3. Atherosclerosis is the leading cause of
Morbidity and Mortality in Western Society
Most Common Factors:
Hypertension
Smoking
Hypercholesterolemia
Diabetes
4. Risk Factors
• Dyslipidemia: When in excess, LDL accumulates in subendothelial space and can start to
damage the intima, initiating and perpetuating development of atherosclerotic lesions.
Treatments slow progression of atherosclerotic plaques.
• Smoking: Tobacco smoking could lead to atherosclerotic disease in several ways, including
enhanced oxidative modification of LDL, decreased circulating HDL levels, endothelial
dysfunction owing to tissue hypoxia and increased oxidant stress, increased platelet
adhesiveness among others.
• Hypertension: Hypertension injures vascular endothelium and may increase the
permeability of the vessel wall to lipoproteins. Antihypertensive results like lipid-reducing
treatments, halting of atherosclerotic progression
• DM: High blood sugar may result in nonenzymatic glycosylation of lipoproteins (which
enhances uptake of cholesterol by scavenger macrophages, as described earlier), or to a
prothrombotic tendency and antifibrinolytic state that is often present. Diabetics frequently
have impaired endothelial function, gauged by the reduced bioavailability of NO and
increased leukocyte adhesion. Managing DM may halt progression
• Elevated CRP: Atherosclerosis is thought to arise from an inflammatory reaction; CRP is a
marker of inflammation.
8. What are the steps of Atherosclerosis?
• Endothelial Activation
• LDL, monocytes, endothelium
• Foam Cells
• Oxidized LDL, macrophages
• Fibrous Cap
• SMCs
• Calcification
• Ulceration
• Thrombosis
9.
10.
11. Name the important molecules involved in
mediating atherosclerosis
• 1. Monocyte attaches to VCAM-1
• 2. MCP-1 is released to attract more monocytes
• 3. Macrophages release MPO to oxidize LDL
• 4. Scavenger receptor on macrophage allows LDL uptake
• 5. Lipid core releases PDGF to stimulate SMCs
• 6. SMCs release MMP, plaque is destabilized
12. What are the important complications of
atherosclerosis?
• Occlusion of vessel
• Thrombus
• Ulceration and hemorrhage
• Atheroembolism
• Narrowing of lumen (stenosis)
• Weakening of wall (aneurysm)
15. Dangers of Complicated Plaques
• Simple atheromas have a fibrous cap that conveys a great deal of
plaque stability. Thus with simple atheromas, patients may present
with arterial stenosis resulting in hypoperfusion but are unlikely to
present with thrombotic or embolic events.
• Complicated atheromas can have an ulcerated cap, which expose
procoagulants in plaque to circulation increasing chance of thrombus
at the site or lead to greater occlusion of vessel. Rupture of a plaque
in complicated atheromas can also lead to hemorrhage. Also
complicated atheromas can have calcifications, which can increase
the fragility of the plaque and thus likelihood of thrombotic events.
18. Mechanism Competitively inhibit HMG-CoA reductase:
(1) Decreases intracellular cholesterol induces SREBP
increases expression of LDL-R
(2) VLDL and IDL are cleared more rapidly due to cross-recognition
with hepatic LDL-R
(3) Hepatic VLDL production falls due to reduced cholesterol
availability reduced LDL and triglycerides
Modify platelets and endothelium (e.g., enhanced NO
synthesis)
Suppress inflammation
Effects Decreases LDL 18-55%
Decreases TG 7-30%
Increases HDL 5-15% (unclear mechanism)
Side Effects Myopathy (increased w/ niacin, fibrates), hepatotoxicity, drug
interactions (CYP3A4 inhibition: macrolides, azoles, HIV
protease inhibitors)
Statins
19. Mechanism Inhibits NPC1L1 at brush border of epithelial cells in
small intestine reduced chylomicron production
less cholesterol delivered to liver compensatory
increase in hepatic LDL-R increased LDL clearance
Effects Decreases LDL 18%
Has additive effect w/ statins and fibrates on LDL
Side Effects Muscle weakness (slightly higher w/ statin),
transaminitis (slightly higher w/ statin)
Ezetimibe
20. Bile Acid Resins
Mechanism (+)-charged amines bind (-)-charged bile acids and prevent
recycling in liver
hepatic cholesterol (FXR, CYP7A ) LDL-R
UNLIKE statins, new cholesterol production is stimulated (b/c
HMG-CoA reductase is not inhibited) VLDL production
serum TGs
Effects Decreases LDL 15-30%
Increases HDL 4%
No change/slight increase in TGs
Side Effects GI, drug interactions (fat-soluble drugs: esp warfarin, digoxin),
absorption of fat-soluble vitamins, pancreatitis, cholesterol
gallstones
*Not absorbed systemically, so no systemic side effects*
21. Niacin (Vitamin B3)
Mechanism Decreases lipolysis in adipose tissue less FAs available for
TG synthesis in liver
Decreases VLDL synthesis, so less LDL
Increases HDL by decreasing hepatic removal of HDL
Effects Decreases LDL 5-25%
Increases HDL 15-30%
Decreases TGs 20-50%
Side Effects Cutaneous flushing (due to prostaglandins; take aspirin), GI
(nausea, PUD), hepatotoxicity, insulin resistance and
hyperglycemia (caution w/ diabetics), gout (raises serum uric
acid levels), myopathy (increases w/ statin)
22. Mechanism Activate PPARα-RXR
(1) Enhanced oxidation of FAs in liver and muscle
decreased TG levels decreased VLDL
(2) Increased expression of LPL
(3) Increased rate of HDL-mediated reverse cholesterol
transport (due to apo AI transcription)
Effects Decreases LDL 5-20%
Increases HDL 10-20%
Decreases TGs 20-50%
*Larger decreases in TGs and increases in HDL than statins.
Side Effects GI (dyspepsia, abdominal pain, diarrhea), cholesterol
gallstones, myopathy (increased w/ liver and kidney
dysfunction; worse w/ statins), augment effects of oral
hypoglycemic drugs (avoid in diabetes)
Fibrates
Gemfibrozil inhibits glucuronidation of most statins, which can increase statin-related
side effects. Fenofibrate does not.
23. Gemofibrizil vs. Fenofibrate
• Drugs that block CYP3A4 slow statin metabolism, increasing the risk
of side effects.
• Gemfibrozil inhibits the glucuronidation of statins and increases the
chances of side effects.
• Choose Fenofibrate in patients taking Statins.
24. Fish Oil (omega-3 FA)
Mechanism Not well defined, ?agonist of PPARα,
?binds enzymes in TG synthesis but
cannot be utilized
Effects Variable effect on LDL
Increases HDL 9%
Decreases TGs 50%
Side
Effects
Minimal, may prolong bleeding time
(caution use w/ NSAIDs, ASA,
warfarin), caution w/ shellfish
hypersensitivity
27. 4 Major Statin Treatment Groups
• Individuals with clinical atherosclerotic cardiovascular disease (ASCVD).
• Tx recommendations:
• High-intensity statin if < 75 years old
• Moderate-intensity statin if > 75 years old (or < 75 y/o and not a candidate for high-intensity)
• Individuals with primary elevations of LDL-C >190 mg/dL.
• Tx recommendation: High-intensity statin (or moderate if not a candidate)
• Individuals w/ diabetes aged 40-75 yrs with LDL-C 70-189 mg/dL and w/o
clinical ASCVD.
• Tx recommendation:
• Estimated 10-year risk of ASCVD < 7.5%: Moderate-intensity statin
• Estimated 10-year risk of ASCVD > 7.5%: High intensity statin
• Individuals w/o clinical ASCVD or diabetes with LDL-C 70-189 mg/dL and
10 year ASCVD risk > 7.5%.
• Tx recommendation: Moderate or high intensity statin
28.
29.
30. HDL… Good or Bad?
• HDL is an important player in Reverse Cholesterol Transport and
removes cholesterol from circulation. Also there is an inverse
correlation between HDL levels and CVD risk- high HDL = low CVD
risk
• Controversy: Two clinical trials aimed to increase HDL failed in phase
III due to adverse off target effects and lack of efficacy. Another
clinical trial using niacin that increases HDL showed no added benefit.
31. Lifestyle Guidelines
• Consume a dietary pattern that emphasizes intake of vegetables, fruits,
and whole grains; includes low-fat dairy products, poultry, fish, legumes,
nontropical vegetable oils, and nuts; and limits intake of sweets, sugar-sweetened
beverages, and red meats.
• Adapt this dietary pattern to appropriate calorie requirements, personal
and cultural food preferences, and nutrition therapy for other medical
conditions (including diabetes).
• Achieve this pattern by following plans such as the DASH dietary pattern,
the US Department of Agriculture (USDA) Food Pattern, or the AHA Diet.
• Aim for a dietary pattern that achieves 5% to 6% of calories from
saturated fat.
• Reduce percentage of calories from saturated fat.
• Reduce percentage of calories from trans fat.
• Engage in aerobic physical activity to reduce LDL-C and non–HDL-C: 3
to 4 sessions per week, lasting on average 40 minutes per session, and
involving moderate- to vigorous- intensity physical activity.
•
32. PCSK9
• PCSK9 is a protein that promotes the degradation of LDL receptors
and decreases the amount of LDL receptors on cell surface. Any
manipulation that will decrease the functionality or availability of
PCSK9 will result in increased LDL receptors on cell surface and thus
lower circulating LDL levels.
• Potential Future RNA interference drug
34. Define mean arterial pressure (MAP) and
describe how changes in cardiac output
(CO), systemic vascular resistance (SVR),
and central venous pressure (CVP) affect
MAP.
• Mean arterial pressure (MAP) - the average arterial pressure during a
single cardiac cycle.
• MAP=(CO x SVR) + CVP
• MAP = PDIAS + PPULSE/3
• MAP is not the arithmetic mean of PDIAS and PSYS since the heart
spends twice as long in diastole than systole under resting conditions
• Increases in the cardiac output (CO), systemic vascular resistance
(SVR), and central venous pressure (SVR) will increase the mean
arterial pressure.
35. Compare the pressures, flows, and
resistances in the pulmonary circulation
with those in the systemic circulation.
• Pressure: Pulmonary < Systemic
• Flow: Pulmonary = Systemic
• Resistance: Pulmonary < Systemic
• Pulmonary v. Systemic- Pressures in the pulmonary circulation are
not as high as the pressures found in the systemic circulation. The
pressure in the pulmonary circulation is 25/10mmHg. The blood
volume output has to be equal on both sides of the heart so as to
ensure that there are no major blood volume changes between the
pulmonary and systemic circulations. Although is there is resistance
within the pulmonary circulation, it is less than the resistance found in
system circulation.
36. Define central venous pressure (CVP)
and how this pressure relates to stroke
volume and cardiac output (CO).
• Central venous pressure (CVP) is the pressure found in the vena
cava near the right atrium.
• Same in same out.
• CVP is a measure of how much blood is going into the heart, which is
equal to how much blood is coming out of the heart. Blood flows from
peripheral venous pool (PVP) to central venous pool (CVP). The
difference in pressure between PVP and CVP is the driving force
pushing blood into the heart. By increasing the difference in pressure
between the two systems, you create a larger flow from PVP to CVP,
which results in more blood going into the right atrium GREATER
STROKE VOLUME AND CARDIAC OUTPUT
37. Explain how each of the following affects
CVP: Blood volume, venous compliance,
gravity, respiration, and muscle
contraction.
• Blood volume: increased blood volume increased venous return increased CO
• Venous compliance: decrease in venous compliance increases central venous
pressure.
• Gravity: Blood pools in LE momentary decrease in venous return/CO before
compensatory mechanisms kick in
• Respiration: during inspiration, the intrapleural pressure decreases. This leads to a
decrease in CVP, increase in pressure gradient, increase in venous return/CO
• Muscle Contraction: muscle contraction in the leg helps facilitate the movement of
blood from the veins in the lower extremities. This mechanism works against gravity to
help increase CVP and increase CO.
38. Define the formula that relates blood flow
through an arteriole to (a) pressure
difference down the length of an arteriole
and (b) resistance to that flow.
• The formula that relates blood flow (F) through an arteriole to
pressure (P) down a length and resistance (R) is
• Q = ΔP/R
39. Explain what key factors are responsible
for the pressure difference and resistance
to flow.
• Resistance depends upon viscosity of blood (n), vessel length (l) and
vessel radius (r)
• R = (n*l)/ (r^4)
• Q = Delta P * (r ^4)/ (n*l)
• Flow is directly related to pressure difference and inversely related to
resistance
40. Explain why the decrease in pressure
across arterioles is much greater than the
pressure drop across other vessel types.
• Resistance is related to radius to the 4th power, vessel length and
viscosity of the blood.
• Resistance is strongly related to the diameter of the vessel lumen: the
smaller the diameter of the vessel lumen, the greater the resistance.
Taken as an individual vessel, the individual capillary would exhibit
greater resistance than the individual arteriole, because the diameter of
the typical capillary lumen is smaller, but, if one looks at the entire
vascular system as a whole, much more of the resistance of the system
is contributed by arterioles than by capillaries
• There are so many more capillaries and with many capillaries in parallel,
that allows collectively a lot of blood flow whereas arterioles tend to be
found individually and they also tend to be much longer than capillaries
(which also increases resistance). Thus, In the larger system, arterioles
are the greater contributor to resistance.
41. Define the formula that relates resistance
to blood flow to (a) length of the arteriole,
(b) viscosity of blood, and (c) internal
radius of the arteriole.
• Resistance = (viscosity * length)/ (radius^4)
• The radius has the greatest effect (note it is to the fourth power), so
vasoconstriction and vasodilation greatly affect resistance.
42. Explain which one of these factors has the
greatest influence on the resistance to
blood flow and what in turn are the
greatest influences on it.
• Radius has greatest effect on flow because it is to the fourth power
• Blood volume and vessel compliance, vasodilation/constriction, and
pathologic sclerosis may affect radius.
43. Predict the relative changes in flow
through an arteriole caused by changes in
arteriole length, arteriolar radius, fluid
viscosity, and pressure difference.
• Using the equations Q = ΔP/R and Resistance = (viscosity *
length)/radius4
• Increase in length → more resistance → less flow
• Increase in radius → less resistance → more flow
• Increase in viscosity → more resistance → less flow
• Increase in pressure difference → more flow
44. Differentiate between the pressures and
forces that influence the caliber of intra-alveolar
capillaries and those that
influence extra-alveolar resistance
vessels.
• Intra-alveolar capillaries are very closely associated with alveoli, which expand
upon inhalation. This causes the capillaries to also stretch, thus decreasing their
diameter. This results in a greater resistance.
• For capillaries, increased lung volume means greater resistance
• Extra-alveolar resistance vessels, on the other hand, are tethered to the pleural
cavity. When the lung volume expands, the connective tissue attaching them to
the pleural cavity pulls on their walls to expand their diameter
• For bigger vessels, decreased lung volume means greater resistance
• There is a sweet spot in the middle where the lung volume causes the resistance
to be the least for both capillaries and the resistance vessels and this is the
“working lung volume.”
45. Explain the effects of gravity on
pulmonary blood flow.
• When standing up, CVP drops since venous blood pools in the legs.
This decreases venous return and cardiac output, also decreasing
pulmonary blood flow. Also when the person is standing up, the blood
flow is lowest at the apex of the lung and highest at the base.
46. Describe how pulmonary blood flow
varies from the base of the lungs to the
apex.
• Due to effects of gravity, the base of the lung receives more blood
than the apex. This leads to poor “V/Q” matching, since ventilation (V)
is not matched to blood flow (Q) at different areas of the lung.
• The V/Q ratio at the top of the lungs is high, while the V/Q ratio at the
base of the lungs is low.
47. Describe the changes in pulmonary
vascular resistance when the pressures in
pulmonary arteries and pulmonary veins
increase.
• Q = ΔP/R;
• If pressure increases, resistance also increases proportionately in
order to keep the flow constant. However, pulmonary circulation has a
much lower resistance because the vessels have thinner walls, have
less smooth muscle, are more distensible and they can do
“recruitment”. Therefore, the pressure can remain low while
maintaining the same flow
48. Describe the roles of recruitment and
distension in decreasing pulmonary
vascular resistance.
• The CO of the right and left sides of the heart are equal. Because
the pressures on the systemic side is so much greater than on the
pulmonary side, the pulmonary system must have much less
resistance. Pulmonary circulation is able to accomplish this lower
resistance with thinner vessel walls, less smooth muscle in the vessel
walls, greater distensibility, and recruitment of non-perfused vessels.
• Recruitment is adding new vessels in parallel circuit to lower the total
resistance, while distension is decreasing the resistance in each
vessel by expanding its diameter
49. Use the Fick Principle to estimate
pulmonary blood flow.
• Assumption: in the steady state, the cardiac output of the L and R
ventricles are equal
• O2 consumption = Blood flow ( Arterial-venous O2 Difference)
50. Explain the mechanism and significance
of hypoxic vasoconstriction.
• When PAO2 is normal (around 100 mmHg), O2 diffuses from the
alveoli into the nearby arteriolar smooth muscle cells, keeping the
arterioles relatively relaxed and dilated. When PAO2 decreases to
below 70 mmHg, the smooth muscle cells can recognize the reduced
amount of O2 coming in from the alveoli. This causes them to
contract, reducing the amount of pulmonary blood flow to that region
• Significance:
• This reduces pulmonary blood flow to poorly ventilated areas.
Pulmonary blood flow is directed away from poorly ventilated regions
of the lung and redirected to other, better oxygenated regions
54. Summarize the mechanism for the
initiation of a blood clot and identify the
essential enzymes involved in this
mechanism.
• Tissue Factor (TF) is usually in the subendothelial membrane on
smooth muscle and collagen. When tissue is injured, it is released,
activating the coagulation cascade. This activates the Extrinsic
Pathway by forming a complex with factor 7a.
55. Predict the effect of vitamin K deficiency
on the coagulation system
• Factors II, VII, IX, and X require gamma carboxylation
from Vitamin K in order to bind Ca on the surface of a clot. Vitamin K is
absorbed in the intestine and metabolized in the liver. Therefore, people
with end-stage liver disease or people who are not adequately absorbing
Vit K in their intestines will see prolongation of the PT. We see a
prolongation of the PT because the Extrinsic Pathway is most affected.
• Vitamin K is also required for activation of anticoagulant proteins C and
S. These proteins are the first to drop in Vit K deficiency, so we often see
a transient pro-thrombotic state before the clotting factors drop.
• (This is especially important to remember with administration of heparin).
56. Explain why a patient with end stage liver
disease may have abnormal coagulation
function.
• Vitamin K is metabolized in the liver. Therefore, people with end
stage liver disease are going to have a Vitamin K deficiency and won’t
be able to activate Factors II, VII, IX, and X.
57. Describe the conversion of fibrinogen to
fibrin and the role of factor XIII in this
reaction.
• Thrombin (IIa) converts fibrinogen (I) into fibrin (Ia), which is
necessary to form a clot. Once fibrinogen gets converted into fibrin, it
creates fibrin bonds and forms a fibrin mesh with crosslinks. That
mesh gets activated and covalently bonds in the presence of factor
XIII (activated by thrombin). Factor XIII stabilizes the clot in normal
hemostasis. Factor XIII does not prolong PT or PTT.
58. Outline the steps of fibrinolysis and
identify the inhibitors of fibrin degradation.
• Tissue plasminogen activator (t-PA) is released from damaged
vessels and cleaves plasminogen to the active enzyme plasmin.
• In the circulation, plasminogen activator inhibitors 1 and 2 rapidly
inactivate t-PA.
• However, t-PA binds to fibrin locally at the site of release, and
converts fibrin-bound plasminogen to plasmin. Plasmin splits both
fibrinogen and fibrin into degradation products (D-dimer), and if this
occurs at the site of a thrombus it produces lysis of the clot matrix.
59. Diagram the formation of the D-dimer and
explain its utility in diagnosis of venous
thromboembolic disease.
• D-dimer: cross-linked regions of fibrin that have been degraded - “you
have a clot, you’ve broken it down, and now you have d-dimer in your
blood” - specific for fibrinolysis (however, not fibrinogenolysis) and
useful for excluding thrombosis
60. Given values for various clotting factor
concentrations, be able to predict which
screening tests of coagulation will be
abnormal.
• PT (prothrombin time): tests function of common and extrinsic
pathway (factors I (Fibrinogen), II (Prothrombin) , V, VII, and X).
Defect in any of these factors => increased PT
• PTT (partial thromboblastin time): tests function of common and
intrinsic pathway (factors I, II, XII, XI, IX, VIII, X). Defect in any of
these factors => increased PTT
• Vitamin K deficiency => increase in both because factors II, VII, IX, X
require Vitamin K, so all pathways are affected).
61. Explain how activated protein C and
antithrombin act as inhibitors of
coagulation.
• Thrombomodulin (TM), which is normally present on the endothelial
cells, binds thrombin.
• Protein C (a vitamin K dependent factor that is normally found in the
blood) binds to the Thrombin/TM complex, and becomes activated as
Activated Protein C.
• Protein S binds activated Protein C (APC), accelerating its activity.
• APC inhibits coagulation by inactivating Factors V and VIII.
63. Define the roles of (a) If Na+-channels, (b)
K+-channels, (c) voltage-gated Ca2+-
channels, and (d) K-Ach channels, in
pacemaker activity of SA cells.
• a) If Na+-channels: Voltage and receptor gated. Contribute to phase 4 pacemaker funny
current (repolarized state to depolarized state) due to a slow inward movement of Na+.
• Note: “diastolic depolarization” refers to pacemaker phase/phase 4 and it represents the non-contracting
time between heartbeats (diastole)
• b) K+ channels: outflux of K+ in phase 3 contributes to repolarization
• c) Voltage-gated Ca2+ channels: influx of Ca2+ during phase 0 contributes to depolarization
• d) K-ACh channels: ACh activated K+ channels are activated by ACh and adenosine and are
G-protein coupled. They slow SA nodal firing upon VAGAL stimulus.
• 1. ACh is released from vagal nerve terminals (parasympathetic innervation of heart) near SA node
• 2. ACh binds to ACh activated K+ channels and K+ channels open
• 3. Resting potential approaches reversal potential for K+, about -90 mV
• 4. As a result, SA cells take longer to reach threshold for firing
64. Describe the effects and mechanisms by
which NE and Ach affect the activity of
these ions channels and therefore HR.
• NE: causes positive chronotropy (increase in heart rate).
• Sympathetic activation of SA node increases slope of phase 4 and lowers
threshold, increasing pacemaker frequency
• NE released by sympathetic adrenergic nerves binds to 훃1 adrenoreceptors (훃
1AR above) coupled to a stimulatory Gs-protein which activates adenylyl cyclase
and increases cAMP
• This leads to an increase in funny current (If) and an earlier opening of Ca2+
channels, both of which increase rate of depolarization
• Ach: causes negative chronotropy (slowing of heart rate).
• Vagal nerve stimulation releases ACh at SA node which decreases slope of phase
4 by inhibiting funny currents, hyperpolarizing the cell, and increasing threshold
voltage required to trigger phase 0.
• ACh binds to M2 receptors and decreases cAMP via inhibitory Gi protein
• ACh also activates K-ACh channels that hyperpolarizes the cell by increasing K+
conductance
65. Define the roles of (a) fast Na+-channels,
(b) K+-channels, (c) voltage-gated Ca2+-
channels, and (d) Na+-Ca2+ exchanger,
in cardiac muscle contraction.
• a) Fast Na+ channels: voltage-gated, open during phase 0, results in rapid
depolarization. The upstrokes of all the ventricular muscle cell APs corresponds to
the QRS complex
• b) K+ channels: Two types; Transient outward type involved in phase 1 initial
repolarization. Delayed rectifier type involved in phase 3 repolarization
• c) Voltage-gated Ca2+ channels: contribute to slow inward, long-lasting current,
plateau phase 2
• d) Na+-Ca2+ exchanger: one mechanism to remove calcium from cells after it
accumulates after action potentials. 3 Na+ ions in exchanged for 1 Ca2+ ion out.
66. Membrane Potentials
• Chemical or Concentration Gradient:
• created by concentration differences of ions
• Electrostatic gradient:
• positive ions will move to negative charge and vice-versa
• Nernst Equation provides information about the membrane potential that
is necessary to oppose the outward movement of a particular ion down
its concentration gradient (the equilibrium potential of particular ion).
• Ek=-61log[K+]inside/[K+]outside=-96 mV
• But the membrane potential is also dependent on the conductance. This
is where the semi-permeable characteristic of plasma membranes
becomes important.
• Em=g'K(EK)+g'Ca(ECa)+g'Na(ENa)
• The equilibrium potential changes very little due to the relatively small
changes in ion concentration. Thus the most important factor determining
membrane potential is the differences in ion conductances.
67. List the major ions involved in establishing
the cardiac membrane potential.
• Na+, K+, and Ca2+ are the major ions that dictate membrane potential.
68. Define equilibrium potential and know its
normal value for K+ and Na+ ions.
• Equilibrium potential: the potential difference across the membrane
required to maintain the concentration gradient across the membrane.
• NOTE: Resting membrane potential for a cardiomyocyte is -90 mV
(quite close to the equilibrium potential for K+). This is due to the fact
that the membrane is much more permeable to K+ in a resting state.
71. Describe the ion channels that contribute
to each phase of the cardiac AP.
• Nodal: Ca+ inflow, K+ Outflow, If current
• AV node: Ca+ inflow, K+ Outflow, If current
• Ventricular muscle: Na+ inflow, K+ outflow, Ca2+ inflow, K+ outflow
• Purkinje cells: Na+ and Ca2+ inflow, K+ outflow, K+ outflow, If current
72.
73.
74. Describe the role of ion channels in AP
generation and the effects of sympathetic
and parasympathetic nerves on AP
generation and HR.
• Ion channels dictate the speed at which signals propagate through the heart. For
instance during phase 0 in nonpacemaker cells, the rate of depolarization
depends on the number of activated fast sodium channels. The more sodium
channels the more rapidly the cell depolarizes. The faster the cell depolarizes,
the faster the adjoining cell will depolarize and thus the more quickly the signal
will propagate through the tissue.
• Therefore conditions that decrease the availability of fast sodium channels (e.g.,
depolarization caused by cellular hypoxia), decreases the rate and magnitude of
phase 0, thereby decreasing conduction velocity within the heart.
• Sympathetic NS act on 훃1-adrenoceptors with norepinephrine to increase
conduction velocity and thus heart rate.
• Parasympathetic NS act on M2 receptors with acetylcholine to decrease
conduction velocity and thus heart rate.
76. Describe the spectrum of ischemic heart
disease and its societal effects.
• Ischemic heart disease is the leading cause of death in the world
among men and women (7 million per year).
• Coronary arteries cannot provide enough perfusion to keep up with
myocardial demand. This results over time due to atherosclerotic
narrowing of the arteries, along with superimposed degrees of plaque
changes, thrombosis, and vasospasm.
• CAD usually presents as an MI, Angina pectoris (most common),
Chronic IHD with heart failure, and sudden cardiac death.
78. What is the most common ECG finding
during episodes of stable and unstable
angina?
• ST Depression
79. Define subendocardial versus transmural
infarction and be able to differentiate the
ECG segment changes
• Subendocardial infarction involves small areas in the subendocardial
wall of the left ventricle, ventricular septum, or papillary muscle ; ST
depression.
• Transmural infarction is associated with atherosclerosis in a major
coronary artery; the infarct extends through the thickness of the heart
muscle, resulting from nearly complete occlusions; ST elevation.
80. Identify ST elevation and pathologic Q
waves and distinguish these findings
associated with the anterior, lateral, or
inferior walls.
81. Coronary Atheromatous Plaque
• Plaque disruption is initiated by the release of substances from
inflammatory cells within the fibrous cap. These weakened caps could
then either rupture spontaneously or be due to a physical force such as
in increase in intraluminal BP.
• Following plaque rupture, a thrombus forms due to the activation of
platelets (subendothelial collagen), the coagulation cascade, and
narrowing of the vascular lumen (vasoconstrictors).
• Dysfunctional endothelium no release of vasodilators such as NO,
which would normally oppose the effects of the vasoconstrictors and
reduce platelet aggregation.
• Destruction of myocytes in acute coronary syndromes quickly impairs
ventricular contraction, which is seen as systolic dysfunction.
• Ischemia/infarction will also impair diastolic relaxation, which reduces left
ventricular compliance and leads to elevated filling pressure.
82.
83. Identify the main difference between
stunned and hibernating myocardium.
• Stunned myocardium occurs when transient ischemia produces a
prolonged (days to weeks) yet reversible period of contractile
dysfunction. This may occur in UA (unstable angina) patients or
surrounding areas of infarction.
• Hibernating myocardium occurs when blood supply is chronically
reduced, resulting in chronic contractile dysfunction. It promptly
improves when adequate perfusion is restored.
84. Diagnostic Tests for CAD
• ECG - look for ST segment elevation/depression and T wave changes
- easy but may not “catch” episodes in outpatients
• Stress test - provocative exercise or pharmacologic
• Nuclear imaging - Te99 or Th201 perfusion studies
• Coronary angiography
• CT
86. Describe the two main determinants of
coronary blood flow.
• The two main determinants of coronary blood flow are (diastolic)
pressure and resistance (governed most strongly by a r^4 term).
87. Differentiate endothelial-dependent
vasodilation from endothelial-independent
vasodilation, and name one compound
that works through each mechanism.
• Endothelial-dependent vasodilation
• NO
• Prostacyclin
• In atherosclerotic vessels, the endothelium is dysfunctional and
fewer of these vasodilating molecules are released.
• Endothelial-independent vasodilation
• Adenosine
• Lactate
• Acetate
• H+
• CO2
89. Name the primary mechanism by which
coronary blood flow is maintained in the
presence of moderate epicardial coronary
artery stenosis.
• Coronary arteries consist of both large, proximal epicardial segments
and smaller, distal resistance vessels (arterioles). Atherosclerosis and
narrowing almost always occur in the proximal vessels while the
arterioles usually stay free of flow-limiting plaques. Thus, blood flow is
maintained by the arterioles that can adjust their tone and dilate in
response to metabolic needs. However, if the artery narrowing
continues, the arterioles will eventually be unable to fully compensate.
90.
91. Correlate the coronary artery that is
occluded to the anatomic distribution of an
acute myocardial infarction.
92.
93. Complications
Ventricular Wall Rupture: 3 to 7 days (associated with macrophages)
The anterolateral wall at the midventricular level is the most common site. Gross photo shows tan yellow, soft
infarct of 3-5 days duration with rupture of the ventricular wall. Due to excessive phagocytosis from infiltrating
macrophages. Often fatal due to cardiac tamponade.
Papillary muscle dysfunction: 2-7 days (associated with macrophages)
Rupture of a papillary muscle may occur following an MI causing mitral regurgitation. More frequently,
postinfarct mitral regurgitation results from ischemic dysfunction of a papillary muscle and underlying
myocardium and later from papillary muscle fibrosis and shortening, or from ventricular dilation.
Pericarditis: 2-3 days (associated with PMNs)
A fibrinous pericarditis usually develops following a transmural infarct is a result of PMN infiltration in reaction
to necrosis and myocardial inflammation.
Mural thrombus: Within 10 days
With any infarct, the combination of a local abnormality in contractility (causing stasis) and endocardial
damage (creating a thrombogenic surface) can foster mural thrombosis and potentially thromboembolism.
Ventricular Aneurysm:
True aneurysms of the ventricular wall are bounded by myocardium that has become scarred. Aneurysms of
the ventricular wall are a late complication (4-8 wks) of large transmural infarcts that experience early
expansion. The thin scar tissue wall of an aneurysm paradoxically bulges during systole. Complications of
ventricular aneurysms include mural thrombus, arrhythmias, and heart failure; rupture of the tough fibrotic wall
is rarely a concern.
94. Describe the indications for coronary
revascularization, including the need for
coronary stenting
• For angina patients, coronary revascularization is pursued if:
• 1) Angina symptoms do not respond to anti-anginal therapy
• 2) Drug therapy results in unacceptable side effects
• 3) Patient is found to have high-risk coronary disease for which
revascularization is known to improve survival
• Persistent angina
• Significant stenosis in 1 or 2 coronary arteries
• Lower-risk patients with stenosis in all 3 CA
95. Limitations of Stenting
• Restenosis:
• Neointimal proliferation (migration of smooth muscle cells + ECM production) can
occur over the stent, restenosing the vessel
• Solution: cover the stent with an anti-proliferative medication that prevents
neointimal proliferation. This decreases restenosis by 50%.
• Unfortunately, this also slows endothelialization of the stent, resulting in a greater
incidence of thrombosis if antiplatelet therapy is discontinued too early.
• Give Prasugrel or Clopidogrel for 12 months for drug eluting stents and 1-2 months
for bare metal stents
• Thrombosis
• Stent material is thrombogenic (promotes formation of clots)
• Solution: Antiplatelet drug therapy
• Give Prasugrel or Clopidogrel for 12 months for drug eluting stents and 1-2 months for
bare metal stents
96. Coronary Bypass Surgery
• More effective long-term relief of angina than PCI
• Improved survival in patients with:
• >50% left main stenosis
• 3 vessel CAD, especially if LV contractile function is impaired
• 2 vessel disease with >75% LAD stenosis
• Diabetes patients with multiple vessels involved
• More complete revascularization than PCI
• Internal Mammary Artery vs. Veins
• Veins are vulnerable to accelerated atherosclerosis (50% are occluded
after 10 years) and lower 10 yr. patency rate (80%)
• Arteries are have higher 10 yr. patency rates (90%) and are more
resistant to atherosclerosis.
• Specifically, the internal mammary artery appears to be fairly resistant
to atherosclerosis
• Limitations: stenosis of the grafted vessel due to atherosclerosis, surgical
risk v benefits, comparison of benefits of CABG with PCI
97.
98. CAD: PCI versus CABG
PCI
• Brief hospitalization
• Less expensive
• Minimally uncomfortable -
percutaneous
• Restenosis-9%
• Stent thrombosis
• Clopidogrel
CABG
• 5-7 days
• More expensive
• Painful
• Usually definitive
• Survival advantage
• 3VD + reduced LVEF
• Left main CAD
99. Exercise Testing
• Positive if chest pain or ECG abnormalities are produced.
• Exercise test considered markedly positive* if:
• 1. Ischemic ECG changes develop in first 3 minutes or persist 5
minutes after exercise stops
• 2. Magnitude of ST segment depressions > 2 mm
• 3. Systolic blood pressure abnormally falls during exercise (due to
ischemia-induced impairment of contractile function)
• 4. High-grade ventricular arrhythmias develop
• 5. Patient cannot exercise for at least 2 minutes because of
cardiopulmonary limitations
100. Coronary Angiography
• Coronary Angiography
• Most direct means of identifying coronary artery stenosis
• Atherosclerotic lesions visualized radiographically following injection
of radiopaque contrast material into artery
• Procedure generally safe, but small risk of complication due to
invasive nature
• Reserved for patients whose angina symptoms do not respond to
pharmacologic therapy, have an unstable presentation, or when
results of noninvasive testing are so abnormal that severe CAD
warranting revascularization is likely.
• “Gold Standard” for CAD diagnosis, however…
• Only provides anatomic information
• Clinical significance of lesions depends on pathophysiologic consequences
• Standard arteriography does not reveal composition of plaque or vulnerability to
rupture
101. Coronary Blood Flow
• In coronary arteries, most of blood flow to the myocardium occurs during diastole.
• During systole: contraction of myocardium compresses ventricular microvasculature
• Blood flow is reduced to the greatest extent within innermost regions of ventricular
wall (subendocardium) where compressive forces are greatest
• More susceptible to injury in ischemic events, CAD, reduced aortic pressure
• Blood flow reaches peak in early diastole – where compressive forces removed
• Aortic pressure during diastole thus is most
crucial for perfusing coronaries
• In left ventricle – mechanical forces affecting coronary flow are greatest
• Due to the higher pressures associated
• Right ventricle and the two atria show some effects of contraction and relaxation
of blood flow
• However, it’s much less apparent than the L ventricle
102. Explain how arterio-venous O2 difference
and O2 extraction in the heart is unique
when compared with other body organs.
• Unlike most tissues, the heart cannot increase oxygen extraction on
demand, because in its basal state it removes almost as much
oxygen as possible from its blood supply.
• So any additional oxygen requirement must be met by an increase in
blood flow.
• Autoregulation of coronary vascular resistance is most important
mediator of this process
• Factors regulating coronary vascular resistance:
• Accumulation of local metabolites
• Endothelium-derived substances
• Neural innervation
103. Describe what is meant by coronary
vascular reserve and the role of collateral
blood vessels.
• Coronary flow reserve is the maximum increase in blood flow through
the coronary arteries above normal resting volume.
• The CFR is reduced in coronary artery disease, i.e. there is reduced
vasodilator reserve
• When O2 delivery to heart limited by disease, collateral vessels arise
through angiogenesis
• Process stimulated by chronic stress (hypoxia, exercise training, etc.)
• Collateralization increases myocardial blood supply by increasing the
number of parallel vessels
• Reduces vascular resistance within myocardium
104. List the four major coronary arteries and
identify the structures they supply.
• Left main coronary artery
• Left anterior descending artery
• Circumflex Artery
• Right main coronary artery
• Left coronary artery supply
• Left ventricle
• Left atrium
• Interventricular septum
• Right Coronary Artery supply
• Right Atrium
• Right ventricle
• SA node
• AV node
• Interventricular septum
106. Identify the factors that regulate
myocardial oxygen consumption and
myocardial oxygen delivery.
• The myocardium has one of the highest O2 extraction ratio of all body organs. In
a normal human being at rest the heart consumes 11 % of total body oxygen but
receives only about 4 % of the cardiac output as coronary blood flow.
•
• Supply of oxygen depends upon:
• · Oxygen content of blood (systemic oxygenation and hemoglobin)
• · Coronary blood flow (perfusion pressure and coronary vascular resistance)
•
• Myocardial oxygen demand depends upon:
• · Wall stress
• · Heart rate
• · Contractility
•
• O2 demand is increased by ↑ HR, ↑ heart contractility, ↑ preload, ↑ afterload, ↑
ejection time.
• O2 supply is reduced by ↑ HR, ↑ preload, ↓ artery diameter (atherosclerosis).
107. Stable Angina
• Angina is an imbalance between coronary blood flow and cardiac O2
consumption leading to ischemia
• Stable angina (classic angina, or angina of effort; most common
form):
• Ischemia is caused by stable coronary artery narrowing (atheromatous plaque)
• Predictable pain on exertion or psychological stress.
• Unchanged in severity, frequency, and duration over weeks to months
109. Diagram the neural pathway involved in
anginal pain.
• The myocardium is innervated by chemosensitive sensory afferent that are
activated by products of hypoxia such as adenosine (a breakdown product of
ATP), acidification (caused by anaerobiosis) and the release of autacoids such as
serotonin and prostaglandins E.
• The peripheral axons of these sensory afferents travel within the sympathetic
chain. Their cell bodies are located in dorsal root ganglia (DRGs) at thoracic level.
The central process contact spinal interneurons located in the dorsal horn of the
spinal cord which in turn activate spino-reticular and spinothalamic pathways. The
spino-reticular pathway activate the vasomotor center and therefore increases
sympathetic tone to the heart potentially causing further ischemic damage by
increasing oxygen demand.
• Activation of the spinothalamic pathway causes anginal pain (except in people
with silent angina). If pain occurs, this causes further increase in SNA via
descending pathways through the medullary vasomotor center.
• Anginal pain is referred to the neck shoulder and arm region because nociceptive
afferents that originate from these regions of the bodies and cardiac nociceptors
converge on the same spino-thalamic neurons.
110. Recall the mechanism whereby coronary
blood flow is coupled to myocardial
workload.
• Increased contractility/HR increases ATP breakdown leading to
increased local concentration of adenosine, stimulating vasodilation
and increased coronary flow to meet the O2 demands with the
increased myocardial workload.
111. Explain why pain, anxiety or exercise can
exacerbate cardiac ischemia.
• Pain, anxiety or exercise cause release of chemical mediators: NE, 5-HT that
activate the sympathetic nervous system.
• (1) The increase in sympathetic activity (β1 receptors) and the decrease in parasympathetic
activity produce an increase in HR.
• (2) The increase in sympathetic activity (β1 receptors) produces an increase in contractility and a
resulting increase in SV.
• Together, the increases in heart rate and stroke volume produce an increase in
cardiac output.
• This leads increased O2 demand will exacerbate cardiac ischemia.
• Furthermore, pts with cardiac ischemia often have narrowed coronary arteries
(atherosclerosis) so they have dysfunctional endothelium (less
vasodilatory/antithrombogenic properties) along with increased resistance so that
it is hard for the heart to keep up enough of an O2 supply with the increased
workload.
• Stimulation of alpha receptors by catecholemines released during stress, exercise
and pain can lead to vasconstriction and without enough local metabolites like
endothelial NO to offset that with vasodilatiion (dysfunctional endothelium) one
could see less sympatholysis.
112. Identify the main goals of therapy for
patients with stable angina.
• Decrease frequency of anginal attacks
• Prevent acute coronary syndromes
• Prolong survival
113. MOA of nitroglycerin and isosorbide
mononitrate on vascular smooth muscle
and identify which blood vessels are
preferentially targeted by low doses
• Nitroglycerine is converted to Nitric oxide which activates guanylate cyclase leading to
an increase in cGMP in smooth muscle. This leads to dephosphorylation of Myosin
Light Chains which regulate the contractile state of smooth muscle and lead to
vasodilation.
• Nitroglycerin has a fast onset (2-5 minutes) with sublingual administration and a short
duration (30 min). Low dose – relaxation of great veins
• It is used for acute attacks of angina
• Isosorbide Mononitrate: Organic nitrate that causes vasodilation through enzymatic
conversion of sulfhydryl groups to nitric oxide
• Slower onset, longer duration
• Used for chronic treatment
114. Explain why nitroglycerin must be
administered sublingually while isosorbide
dinitrate or mononitrate is given orally.
• Rapid onset of action and are useful as prophylaxis
• Sublingual admin leads to fast absorption directly into the systemic
circulation, thereby avoiding delay inherent to intestinal absorption
• First pass metabolism (degradation) by the liver → nitroglycerin cannot
be taken orally because it would be entirely degraded by the liver
• Very lipid soluble compound that is well absorbed by the mucosa of the
tongue and mouth
• Spray more stable → in this formulation it stays active for years while
tablets take up moisture which degrades the nitroglycerine within a
month
115. Explain why NO donors and PDE5
inhibitors (e.g. sildenalfil) should not be
co-administered.
• The combination of a PDE5 inhibitor (sildenafil (Viagra), etc) and
nitrates extreme hypotension
• If PDE5 is inhibited cGMP cannot be converted to GMP, so much
more cGMP is produced leading to extreme vasodilation
116. Nitrate tolerance
• The main limitation to chronic nitrate therapy is the development of
drug tolerance
• Overcome this with:
• 1) a nitrate-free interval for a few hrs (8-12 hrs each day)
• 2) add drugs that reduce the requirement for nitrates (such as B-blockers
or Ca++ channel blockers)
• Mechanism theories include:
• 1) Sulfhydryl hypothesis depletion of SH groups need for
conversion to NO
• 2) Neurohormonal hypothesis reflex increase in vasoconstrictor
hormones (NE, tissue RAS, endothelin)
• 3) Free radical hypothesis free radicals destroy NO
117. Explain the rationale for the potential
benefit of combining a beta-blocker with a
nitrate in treating stable angina.
118. Statins
Mechanism Competitively inhibit HMG-CoA reductase:
(1) Decreases intracellular cholesterol induces SREBP
increases expression of LDL-R
(2) VLDL and IDL are cleared more rapidly due to cross-recognition
with hepatic LDL-R
(3) Hepatic VLDL production falls due to reduced cholesterol
availability reduced LDL and triglycerides
Modify platelets and endothelium (e.g., enhanced NO
synthesis)
Suppress inflammation
Effects Decreases LDL 18-55%
Decreases TG 7-30%
Increases HDL 5-15% (unclear mechanism)
Side Effects Myopathy (increased w/ niacin, fibrates), hepatotoxicity, drug
interactions (CYP3A4 inhibition: macrolides, azoles, HIV
protease inhibitors)
119. Niacin
Mechanism Decreases lipolysis in adipose tissue less FAs available for
TG synthesis in liver
Decreases VLDL synthesis, so less LDL
Increases HDL by decreasing hepatic removal of HDL
Effects Decreases LDL 5-25%
Increases HDL 15-30%
Decreases TGs 20-50%
Side Effects Cutaneous flushing (due to prostaglandins; take aspirin), GI
(nausea, PUD), hepatotoxicity, insulin resistance and
hyperglycemia (caution w/ diabetics), gout (raises serum uric
acid levels), myopathy (increases w/ statin)
120. Fibrates
Mechanism Activate PPARα-RXR
(1) Enhanced oxidation of FAs in liver and muscle
decreased TG levels decreased VLDL
(2) Increased expression of LPL
(3) Increased rate of HDL-mediated reverse cholesterol
transport (due to apo AI transcription)
Effects Decreases LDL 5-20%
Increases HDL 10-20%
Decreases TGs 20-50%
*Larger decreases in TGs and increases in HDL than statins.
Side Effects GI (dyspepsia, abdominal pain, diarrhea), cholesterol
gallstones, myopathy (increased w/ liver and kidney
dysfunction; worse w/ statins), augment effects of oral
hypoglycemic drugs (avoid in diabetes)
121. List the major side effects of antianginal
medications, including which drugs when
combined have an increased risk of SEs
• Nitrates: headache, lightheadedness, hypoTN, palpitations, nausea, dizziness, reflex sinus
tachycardia (BP decrease causes heart to compensate and beat faster).
• DO NOT ADMINISTER with PDE5 inhibitors.
• B-blockers: bronchospasm AVOID in pts with COPD, reduced HR contraindicated in pts with
bradycardia, fatigue, sexual dysfunction, may worsen diabetic control and can mask tachycardia and
other signs that indicate hypoglycemia *** Diabetic pts
• Calcium channel blockers: associated with an increased incidence of MI and mortality, Headache,
flushing, decreased LV contraction (esp with Verapamil and Diltiazem) , pedal edema (esp with
Nifedipine and Diltiazem), constipation (esp with Verapamil)
• Combining a B-blocker with a nondihydropyridine Ca++ channel blocker (Verapamil or Diltiazem):
negative chronotropic (“changing HR”) effect that can cause excessive bradycardia, combined with
a negative inotropic effect, could precipitate heart failure in pts with LV contractile dysfunction
• Ranolazine: dizziness, headache, constipation, nausea
122. Describe the mechanism of Prinzmetal
(variant) angina
• Prinzmetal’s (variant) angina is ischemia due to focal coronary artery
spasm.
• Mechanism: Patient has intense vasospasm. → Reduced coronary
oxygen supply → Prinzmetal’s Angina.
• The cause of the vasospasm is unknown, but it is thought that it may be
caused by increased sympathetic activity + endothelial dysfunction.
• Patient presentation: Typical anginal discomfort, usually at rest rather
than upon exertion. The pain is often very severe.
• ECG findings: ST segment elevations during the intense vasospasm. ST
segment elevation signifies injury.
• Good antianginal drugs for this type of angina: Verapamil & Diltiazem
• Beta Blockers are contraindicated as they may worsen the condition
123. Describe the typical ECG findings during
an episode of stable angina.
• ST segment and T wave changes
• Transient horizontal or downsloping ST segment
depressions
• T wave flattening or inversions
• Occasionally ST segment elevations are seen,
suggesting more severe transmural myocardial
ischemia
• In contrast to an acute MI, ST deviations
caused by angina quickly normalize with
resolution of the patient’s symptoms.
124. Describe the findings of a positive
exercise ECG treadmill stress test.
• The test is considered positive if the patient’s typical chest discomfort
is reproduced or if ECG abnormalities consistent with ischemia
develop (ex: >1 mm horizontal or downsloping ST segment
depressions)
• The test is considered markedly positive if one or more of the
following signs of ischemic heart disease occur:
• Ischemic ECG changes develop in the first 3 minutes of exercise OR persist 5
minutes after exercise has stopped
• The magnitude of ST segment depressions is >2 mm
• The systolic blood pressure abnormally falls during exercise (i.e. resulting from
ischemia induced impairment of contractile function)
• High grade ventricular arrhythmias develop
• The patient cannot exercise for at least 2 minutes because of cardiopulmonary
limitations
125. Recall the effect of a 60% epicardial
coronary artery stenosis on resting
coronary blood flow versus its effect on
maximal coronary flow.
• This is pointing to the fact that if
an epicardial coronary artery is
stenosed to a level of 60%, this
will limit the maximum amount
of blood that can flow through a
coronary artery (and therefore
may lead to angina when you
are exercising or exerting
yourself), but it will have no
effect on the resting coronary
blood flow, which is much less.
126. Explain why nuclear cardiac imaging and
echocardiography are sometimes
performed in conjunction with exercise
stress testing.
• Some patients have baseline ST segment abnormalities or T wave
abnormalities (particularly LVH with strain). For these patients, the
ECG findings provided by the exercise stress test aren’t very useful.
• Also, the exercise stress test can yield ambiguous results - this is
especially of concern when there is a high clinical suspicion of
ischemic heart disease.
• Exercise stress testing in conjunction with nuclear cardiac imaging or
echocardiography increases sensitivity and specificity.
127. Explain the most common reasons that
percutaneous revascularization (PCI) is
offered to patients with stable angina.
• Many patients with stable angina can be managed with
pharmacologic therapy alone.
• PCI is offered to patients with stable angina if:
• The patient’s symptoms of angina do not respond adequately to
antianginal drug therapy
• Unacceptable side effects of medications occur
• The patient has high risk coronary disease for which
revascularization is known to improve survival
128. Name one criterion by which patients are
selected for CABG instead of PCI.
• CABG is good for:
• >50% left main stenosis
• 3 vessel CAD, especially if LV contractile function is impaired
• 2 vessel disease with >75% LAD stenosis
• Diabetes patients with multiple vessels involved
• PCI is good for:
• Patients with persistent episodes of angina and significant stenoses in one to two
coronary arteries
• Some lower risk patients with three-vessel disease
130. Describe the pathophysiologic events that
change a stable atherosclerotic plaque
into the unstable plaque of ACS
• Increasing size and protrusion of lipid core mechanical stress
focused on plaque border
• Local accumulation of foam cells and T lymphocytes releasing MMPs
increases degradation of ECM.
• Thin fibrous cap vulnerability to rupture
• Rupture of plaque exposure of procoagulants thrombosis
• Causes occlusion and infarction
• Endothelial dysfunction prevents release of endogenous vasodilators
(NO, prostacyclin) which also normally inhibit platelets, thus impairing
protective mechanisms against thrombosis.
131. Compare and contrast the
pathophysiologic and clinical features of
unstable angina, non-STEMI and STEMI.
133. Describe the functional alterations
impairing contractility and compliance.
• Systolic dysfunction - destruction of functional myocardial cells
leading to impaired ventricular contraction
• Hypokinetic: a localized region of reduced contraction
• Akinetic - a segment that does not contract at all
• Dyskinetic - a segment that bulges outward during contraction of the remaining
functional portions of the ventricle
• Diastolic dysfunction - compromise of the left ventricle when
ischemia/infarction causes elevated ventricular filling pressures
134. Define and distinguish the terms “stunned
myocardium”, “ischemic preconditioning”
and “infarct expansion”
• Stunned myocardium - prolonged but reversible period of contractile dysfunction
after a period of transient ischemia. The tissue prolongs systolic dysfunction even
after restoration of blood flow. Contractile force is regained days to weeks later. If
the tissue is simply stunned rather than necrotic, its function will recover.
• Ischemic preconditioning - brief ischemic insults to a region of myocardium that
make that region more resistant to subsequent episodes. Thus, patients who
have an MI after recent anginal pain often have less morbidity and mortality than
those with an “out-of-the-blue” MI. The conditioning may be triggered by
substances released during ischemia like adenosine and bradykinin.
• Infarct expansion - in an early post-MI period, the affected ventricular segment
enlarges without additional myocyte necrosis - occurs by thinning and dilatation of
the necrotic zone from “slippage” between muscle fibers.
• The increase in ventricular size 1) augments wall stress, 2) impairs systolic contractile function,
and 3) increases the likelihood of aneurysm formation
135. Cellular Changes of Acute MI
• Occluded coronary vessel falling O2 levels switch from aerobic to anaerobic
metabolism lactic acid accumulation lowered pH (Metabolic Acidosis)
• The decrease in high-energy phosphates like ATP interfere with Na+/K+ ATPase
elevation in intracellular Na+ and extracellular K+
• Rising intracellular Na+ cellular edema
• Membrane leakage and rising extracellular K+ altered transmembrane
electrical potentials and predisposition to arrhythmias
• Intracellular Ca2+ accumulation activates degradative lipases and proteases and
contributes to final pathway of cell destruction.
• Metabolic changes decrease function within 2 minutes of an occlusive thrombosis.
• Without intervention, irreversible cell injury ensues within 20 minutes
• Proteolytic enzymes leak across membrane and damage myocardium
• Release of macromolecules into circulation (Troponin @ 4 hours)
136. Compare and contrast the use and time
course of troponin and CPK-MB in
diagnosis an acute MI
• Troponins
• The specific troponins used for the diagnosis of MI are cTnI and cTnT, because
these are the cardiac forms of troponin I and are also structurally unique, and thus
easier to assay.
• These markers tend to increase 3-4 hours after onset of discomfort, peak
between 18-36 hrs and may be present for up to 2 weeks.
• CPK-MB
• Isoenzyme of creatine kinase that exists in the heart - CPK-MB.
• The measurement for CPK-MB is calculated by the ratio of CPK-MB: total CPK.
• Values of >2.5% usually indicative of cardiac injury
• Levels of CPK-MB rises between 3-8 hrs following infarction, peaks at 24 hrs and
goes back to normal after 48-72 hrs.
• This makes it a useful indicator for REINFARCTS.
• Neither of these markers are good for early diagnosis of MI, since they take a few
hours to peak. In early situations, ECG and history are most important.
137.
138. Do not use Fibrinolytic treatment
regimens for NSTEMI
139. Name at least two fibrinolytic agents and
explain the benefits, limitations and major
risks of thrombolytic therapy.
• Alteplase, tPA
• Reteplase, rPA
• Tenecteplase - TNK-tPA
• Very effective in lysing the intracoronary thrombi found in STEMI.
Patients who receive FT quickly (within 2 hours of onset of symptoms)
have half the rate of mortality of STEMI pts who get it after 6 hrs
• Fibrinolytic therapy does not benefit patients suffering from UA or
NSTEMI.
• Bleeding is the most common complication of fibrinolytic therapy, patients
who require effective fibrin clotting are contraindicated for this therapy.
That includes post-op patients, those with a bleeding disorder or recent
stroke.
140. Define the term “primary percutaneous
coronary intervention” and explain the
benefits, limitations and major risks
• Angioplasty + stenting of the vessel
• Medications given during PCI: Aspirin, Heparin, IV GP IIb/IIIa receptor antagonist
• *may substitute Direct Thrombin Inhibitor (e.g. Bivalirudin) for Heparin + GP IIb/IIIa antagonist combo
• If receiving a stent → Oral Thienopyridines (e.g. Clopidogrel) given to reduce risk of
ischemic complications & stent thrombosis
• Clopidogrel or Prasugrel given for >12 months after stent placed
• Benefits:
• Treat patients with contraindications to Fibrinolytic therapy or unlikely to do well with
fibrinolysis (e.g. late presentation to hospital - more than 3 hrs with symptoms, in
cardiogenic shock)
• Treat patients initially treated with fibrinolytic therapy without adequate response (e.g.
ST segment elevations)
• In comparison to Fibrinolytic Therapy:
• Greater survival & Lower rates of reinfarction and bleeding
• Preferred method IF performed by experienced operator within 90 mins of arriving
141. TIMI Risk Score
• Patients with “most concerning clinical features” →
identified by risk assessment algorithms (higher scores: ≥
3)TI
• Age > 65 years old
• ≥ 3 Risk factors for coronary artery disease
• Known Coronary Stenosis of ≥ 50% by prior angiography
• ST segment deviations on ECG at presentation
• ≥ 2 anginal episodes in prior 24 hrs
• Use of Aspirin in 7 days prior
• Elevated serum troponin or CK-MB
142. Identify the most important predictor of
post-MI outcome, and describe how to
risk-stratify a patient after acutely treating
their myocardial infarction.
• Most important predictor of post-MI outcome - LV Dysfunction
• Identify patients at high risk for complications:
• Exercise treadmill testing
• Attention to underlying cardiac factors
• Smoking
• Hypertension
• Diabetes
• LV ejection fraction of less than or equal to 30% after MI high risk
of sudden cardiac death
• Prophylactic placement of implantable cardioverter-defibrillator recommended
143.
144. Ejection Fraction of <30% after MI is high
risk for sudden cardiac death and
suggests prophylactic placement of ICD.
158. Criteria for Normal Rhythm
• A P wave morphology P wave (atrial contraction) precedes every
QRS complex
• A QRS complex follows every P wave
• The rhythm is regular, but varies slightly during respirations
• The rate ranges between 60 and 100 beats per minute
• The P waves maximum height at 2.5 mm in II and/or III
• The P wave is positive in I and II, and biphasic in V1
159. Is there a QRS after every P?
• NO
• If rate < 100:
• a) 2 block type I ("Wenkebach," gradually lengthening PR until one
beat is dropped)
• b) 2 block type II (dropped beat without change in PR), or
• c) 3 AV block (no correlation between P and QRS)
• If rate >100:
• atrial or nodal tachycardia (SVT) or atrial flutter, both with block.
160. Is there a P before every QRS?
• NO
• a) if a single slow beat: escape beat
• atrial if different P
• nodal if no P
• ventricular if QRS>0.12
• b) if a slow rhythm: escape rhythm
• nodal if no P at rate 50-60
• ventricular if QRS>0.12 & rate <40
• c) if a single fast beat: premature beat
• PAC if different P
• PJC if no P
• PVC if QRS>0.12
161. Tachycardic
• a) if wide (>0.12) and rate >120 then ventricular tachycardia until
proven otherwise
• b) if narrow and regular then atrial (with preceding P) or AV nodal (no
P) tachycardia
• c) if irregularly irregular then either
• 1) atrial fibrillation (no P waves and coarse baseline)
• 2) multifocal atrial tachycardia (MAT, three different P wave morphologies).
164. Determine the mean electrical axis from
knowledge of the magnitude of the QRS
complex in the standard limb leads.
• Inspect limb leads and
determine QRS that is most
isoelectric, the mean axis is
perpendicular to that lead
• Inspect the lead that is
perpendicular to the
isoelectric complex, if the
QRS is primarily upward,
then the mean axis points
towards the (+) pole of the
lead.
167. Intervals
• PR
• Measure of the health of the AV node and bundle of His
• Normal: < 0.2 s (1 big box)
• Pathology: Prolonged interval: AV blocks 1,2,3
• QRS
• Measure of the health of the His-Purkinje system
• Normal: < 0.12 s (3 small boxes)
• Pathology: Conduction delay: LBBB,RBBB, fascicular blocks
• QT
• Measure of repolarization
• Normal: < 0.45 s
• Pathology: Long QT syndrome, electrolyte imbalance, ischemia
169. Second Degree AV Block-Wenkebach
• In second degree AV block type I, the PQ interval prolongs from beat
to beat up until the drop-out of one QRS complex. The characteristics
of a Wenkebach block:
• QRS complexes cluster
• The PQ interval prolongs every consecutive beat
• The PQ interval that follows upon a dropped beat is the shortest.
• The amount of block decreases during exercise
170. Second Degree AV Block – Mobitz II
• In second degree AV block type II, beats are dropped irregularly
without PQ interval prolongation.
• As the drop out of beats is irregular, no clustering of QRS complexes can be seen
as in second degree block type I.
• Second degree AV block type II marks the starting of trouble and is a class I
pacemaker indication
171. Third Degree AV Block
• Third degree AV block is synonymous to total block: absence of
atrioventricular conduction. The P-waves and QRS complexes have
no temporal relationship: AV dissociation. The ventricular rhythm can
be nodal, idioventricular or absent.
• During third degree AV block the blood supply to the brain can insufficient, leading to
loss of consciousness. Adams Stokes attacks attacks are attacks of syncope or pre-syncope
in the setting of third degree AV block.
172. QRS Interval
• Measure QRS interval, if > 0.12 then Look at V1 for LBBB and RBBB
• Left bundle branch block (downgoing)
• Right bundle branch block with (bunny ears and upgoing)
175. LAFB
• Left Axis Deviation
• qR in the lateral leads
• rS in the inferior leads
• Mild QRS widening
176. LPFB
• Right Axis Deviation
• rS in lateral leads
• qR in inferior leads
• Mild or no QRS widening
177. QT Interval
• Bazett’s Formula
• QTc = [QT Interval] / √[R-R interval]
• Important due to R on T risks
• Acquired
• Medications
• Electrolyte abnormalities
• Ischemia
• Hypothermia
• Genetic
• Sodium Channel abnormalities
• Potassium Channel abnormalities
• High risk for ventricular fibrillation
178.
179. Brugada Syndrome
• ST elevation ≥2 mm and a coved type ST segment followed by a
negative T wave. This morphology must be present in >1 right
precordial lead (V1-V3).
183. Differentiate left atrial enlargement from
right atrial enlargement on an ECG
• Right Atrial Enlargement
• Lead II – P wave > 2.5 mm
• Lead V1 – Biphasic p wave with upright deflection larger
• Left Atrial Enlargement
• Lead II – The P wave is broader
• P mitrale
• Lead V1 – Biphasic p wave with terminal component larger
193. Infarction
• Ischemia: inverted T waves or ST depression
• Injury: ST elevation
• Necrosis: Pathologic Q waves
194. Myocardial Ischemia
• ST depression and T-wave changes.
• New horizontal or down-sloping ST depression >0.05 mV in two contiguous leads;
and/or T inversion ≥0.1 mV in two contiguous leads with prominent R-wave or R/S
ratio ≥ 1
• ST elevation
• New ST elevation at the J-point in two contiguous leads with the cut-off points: ≥0.2
mV in men or ≥ 0.15 mV in women in leads V2–V3 and/or ≥ 0.1 mV in other leads.
196. Myocardial Necrosis
• Pathologic Q waves – irreversible injury
• Localize based upon which arteries are involved
• Any Q wave > 1 small box in duration and more than 1/3 the height of
the R wave in 2 contiguous leads.
197. Predict which coronary artery is affected in
a patient experiencing an acute
myocardial infarction.
203. Outline the phases of the cardiac cycle
and describe which phases demarcate
systole and diastole.
• There are 7 phases in the cardiac cycle.
• Systole: phases 2-4
• ventricular contraction and ejection
• Diastole: phases 5-7 and 1
• ventricular relaxation and filling
204.
205. The Cardiac Cycle
• 1. During diastole the mitral valve is open so LA and LV have equal
pressure
• 2. Late diastole, LA contraction causes small rise in pressure (a wave)
• 3. Systolic contraction, LV pressure rises and MV closes when LV
exceeds LA pressure (S1)
• 4. When LV pressure exceeds aortic pressure, AV valve opens (silent)
• 5. Ventricle relaxes, pressure drops below aorta, AV closes (S2)
• 6. LV pressure falls below and MV opens (silent)
206. Atrial Waveform
• a wave: Increase due to atrial contraction.
• x descent: Fall in atrial pressure due to end of atrial contraction.
• c wave: Increase due to bulging of AV valves back into atrial
chambers.
• x’ descent: Fall in atrial pressure after ‘c wave’ due to rapid ventricular
ejection.
• v wave: Peak due to continuing venous return just prior to AV valves
opening.
• y descent: Rapid fall in atrial pressure after ‘v wave’ due to opening of
AV valves.
208. Derive the stroke volume and left
ventricular ejection fraction from the left
ventricular end-systolic and end-diastolic
volumes.
• SV= LVEDV-LVESV
• EF = SV/LVEDV
• Normal ≥ 55%
• The left ventricular ejection fraction is the percentage of blood that
leaves the left ventricle with each contraction.
209. Diagram the timing of the s1, s2, s3, and
s4 heart sounds to the left ventricular
pressure curves and identify the
mechanical events that cause each
sound.
• S1 = Mitral valve closes
• S2 = Aortic valve closes
• S3 = Mitral valve opens. This can be normal in children and pregnant
women but is pathological in adults. Systolic defect associated with
ventricular dilation.
• S4 = Pathological. Blood is being forced against a stiff ventricle. Ex:
Left ventricular hypertrophy. Diastolic defect.
210.
211. Describe the relative contribution of
passive and active left ventricular filling
and the effects of heart rate and
sympathetic activation on this ratio.
• Active ventricular filling is associated with atrial contraction, while passive ventricular
filling depends on venous return and occurs before atrial contraction.
• At Rest: Active filling accounts for approximately 10% of total left ventricular filling.
• At High Heart Rates (Exercise): Active filling accounts for up to 40% of left ventricular
filling. This increased contribution results from two factors:
• Increased heart rate leads to shortened periods of diastolic filling → Reduced amount of blood
entering the ventricle during passive filling.
• Sympathetic nerve activation increases the force of atrial contraction → Increased amount of
blood entering the ventricle during active filling.
• This phenomenon is known as “atrial kick”
• Clinical Aside: In atrial fibrillation, atrial contraction does not contribute to ventricular
filling. This leads to inadequate filling that is exacerbated during physical activity.
212. State the mean right and left atrial
pressures and peak and mean right and
left ventricular pressures
• Mean Right Atrial Pressure: 4 mmHg (average)
• Mean Right Ventricular Pressure: 25 mmHg (systolic) and 4 mmHg
(diastolic)
• Mean Left Atrial Pressure: 8 mmHg (average)
• Mean Left Ventricular Pressure: 120 mmHg (systolic) and 8 mmHg
(diastolic)
• The left heart has higher average pressures because the left ventricle
must eject blood into the entire systemic circulation. The right heart
has lower average pressures because it is responsible for ejecting
blood only to the lungs.
213.
214. Dicrotic Notch in Pressure Tracing
• A very brief and transient increase in aortic pressure that corresponds
with closure of the aortic valve at the conclusion of systole.
215. Define cardiac output and cardiac index
and describe their relationship
• Cardiac Output: CO = SV X HR
• Cardiac Index (CI) = CO / BSA
• Cardiac index is a variation of cardiac output that normalizes for the
size of the individual.
216. Describe the relationship between SV and
HR and their relative influence on cardiac
output.
• CO = HR X SV is the basic relationship. However, since changes in
heart rate can affect stroke volume, changes in heart rate do not
correspond to an exactly proportional change in cardiac output.
• Examples:
• As heart rate increases through pacemaker stimulation, ventricles
have less time to fill with blood during diastole. Less ventricular filling
corresponds with a decreased stroke volume.
• When heart rate increases by 2X due to pacemaker stimulation alone,
cardiac output increases less than 2X.
• When heart rate increases by 2X due to exercise, cardiac output
increases more than 2X.
218. Know the symptoms and signs acute
coronary syndrome
• Retrosternal pressure radiating to neck, jaw or left shoulder and arm
(C7-T4); more severe and lasts longer than previous anginal attacks
• Sympathetic response: Diaphoresis, tachycardia, cool, clammy skin
• Systolic dysfunction: dyspnea
• Ventricular noncompliance: S4 and S3 heart sounds
• Inflammation: Fever
• Serum Markers: Increased troponin and CK-MB
• ECG: ST depression or elevation, inverted T wave, Q wave
223. Localize the site of an infarction and know
the likely infarct related artery based on an
ECG.
224. Ventricular Fibrillation and Tachycardia
• Rapid, disorganized electrical activity of the ventricles
• Most fatal before arrival at hospital
• If present 48 hours after MI, then typically reflects severe left
ventricular dysfunction and is associated with high mortality rates
• If it presents <48 after MI, prognosis is much better and often due to
transient electrical instability
225. Atrial Fibrillation
• Result from atrial ischemia or atrial distension second to LV failure
226. Sinus Tachycardia and Bradycardia
• Bradycardia: due to excessive vagal stimulation or SA nodal ischemia
in the setting of inferior wall MI
• Tachycardia: due to pain, anxiety, heart failure, drug administration or
intravascular volume depletion
• Can exacerbate ischemia
227. Complete Heart Block
• May result from ischemia or necrosis of conduction tracts
• May develop transiently from increased vagal tone
228. Explain the difference between ST
elevation MI (STEMI) and non STEMI and
discuss why a timely diagnosis is most
important for a STEMI.
• A STEMI involves the complete occlusion of one of the coronary arteries
and leads to severe ischemia
• ST elevation localizes on ECG based on which artery is involved
• A timely diagnosis is extremely important for as irreversible damage to
myocytes begins to occur after about 20 minutes.
• Changes seen later in ECG such as inversion of the T wave and
abnormal Q waves can also be avoided following successful treatment if
MI is recognized.
229.
230. Fibrinolysis vs. primary PCI for treatment
of an acute MI.
• NSTEMI: With a NSTEMI, fibronolysis is never used as patients do not benefit
from this therapy. The decision whether to proceed with PCI is based upon a
patient’s TIMI score. An early invasive strategy is recommended in patients with
higher scores (≥3). If an early invasive approach is adopted, the patient should
undergo angiography within 24 hours.
• STEMI: In contrast to UA and NSTEMI, the culprit artery in STEMI is typically
completely occluded, and therefore, the major focus of acute treatment is to
achieve prompt reperfusion of the jeopardized myocardium using either fibrinolytic
drugs or percutaneous coronary mechanical revascularization.
• Primary PCI is usually the preferred reperfusion approach in acute STEMI, if
the procedure can be performed by an experienced operator within 90
minutes of hospital presentation.
• In addition, primary PCI is preferred for patients who have contraindications to
fibrinolytic therapy or are unlikely to do well with fibrinolysis, including those who
present late (>3 hours from symptom onset to hospital arrival) or are in
cardiogenic shock. Furthermore, “rescue” PCI is recommended for patients
initially treated with fibrinolytic therapy who do not demonstrate an adequate
response.
231. Describe the rationale and the indication
for adjunctive therapies for the
management of the ACS
• Focus of treatment for STEMI, UA and NSTEMI consists of anti-ischemic
medications to restore the balance between myocardial
oxygen supply and demand and anti-thrombotic therapy aimed at
preventing further growth, and facilitating resolution of the underlying
occlusive coronary thrombus.
• Beta blocker: lower heart rate
• Propanolol
• Metoprolol, Atenolol, esmolol, acebutolol
• Aspirin/Clopidogrel: antiplatelet
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelor
• ACE Inhibitors: reduces LV remodeling
• Statins: treats atherosclerosis
232. Define "cardiogenic shock" and explain
the clinical manifestations of this
syndrome.
• Cardiogenic shock is a condition of severely decreased cardiac
output and hypotension (systolic blood pressure < 90 mm Hg) with
inadequate perfusion of peripheral tissues that develops when
>40% of the LV mass has infarcted (after MI).
• Chest pain/pressure, tachypnea, tachycardia, weak pulse, skin that is
pale/blotchy/sweaty, lightheaded, disoriented, syncope, coma,
decreased urination.
233. List the four types of "non-cardiogenic
shock" and be able to explain the
differences from cardiogenic shock.
• 1. Hypovolemic shock accompanies significant hemorrhage, or fluid loss from severe burns,
chronic diarrhea, or prolonged vomiting. The direct consequence of hypovolemia is
inadequate cardiac filling and reduced stroke volume reduced CO.
• 2. Anaphylactic shock is a result of an allergic reaction. This immediate hypersensitivity
reaction is mediated by histamine, prostaglandins, leukotrienes, bradykinin that results in
substantial arteriolar vasodilation, increases in microvascular permeability, and loss of
peripheral venous tone. These combine to reduce both total peripheral resistance and
cardiac output.
• 3. Septic shock is also caused by profound vasodilation but specifically from substances
released into the circulating blood by infective agents
• 4. Neurogenic shock is produced by loss of vascular tone due to inhibition of the normal tonic
activity of the sympathetic vasoconstrictor nerves and often occurs with deep general
anesthesia or in reflex response to deep pain associated with traumatic injuries. It may also
be accompanied by an increase in vagal activity, which significantly slows the cardiac beating
rate. This type of shock is often referred to a vasovagal syncope.
234. Explain the cardiovascular alterations
occurring in shock (both compensatory
and decompensatory).
• Compensatory: Increased sympathetic and decreased
parasympathetic response.
• Rapid, shallow breathing increase venous return
• Renin, vasopressin, epinephrine release increase vasoconstriction,
• Glycogenolysis fluid shift
• Decreased organ blood flow (particularly kidneys)
• Decompensatory : Reduced organ blood flow Drive to reduce
arterial pressure positive feedback cycle
• These decompensatory mechanisms are compounded by a reduction in
sympathetic drive and a change from vasoconstriction to vasodilation with
a further lowering of blood pressure. Can lead rapidly to death.
235. Outline the initial management in the
treatment of cardiogenic shock.
• Early cardiac catheterization and revascularization can improve
prognosis prior to occurrence.
• Tx of shock:
• IV inotropic agents Dobutamine, Dopamine
• Increase contractile force
• Arterial vasodilators Hydralazine and Ca2+ Channel Blockers
• Once BP improves to reduce resistance to LV contraction
• Placement of intra-aortic balloon pump into aorta via femoral artery
• Percutaneous Left Ventricular Assist Device (LVAD)
236. Main difference of cardiogenic shock vs.
noncardiogenic shock physiology is that
cardiogenic shock causes decreased CO
by DIRECTLY IMPACTING THE
CONTRACTILITY OF THE
MYOCARDIUM while the other forms of
shock indirectly impact CO.
237. Describe how the susceptibility to
infarction varies between the myocardial
layers.
• Transmural infarcts
• Span the entire thickness of the myocardium
• Result from total, prolonged occlusion of an epicardial coronary artery
• Subendocardial infarcts
• Exclusively involve innermost layers of the myocardium (usually of the
left ventricle, ventricular septum, or papillary muscles)
• Subendocardium is MORE susceptible to ischemia because:
• It is the zone subjected to highest pressure from the ventricular chamber
• It has few collateral connections that supply it
• It is perfused by vessels that must pass through layers of contracting
myocardium
238. Factors Determining Infarct Size
• The amount of tissue that infarcts relates to:
• The mass of myocardium perfused by the occluded vessel
• The magnitude and duration of impaired coronary blood flow
• The oxygen demand of the affected region
• The adequacy of collateral vessels that provide blood flow
• The degree of tissue response that modifies the ischemic process
239.
240. Arrhythmias
• Occur frequently during acute MI and are a major source of mortality
prior to hospital arrival
• Upon arrival, arrhythmia associated deaths are uncommon
• Due to anatomic interruption of blood flow to conduction structures
• Accumulation of toxic metabolic products
• Membrane leaks causing abnormal cellular ion concentrations
• Autonomic stimulation
• Administration of arrhythmogenic drugs
• Detection: EKG
241. Ventricular arrhythmias within 48 hours
solely suggest unstable electrical currents,
but after 48 hours it is an indication for
ICD implantation
242. Pericarditis
• Early in post-MI period: Days 1-3
• Cause: inflammation from necrosis/healing spreads from myocardium
to pericardium
• Detection:
• Sharp pleuritic pain
• Fever
• Pericardial Friction Rub
• Resolved with aspirin
• Incidence limited by acute reperfusion strategies post MI
• Anticoagulants contraindicated
243. Mechanical Complications
• LV Papillary Muscle Rupture:
• Detection: Loud holosystolic murmur due to severe acute mitral regurgitation may be fatal
• Partial rupture moderate regurgitation sxs of heart failure or pulmonary edema
• Posteromedial LV papillary muscle is more susceptible
• Ventricular Free Wall Rupture (rare/infrequent): occurs within 2 weeks following
MI
• Necrotic myocardium free wall rupture hemorrhage into pericardial space rapid cardiac
tamponade (restricts ventricular filling)
• Fatal
• Detection: Imaging studies surgical repair
• Ventricular Septal Rupture 3-7 days
• Blood shunted from LV to RV congestive heart failure (JVD)
• Detection: Loud holosystolic murmur @ Left Sternal Border (transseptal flow)
• Use Doppler echocardiography to distinguish between acute mitral regurgitation (or O2
saturation in chambers)
• True Ventricular Aneurysm: Late complication (weeks to months after MI)
• Weakened ventricular wall due to phagocytic clearance of necrotic tissue outward bulge
• Suspected with persistent ST segment elevations on ECG (weeks later) and/or bulge on CXR
• Detection: Confirmed by echocardiography
250. ESPVR and EDPVR
• The end-diastolic pressure-volume relationship is the passive filling
curve of the ventricle, the slope of which is the inverse of ventricular
compliance. (A completely stiff, non-compliant ventricle would have a
really steep slope.)
• The end-systolic pressure-volume relationship is the max pressure
that the ventricle can muster for a specific volume given a specific
inotropic state. The PV curves cannot “cross” this limit.
251. Preload
• Preload is the initial stretching of cardiac myocytes prior to
contraction. EDV and EDP are used as estimates.
• Increasing venous return and ventricular preload leads to an increase in SV.
252. Determinants
• Factors directly proportional to preload
• Venous pressure - Increase in venous BP → more atrial filling → more ventricular filling
• Ventricular compliance - increased compliance, increased ventricular filling at given pressure
• Atrial inotropy - increase in atrial contraction by sympathetic activation can enhance
ventricular filling
• Outflow resistance -Increase in outflow resistance impairs the ability of the RV to empty
Increase in preload.
• Examples: Pulmonic valve stenosis, pulmonary hypertension, aortic valve stenosis, elevated aortic
pressure
• Factors inversely proportional to preload
• Heart rate - Increased heart rate → Less time in diastole → less time for filling → lower
preload.
• Inflow resistance - Elevated inflow resistance reduces the rate of ventricular filling and
decreases ventricular preload
• Example: Tricuspid valve stenosis, mitral valve stenosis
• Ventricular inotropy - Reduced inotropy → higher end-systolic volume → blood “backs up” in
ventricle and proximal venous circulation → increased preload
• Venous compliance - i.e. venodilation by NO increases compliance, reducing preload and O2
demand.
253. Ventricular Compliance
• Compliance = ΔV/ΔP, but usually we think of it as the inverse of the
slope of passive filling on a PV curve.
• Ventricular compliance is determined by the physical properties of the
tissues making up the ventricular wall and the state of ventricular
relaxation.
254.
255. Length Tension Relationship
• Length ∝ tension. When a myocyte is stretched, it’s passive tension
increases (like a stretched rubber band) and it’s active tension
increases (more forceful contraction when electrically stimulated).
This means that increasing preload aka End Diastolic Pressure will
create a bigger End Systolic Pressure (afterload).
256. Describe the three possible explanations
for length-dependent activation.
• Increased sarcomere length sensitizes troponin C to calcium.
• Fiber stretching alters calcium homeostasis
• Actin and myosin are brought in closer proximity to each other
258. Afterload
• Afterload- The load against which the heart must contract to eject
blood.
• Left ventricle afterload ~ aortic pressure
• Right ventricle afterload ~ pulmonary artery pressure
259. Wall Stress
• La Place Equation: Wall stress, σ, is the average tension each
myocyte must produce to shorten against the intraventricular
pressure. Wall stress is directly proportional to afterload.
• P = intraventricular pressure, r = ventricular radius, h = wall thickness
• Intraventricular pressure is directly proportional to wall stress
• Ventricular chamber dilatation increases wall stress (increased R)
• Hypertrophy decreases wall stress (increased H)
260. Afterload and Velocity of Contraction
• Afterload is like the weight that the muscle must lift, so increasing
afterload (force) decreases velocity of contraction.
261. Preload and Velocity of Contraction
• Increasing preload increases velocity of contraction for a given
afterload. However, note that the y-intercepts are equal, meaning that
the theoretical max velocity of contraction (what would occur against
zero force) remains the same.
262. Afterload and Stroke Volume
• At a given preload, increasing afterload decreases stroke volume.
267. Inotropy and ESVPR
• Increased inotropy shifts ESPVR (end systolic pressure volume
relationship) to the left and makes it steeper because the ventricle
can generate increased pressure at any given volume
• Increasing Inotropy also increases stroke volume and ejection fraction
(EF)
268. Determinants of Inotropy
• Sympathetic nerve activation: Sympathetic nerves release
norepinephrine which binds to β-1 adrenoceptors on myocytes and
play a role in ventricular and atrial inotropic regulation
• Circulating catecholamines: have positive inotropic effects.
• Afterload: an increase in afterload can cause modest increase in
inotropy by a somewhat unknown mechanism.
• Heart rate: increased heart rate has positive inotropic effects.
• This is due to an inability of the Na+/K+ ATPase to keep up with the sodium influx at
higher frequency of action potential at elevated heart rates leading to an
accumulation of intracellular calcium via sodium calcium exchanger.
270. Dynamic effects of Increased Preload
• Primary change: Increased EDV and SV (right shift, solid red line)
• Secondary change: Increased afterload (due to increased CO and
BP).
• Inotropy is not affected. ESV also increases slightly due to higher
afterload.
Myocardial Infarction, stenosis, ulceration/gangrene, atheroembolism (look for clear spaces, cholesterol clefts, often found in kidney), aneurysm
Very commonly used (1st line for hyperlipidemia)
SREBP = sterol regulatory element binding-protein
Pravastatin, rosuvastatin, and fluvastatin are not dependent on cyt P450 as much, so less likely to cause myopathy in combination w/ other drugs
LO 10, 12, 13
Less commonly used (2nd line for hyperlipidemia)
NPC1L1 = Niemann-Pick C1-like 1
LO 10, 12
Rarely used (3rd line for hyperlipidemia)
CYP7A encodes cholesterol 7-alpha hydroxylase, which is the rate-limiting step in bile acid synthesis.
FXR = farnesoid X receptor; bile acids bind and increase FXR’s transcriptional activity. FXR induces repressors of transcription that inhibit expression of CYP7A (so when there are enough bile acids, FXR represses transcription of the enzyme, CYP7A, that makes bile acids).
LO 10, 12, 13
Somewhat commonly used, going out of style (indicated for primary hyperlipidemia, low HDL)
Niacin makes it so the liver takes cholesterol from HDL particles but does not actually take up the HDL and destroy it by breaking down its apoprotein, apo AI.
LO 14, 15
Commonly used (indicated for hypertriglyceridemia, 2nd line for hypercholesterolemia, used when HDL is low and LDL is high)
PPAR = peroxisome proliferator activated receptor alpha. When FAs are high, PPAR induces genes for FA oxidation, which decreases TG production, inhibiting VLDL synthesis. Also enhances expression of lipoprotein lipase (LPL)
LO 13, 17
Commonly used (severe hypertriglyceridemia, esp pancreatitis. Used when HDL is low and LDL is high)
LO 17
SA node, AV node and bundle of His all supplied by RCA, posterior/inferior infarctions serious arrhythmias
Prodromes are a good sign. Palpitations or no signs are concerning
