Angina + CHD Flashcards
Describe cardiac metabolism?
Highly aerobic w/ high oxygen demand. The major energy source is FA oxidation and some oxidation of carbohydrates.
Myocardial contraction uses the majority of ATP, followed by basal resting activity (regulating ion balance), and cardiac relaxation (SERCA2a)
Describe coronary blood flow (CBF)
Most blood supply to the left and right heart is via the left coronary artery, whereas the right coronary artery supplies the SAN and AVN.
Venous blood returns mostly into the right atrium via the coronary sinus and anterior cardiac vein.
and 5% into heart chambers directly via thebesian veins.
Collateral vessels are usually collapsed, except when normal coronary arteries are blocked. When pressure rises, collateral blood vessels open.
How does CBF adjust to meet cardiac oxygen demand?
The autonomic NS has little effect on CBF, rather it is metabolic autoregulation of the CBF which adjusts to meet cardiac oxygen demand.
Most (80%) CBF occurs in diastole, with little occurring in systole (20%).
When HR increases, diastolic time decreases.
However, oxygen extraction from haemoglobin increases and CBF increases due to:
Hyperaemia = metabolic vasodilation of coronary blood vessels.
What is the mechanism of CBF hyperaemia?
What are the metabolites involved?
Increased HR, decreases diastolic time, which should decrease CBF as most CBF occurs during diastole (80%).
However, increased cardiac workload drives increased cardiac metabolism, causing a local release of metabolites and hypoxia (leading to increased oxygen extraction)…
= leading to vasodilation of coronary arteries and an increased CBF.
Adenosine + Potassium
How does adenosine regulate CBF?
Increased cardiac workload leads to an increase in ATP breakdown in cardiac myocytes into AMP.
CD73 converts AMP to adneosine in cardiac myocytes.
Adenosine itself has a negative effect on HR due to A1 receptors (Gi/Go coupled)
However, adenosine is released and in coronary artery smooth muscle…
Adenosine activates A2A receptors (Gs coupled), which stimulates AC, increases cAMP, and triggers vasodilation, leading to increased CBF.
How does potassium regulate CBF?
Increased cardiac workload occurs with (increased HR=increased AP frequency).
This leads to an increased extracellular K+ concentration.
Activation of electrogenic Na+/K+ ATPase in coronary SM = making the coronary smooth muscle more hyperpolarised!
Hyperpolarisation inhibits L-VACCs in coronary smooth muscle, leading to vasodilation and increased CBF.
How does hypoxia lead to CBF autoregulation?
Increased cardiac workload requires more ATP and therefore more O2 consumption + extraction.
Leading to hypoxia = decreased O2, and reduced ATP in coronary smooth muscle.
Reduced ATP causes the opening of ATP-sensitive K+ channels in coronary smooth muscle.
= hyperpolarisation of coronary SM, inhibition of L-VACCs and vasodilation, leading to increased CBF.
How do atheromatous disease lead to angina?
When coronary atherosclerosis causes the partial occlusion of coronary arteries, they are less responsive to metabolic autoregulation when cardiac workload increases.
Therefore, CBF cannot increase to compensate for increased Oxygen demand and causes local myocardial ischaemia.
= symptoms of angina.
What are the different types of angina?
RARE = variant angina.
Local myocardial ischaemia leads to coronary vasospasm at rest (symptoms of angina at rest).
Stable angina = coronary atherosclerosis leads to partial narrowing of the coronary artery. Symptoms during exercise/stress.
Acute Coronary Syndrome (ACS) includes myocardial infarction (MI) and unstable angina.
MI = coronary atherosclerosis leads to coronary thrombosis, so symptoms of angina occur at rest.
Unstable angina = coronary atherosclerosis leads to plaque rupture and platelet aggregation, causing symptoms at rest.
What is angina pectoris/stable angina and itssymptoms?
Atheromatous disease of coronary arteries leading to partial occlusion of coronary arteries.
Symptoms are triggered by exercise/stress and stop soon after resting.
Chest pain, which can be stabbing/sharp pain, which can spread to the left arm, neck, back etc.
Can also include breathlessness, nausea, indigestion symptoms, and fatigue.
What are the therapeutic strategies (no drug names) for treating stable angina?
Reduce oxygen demand by reducing heart rate and cardiac workload - in order to increase diastolic time and reduce O2 demand…
Increase oxygen supply by increasing CBF and regional collateral blood flow through vasodilation.
Prevent the progression of atheromatous disease with lipid-lowering drugs and lifestyle changes.
What are the first and second line treatments for stable angina?
CCB or beta blockers.
= CCBs are negative inotropes, so will reduce cardiac workload, ATP consumption and oxygen demand. (Vascular CCBs also cause vasodilation)
= Beta blockers would lower heart rate.
Second-line treatments (with CCB or Beta-blocker or alone):
Organic nitrate vasodilators.
Nicorandil = K+ channel activator (vasodilation).
Ivabradine = IF current inhibitor.
Ranolazine = inhibitor of cardiac late Na+ current.
What Beta blockers and CCB’s are utilised for stable angina?
Beta-blockers:
Atenolol = B1 selective.
Acetbutolol = B1 selective, partial agonist.
Pindolol = B1 selective, partial agonist.
Propranolol = non-selective Beta antagonist.
LABETALOL = A/B mixed antagonist = A1 antagonism in the periphery would cause vasodilation too.
CCBs:
Dihyopyridines = Nifedipine and Amlodipine = Vascular and cardiac selectivity! = vasodilation.
Diltiazem = relatively cardiac selective, so it CANNOT be used with beta-blockers (otherwise would cause bradycardia, AV block + severely reduced contractility!!!)
Don’t use Verapamil either as cardiac selective!
What are organic nitrate vasodilators? + MOA?
Used as second-line treatments for stable angina:
GTN = is a short-acting vasodilator. = used for stable angina (sublingually) and unstable angina (IV).
Isosorbide dinitrate/mononitrate are longer-acting vasodilators given orally for stable angina.
All three are NO donors but need to be bio-converted first.
NO stimulates GC to produce cGMP, triggering relaxation.
However, prolonged use = development of tolerance.
How do organic nitrates cause vasodilation?
Potent venodilatation is the main effect, with some arteriodilatation.
Causing a decreased cardiac preload, and afterload, reducing cardiac workload and oxygen demand.
Dilation of collateral vessels leads to increased Oxygen supply in the ischaemic myocardium.
