metabolites --> vasodilation --> inc blood flow
• What is autoregulation and how does it affect coronary blood flow?

  The ability of blood vessels to maintain blood flow despite changes in perfusion pressure e.g. dec diastolic arterial pressure

  For example, if diastolic arterial pressure inc, bloodflow will initially decrease BUT after about 30-60s the arterioles contract to decrease blood flow and visa versa

  This is due to the prescence ofstretch-sensitive ion channelsin the smooth muscle cells of arterioles - inc stretch --> inc Ca2+ --> vasoconstriction

  This intrinsic response of the coronary vasculature to minute-to-minute changes in perfusion pressure helps to maintain near constant blood flow over a range of perfusion pressures
• How do catecholamines affect coronary blood flow?

  Inc SNS activity --> inc HR and inotropy --> inc CO and metabolic activity of the heart --> inc metabolic hyperaemia --> vasodilation of coronary vessels

  
• How does NO affect coronary blood flow?


  Production of NO --> upstream vasodilation --> inc coronary blood flow
• What inc NO production? How does it result in upstream vasodilation?

  Inc shear stress of the endothelium --> inc activation of eNOS --> inc production of NO from L-arginine

  
  

  NO rapidly diffuses from the endothelium to the neighbouring vascular smooth muscle cells and activates guanylyl cyclase --> inc cGMP --> activation of PKG --> inhibition of MLCK --> less VSMC contraction = vasodilation

  
• What regulates the action of NO?

  Phosphodiesterase (PDE5)- degrades cGMP to GMP

  
• What happens if blood flow to the mycocardium is impaired?

  Reduced coronary blood flow --> reduced O2 supply to the myocardium (doesn't match demand) -->ischaemiaof underperfused area

  = Ischaemic heart disease
• What is ischaemic heart disease?

  A broad term that encompasses various conditions resulting inreduced or obstructed blood flow to the myocardium and subsequent ischaemic injury or death

  Made up of chronic coronary artery disease and acute coronary syndromes, depedening on the level of occlusion

  
• What is the most common cause of IHD?

  Athersclerosis--> formation of an atheroma (raised lesion of athersclerotic plaque) --> narrowing or blockage of the coronary arteries --> reduced blood flow to the myocardium...
• What is an atheroma?


  A cholesterol-rich lesion or plaque that limits blood flow - forms as a result of athersclerosis

  
  

  A.k.a athesclerotic plaque
• Why are the coronary arteries a common site for atheroma?

  As they experience highshear stressdue to the continuous pulsatile flow of blood driven by the contraction and relaxation of the heart --> endothelial injury...
• Describe the formation of an atheroma

  1. Endothelial injury or dysfunction --> inc permability

  2. LDL infiltration into the subendothelial space

  3. Oxidation of LDL to oxLDL by free radicals produced by macrophages (within tunica intima) and the endothelial cells

  4. Prescence of oxLDL --> inflammatory response (macrophages release TNF-a, IL-1 and IL-6 and well as CXCL8) --> upregulation of adhesion molecules and infiltration of monocytes into tunica intima where they become macrophages

  5. Macrophages engulf oxLDL particles through receptor-mediated endocytosis --> formation of foam cells (lipid-laden macrophages)

  The accumulation of foam cells, along with other immune cells and lipids, forms an initial lesion known as afatty streak

  6. These foam cells secrete PIC --> recruitment of more monocytes and proliferation of tunica media's VSMCs into intima and produce extracellular matrix components, such as collagen

  7. The inflammatory environment within the plaque promotes further immune cell infiltration --> inc foam cell production from taken up LDL

  8. Over time, these foam cells begin to die --> expulsion of their lipid contents

  This forms a lipid core which is surrounded by a fibrous cap of collagen =stable atheroma

  Breakdown of the fibrous cap and exposure of the lipids contents --> formatuon of thrombus =unstable atheroma

  
• What are some risk factors for developing IHD?

  (factors which can initiate athersclerosis)Hypertension, smoking, hyperlipidemia, and diabetes --> endothelial injury or dysfunction --> inc permeability
• How can hyperlipidemia result in endothelial dysfunction and initiate atherosclerosis?

  Like smoking and obesity, hyperlipidemia --> chronic low-grade inflammation --> inc permability of the endothelial wall and upregulation of adhesion molecules
• How can diabetes result in endothelial dysfunction and initiate atherosclerosis?

  Hyperglycaemia --> non-enzymatic glycation of proteins and LDL --> formation ofAGE products

  AGE products stick to endotheialRAGE- makes them sticky - LDL sticks

  Type 2 diabetics have increased levels of LDL (bad chlesterol) in the blood due to inc levels of de novo lipogenesis causing inc VLDL production which is then broken into FFAs, LDLs and glycerol
• What is the key factor contributing to the build-up of atherosclerotic plaques?

  Hyperlipidemia, particularly high levels of LDL --> inc endothelial dysfunction and permeability as well as inc substrate for uptake