CARDIOVASCULAR

ATHEROSCLEROSIS

Atherosclerosis is the leading cause of

Morbidity and Mortality in Western Society

Most Common Factors:

Hypertension

Smoking

Hypercholesterolemia

Diabetes

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.

ATHEROSCLEROSIS

Atherosclerosis is an INTIMAL PROCESS

Progression of Atherosclerosis

What are the steps of Atherosclerosis?

• Endothelial Activation

• LDL, monocytes, endothelium

• Foam Cells

• Oxidized LDL, macrophages

• Fibrous Cap

• SMCs

• Calcification

• Ulceration

• Thrombosis

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

What are the important complications of

atherosclerosis?

• Occlusion of vessel

• Thrombus

• Ulceration and hemorrhage

• Atheroembolism

• Narrowing of lumen (stenosis)

• Weakening of wall (aneurysm)

Atherosclerosis end results

Name the Complications

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.

Atheroembolism will show cholesterol

plaques

Hyperlipidemia Drugs

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

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

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*

Bile Acid Resins

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)

Niacin (Vitamin B3)

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.

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.

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

Fish Oil (omega-3 FA)

Major SE of Hyperlipidemia Tx

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

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.

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.

•

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

CARDIOVASCULAR

HEMODYNAMICS

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.

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.

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

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.

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

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

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.

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.

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.

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

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.”

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.

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.

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

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

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)

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

COAGULATION CASCADE

PT- Extrinsic Pathway

PTT – Intrinsic Pathway (TENET)

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.

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).

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.

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.

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.

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

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).

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.

CV ELECTRICAL ACTIVITY

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

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 𝛃1 adrenoreceptors (𝛃1AR above) coupled to a stimulatory Gs-protein which activates adenylyl cyclaseand 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

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.

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.

List the major ions involved in establishing

the cardiac membrane potential.

• Na+, K+, and Ca2+ are the major ions that dictate membrane potential.

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.

Sketch a typical action potential in a

pacemaker cell.

Sketch a typical action potential in a

ventricular cell.

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

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 𝛃1-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.

SPECTRUM OF CAD

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.

Compare Stable angina pectoris,

Unstable angina pectoris, Acute MI.

What is the most common ECG finding

during episodes of stable and unstable

angina?

• ST Depression

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.

Identify ST elevation and pathologic Q

waves and distinguish these findings

associated with the anterior, lateral, or

inferior walls.

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.

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.

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

Diabetics may be more likely to have

silent angina

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).

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

Myocardial O2 Supply and Demand

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.

Correlate the coronary artery that is

occluded to the anatomic distribution of an

acute myocardial infarction.

ComplicationsVentricular 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.

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

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

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

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

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

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

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

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

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

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

CHRONIC CORONARY

SYNDROMES

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).

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

Pharmacologic treatments for angina

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 nociceptorsconverge on the same spino-thalamic neurons.

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.

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.

Identify the main goals of therapy for

patients with stable angina.

• Decrease frequency of anginal attacks

• Prevent acute coronary syndromes

• Prolong survival

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

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

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

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

Explain the rationale for the potential

benefit of combining a beta-blocker with a

nitrate in treating stable angina.

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)

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)

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)

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

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

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.

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

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.

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.

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

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

ACUTE CORONARY

SYNDROMES

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.

Compare and contrast the

pathophysiologic and clinical features of

unstable angina, non-STEMI and STEMI.

Recognize the non-atherosclerotic causes

of an acute coronary syndrome.

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

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

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)

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.

Do not use Fibrinolytic treatment

regimens for NSTEMI

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.

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

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

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

Ejection Fraction of <30% after MI is high

risk for sudden cardiac death and

suggests prophylactic placement of ICD.

INTRO TO EKG

Know the electrode placements and

polarities for a 12‐lead electrocardiogram

Frontal Plane Electrodes

Standard values for EKG print out

Correlate tracing to electrical state of heart

Systematic Approach

• Rate

• Rhythm

• Axis

• Intervals

• Hypertrophy

• Ischemia

• Special Changes

RATE

A rate of 60-100 is normal <60 is

bradycardia and >100 is tachycardia

Method 1 for Determining Rate

Method 2 for Determining Rate

Method 3 for Determining Rate

RHYTHM

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

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.

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

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).

AXIS

Define mean electrical vector (axis) of the

heart and give the normal range.

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.

Quadrant Approach

INTERVALS

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

First Degree AV Block

• Prolonged PQ Interval >.2s

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

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

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.

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)

LBBB

RBBB

LAFB

• Left Axis Deviation

• qR in the lateral leads

• rS in the inferior leads

• Mild QRS widening

LPFB

• Right Axis Deviation

• rS in lateral leads

• qR in inferior leads

• Mild or no QRS widening

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

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).

Wolff Parkinson White

• Short PR interval with delta wave

Digoxin Intoxication

HYPERTROPHY

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

Atrial Enlargement

Right Atrial Enlargement

Left Atrial Enlargement

LEADS II AND V1 ARE MOST PARALLEL

TO ATRIAL DEPOLARIZATION BEST

AREA TO VIEW P WAVE

ECG of ventricular hypertrophy

Left Ventricular

Hypertrophy

• R in V5 or V6 + S in V1 >35 mm

Look for ST depression STRAIN

Right Ventricular

Hypertrophy

• QRS duration < 120ms

• Right heart axis (> 110 degrees)

• Dominant R wave in V1

INFARCTION

Infarction

• Ischemia: inverted T waves or ST depression

• Injury: ST elevation

• Necrosis: Pathologic Q waves

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.

Myocardial Infarction

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.

Predict which coronary artery is affected in

a patient experiencing an acute

myocardial infarction.

Anterior Hemiblock

• LAD occlusion

• Normal or slightly widened QRS

• Q1S3

The only upside down QRS complex

allowed is in AVR. Do not assess Q waves

in AVR.

ST segment depression in NSTEMI is

nonlocalizing to specific arteries

Be careful about diagnosing an infarct in

the presence of LBBB.

THE CARDIAC CYCLE

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

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)

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.

Systole occurs approximately between

the S1 and S2 heart sounds

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.

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.

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.

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.

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.

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.

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.

STEMI TBL

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

ECG of Unstable Angina and NSTEMI

ECG findings of an acute MI

Localize the site of an infarction and know

the likely infarct related artery based on an

ECG.

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

Atrial Fibrillation

• Result from atrial ischemia or atrial distension second to LV failure

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

Complete Heart Block

• May result from ischemia or necrosis of conduction tracts

• May develop transiently from increased vagal tone

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.

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 fibrinolyticdrugs 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.

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

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.

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.

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.

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)

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.

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

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

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

Ventricular arrhythmias within 48 hours

solely suggest unstable electrical currents,

but after 48 hours it is an indication for

ICD implantation

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

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

Holosystolic Murmurs

• VSD

• Mitral Regurgitation

• Tricuspid Regurgitation

Heart Failure

• Due to impaired LV contractility (systolic dysfunction) and myocardial

stiffness (diastolic dysfunction)

• Detection:

• Dyspnea

• Pulmonary Rales

• Third heart sound (S3)

• Rx: ACE inhibitors, Diuretics, Beta blockers,

• Beta Agonists

• Vasodilators

Cardiogenic Shock

• When >40% of LV mass has infarcted

• Decreased Cardiac Output (CO)

• Hypotension: Systolic BP <90 mmHg

• Low BP decreased coronary perfusion increases ischemic

damage decreased stroke volume increased LV size

enhances myocardial oxygen demand

• Mortality >70%

PRESSURE VOLUME

LOOPS

Diagram a pressure-volume loop

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.

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.

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.

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.

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).

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

Frank Starling Mechanism

Afterload

• Afterload- The load against which the heart must contract to eject

blood.

• Left ventricle afterload ~ aortic pressure

• Right ventricle afterload ~ pulmonary artery pressure

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)

Afterload and Velocity of Contraction

• Afterload is like the weight that the muscle must lift, so increasing

afterload (force) decreases velocity of contraction.

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.

Afterload and Stroke Volume

• At a given preload, increasing afterload decreases stroke volume.

What is a normal ejection fraction

•55%

With changes in preload, EDV will change

and with changes in afterload, ESV will

change.

Inotropy

• Increased Inotropy Increased Stroke Volume

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)

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.

Preload, Afterload and Inotropy

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.

Dynamic effects of Increased Afterload

• An increase in afterload leads to a decrease in SV via an increase in

ESV. The increased ESV inside the ventricle is added to the venous

return, increasing EDV.

• After several beats, a steady state is achieved in which the increase

in ESV is greater than the secondary increase in EDV so that the

difference between the two (SV) is decreased.

• This increase in preload secondary to an increase in afterload

activates the Frank-Starling mechanism, which partially compensates

for the reduction in SV caused by the initial increase in afterload.

Dynamic effects of Increased Inotropy

• The direct, independent effects of an increase in inotropy are an increase in SV and a decrease in ESV/afterload.

• However, the increased SV increases CO and arterial pressure, which increases afterload on the ventricle.

• Increased afterload tends to increase ESV, which partially offsets the effects of increased inotropy on ESV. With a decrease in ESV from control, less blood remains in the ventricle that can be added to the venous return, so the EDV will be smaller, although this will be partially offset by the tendency of the increased afterload to increase EDV.

• After a new steady state is reached following the increase in inotropy, the net effect is an increases in SV, which is accompanied by a reduction in ESV and a smaller reduction in EDV.

Myocardial O2 Consumption

• Myocardial oxygen consumption (MVO2) is equal to the coronary blood flow (CBF) multiplied by the amount of oxygen extracted from the blood (the arterial-venous oxygen difference).

• MVO2= CBF * (CaO2 – CvO2)

• CBF= coronary blood flow

• CaO2= arterial oxygen content

• CvO2= venous oxygen content

• The pressure-rate product has been used to estimate myocardial oxygen consumption noninvasively. To find it, you multiply heart rate and systolic arterial pressure (mean arterial pressure is sometimes used instead). This product assumes that the pressure generated by the ventricle is not significantly different than the aortic pressure (i.e. there is no aortic valve stenosis).

Determinants

VALVULAR DISEASE

Mitral Stenosis

• Most common cause: Rheumatic Fever, also calcificic/degenerative and

SLE

• Pathology: Fibrous thickening and calcification of valve leaflets, fusion of

commisures, thickening of chorda tendineae

• Pathophysiology:

• 1. High LA pressure transmitted to pulmonary circulation Dyspnea

• 2. Chronic elevation of RV pressure leads to dilatation Right heart failure

• 3. High LA pressure LA enlargement and atrial fibrillation

• Presentation: Dyspnea, reduced exercise capacity, pulmonary

hypertension, right sided heart failure, JVD, hepatomegaly, ascites,

peripheral edema, compression of recurrent laryngeal nerve, atrial

fibrillation, thromboembolism, infective endocarditis, hemoptysis

MS Diagnostics

• Auscultation: Right ventricular tap (loud S1), Opening snap following

S2, Diastolic rumble over apex

• EKG: LA enlargement, RVH, A-fib

• Echo: Thickened mitral leaflets and abnormal fusion of commissures

with restricted separation during diastole

• Rx: Diuretics (vascular congestion), β blocker/CaCh Blocker (A-fib),

Anticoagulants (thromboembolism), ACE inhibitors.

• Surgery: Percutaneous Balloon Mitral Valvuloplasty

Tachycardia and MS

• Increased HR decreased time in diastole even less LV filling

• This leads to a build-up of greater pressure in the LA which backs up

into the pulmonary system

• Beta blockers act to decrease the HR, helping to avoid the worsened

symptoms that accompany tachycardia

Antibiotic Prophylaxis

• All patients with evidence who have had ARF or evidence of RHD

should be given antibiotic prophylaxis

Mitral Regurgitation Etiology

Primary vs. Secondary Causes

Primary mitral regurgitation

• Myxomatous mitral valve: enlarged redundant leaflets bow excessively into LA during systole instead of opposing each other normally

• Endocarditis: leaflet perforation/rupture due to infected chordae tendinae

• Rheumatic heart disease: excessive shortening of chordae tendinae & retraction of leaflets

Secondary mitral regurgitation

• Dilated cardiomyopathy: spatial separation between papillary muscles/mitral annulus stretching

• Ischemic cardiomyopathy: scar/transient dysfunction of papillary muscle

Mitral Regurgitation

• Pathophysiology: Fraction of LV stroke volume is ejected backward

into LA elevation of LA volume and pressure, reduction of CO and

wall stress on LV during diastole, Frank Starling mechanism elicits

compensatory increase in SV

• Acute MR (chorda rupture) – little compensation in LA size and

compliance High LA pressure

• Pulmonary congestion and edema.

• Chronic MR (Rheumatic valve disease) – LA undergoes

compensatory changes (dilatation) reduced CO

• Weakness and fatigue and potential A-fib

• Eventual deterioration of systolic ventricular function

MR

MR Diagnostics

• Auscultation: Loudest at apex

• Chronic MR: Apical holosystolic murmur that radiates to axilla

(have patient clench wrists to enhance murmur), S3 is common

• Acute MR: Decrescendo systolic murmur

• EKG: LA enlargement and signs of LVH

• Echo: Useful to identify structural cause, Doppler can grade severity

• Rx:

• Acute MR: Diuretics (Furosemide), Vasodilators

• Chronic MR: Mitral valve repair over replacement

Severe MR can be masked by a slightly

elevated ejection fraction!

Mitral Valve Prolapse

• Common asymptomatic billowing of mitral leaflets into LA during

systole

• Autosomal dominant disorder or related to Marfan’s, Ehlers-Danlos and

other connective tissue diseases

• Accumulation of glycosaminoglycan (dermatan sulfate) in spongiosa layer

with secondary disruption of underlying fibrosa layer.

• Pathophysiology: Principally affects posterior leaflet.

• Usually asymptomatic but can lead to arrythmias

• Chordae may be elongated, thinned, or even ruptured, and the annulus

may be dilated

• Auscultation: Mid-systolic click

• Echo: Shows posterior displacement of mitral leaflets

Aortic Stenosis

• Etiology: Age-related Degenerative Calcific changes, congenital,

rheumatic

• Pathophysiology: LV initially compensates via hypertrophy lower

compliance elevation of diastolic LV pressure

• Angina: due to imbalance of myocardial O2 supply and demand

• Increased muscle mass (hypertrophy)

• Elevated diastolic pressure reduces blood flow

• Exertional Syncope: inability to compensate during exercise

• Congestive Heart Failure: LV may develop contractile dysfunction

overtime leading to increased LA pressure and heart failure

Why CAD and Degenerative Calcific

Disease may be related.

• Studies have shown that, as in atherosclerosis, the valve tissue of

patients with calcific aortic valve disease display cellular proliferation,

inflammation, lipid accumulation, and increased margination of

macrophages and T lymphocytes.

CRUCIAL SIGNS OF SEVERE AORTIC

STENOSIS

• Pulsus parvus et tardus

• Late-peaking murmur

• Soft or absent A2 sound

• Aortic sclerosis will only show ejection murmur

AS Diagnostics• Auscultation: Right upper sternal border

• 1. Coarse late-peaking systolic ejection murmur

• 2. Reduced aortic component of S2

• 3. Weakened and delayed upstroke of carotid artery pulsations due to obstructed LV outflow

• 4. S4

• Palpation: Suprasternal thrill

• EKG: LV hypertrophy

• Echo: identifies and quantifies degree of stenosis• Normal aortic valve cross sectional area = 3-4 cm2

• Mild AS: <2.0 cm pressure gradient between LV & aorta first appears

• Moderate AS: 1.0-1.5 cm

• Severe obstruction: <1.0 cm

• Rx: Aortic valve replacement• Caution in use of medications!!!

AR vs. AS

• AS: A coarse, late-peaking systolic ejection murmur at right upper

sternal border

• AR: A blowing murmur in early diastole (diastolic decrescendo) best

heard at lower left sternal border

AS

Aortic Regurgitation

• Etiology: Abnormalities of leaflets (Congenital, Endocarditis,

Rheumatic), Dilatation of aortic root (Aneurysm, dissection, syphilis,

annuloaortic ectasia)

• Most common cause of Chronic AR – Bicuspid valve

• Pathophysiology:

• Acute AR: LV is of normal size and noncompliant increase in diastolic

pressure transmitted to LA dyspnea/respiratory emergency

• Chronic AR: compensatory adaptation of LV eccentric hypertrophy

reduced aortic diastolic pressure and increased LV stroke volume

(widened pulse pressure) reduced myocardial oxygen supply (angina,

fatigue)

• Presentation: dyspnea, fatigue, sensation of forceful heartbeat

AR: Acute vs. Chronic

• Acute

• Primary: endocarditis

• Secondary: aortic dissection

• Chronic

• Primary

• Bicuspid aortic valve

• Endocarditis

• Inflammatory

• Secondary

• Aortic aneurysm

AR Diagnostics• Auscultation: Left lower sternal border

• 1. Bounding pulse

• 2. Hyper-dynamic LV impulse

• 3. Blowing murmur of AR in early diastole along left sternal border

• 4. Austin Flint murmur (low frequency, mid-diastolic rumbling at cardiac apex)

• 5. WIDE PULSE PRESSURE

• Echo:

• 2D• Leaflet abnormalities

• Enlarged left ventricle

• Dilated ascending aorta

• Doppler• Presence, severity of AR

• Rx: vasodilators to reduce afterload, symptomatic patients should be offered surgery, there are no effective medications and many medications are contraindicated due to disruption of hemodynamics.

AR

Criteria for Aortic Valve Surgery

• Aortic stenosis

• Patients with severe AS who develop symptoms, or when there is

evidence of progressive LV dysfunction in the absence of symptoms

• Aortic regurgitation

• Symptomatic patients or those who are asymptomatic but have

severe AR and impaired LV contractile function (i.e. ejection fraction

<50%)

Does Mitral Stenosis or Mitral

Regurgitation cause LV enlargement?

• Mitral regurgitation

• Aortic Regurgitation

Describe the difference in ventricular

hypertrophy between AS and AR

• AS shows concentric hypertrophy (add sarcomeres in parallel to

thicken wall of ventricle) while AR shows eccentric hypertrophy (add

sarcomeres in series to increase diameter of ventricle).

S1

S2

Systolic Murmurs

• Holosystolic

• Mitral regurgitation

• Tricuspid regurgitation

• VSD

• Systolic ejection

• Aortic sclerosis

• Aortic stenosis

• Pulmonary stenosis

• Hypertrophic

cardiomyopathy

Aortic vs. Mitral Stenosis

Murmurs

• Systolic: Aortic or

pulmonary stenosis or

hypertrophic

cardiomyopathy

• Holosystolic: Mitral or

tricuspid regurgitation or

VSD

• Diastolic: Aortic or

pulmonary regurgitation,

mitral stenosis

Etiology of Murmurs

• A murmur is caused by turbulent blood flow. They can result from:

• 1. Flow across a partial obstruction (e.g. aortic stenosis)

• 2. Increased flow through normal structures (e.g. high output state)

• 3. Ejection into a dilated chamber (e.g. dilation of the aorta)

• 4. Regurgitant flow across an incompetent valve

• 5. Abnormal shunting of blood from one vascular chamber to a lower-

pressure chamber

Dynamic Auscultation

• In dynamic auscultation, you listen to the heart when the patient is

lying down, standing and squatting to see the differences in the heart

sounds. When lying down, the LV is at baseline.

• Upon standing → preload drops (↓ venous return)

• Upon squatting → afterload rises (↑ systemic pressure)

• These maneuvers can change when a murmur occurs and can help

differentiate between aortic stenosis and hypertrophic

cardiomyopathy:

• aortic stenosis- will have NO CHANGE w/ dynamic auscultation

• hypertrophic cardiomyopathy- WILL have change w/ dynamic auscultation

Mechanical vs. Bioprosthetic Valves

• Mechanical

• Impressive durability, with some models functioning well for more than 30 years

• Older mechanical valve models had problems with producing intravascular hemolysis from red blood cell trauma due to their bulky leaflet design, but newer models do not have this issue

• Present foreign thrombogenicsurfaces to circulating blood and thus require lifelong anti-coagulation to prevent thromboembolism

• Bioprosthetic

• Limited durability compared with mechanical valves, and structural failures occur in up to 50% of valves at 15 years

• Valves in the mitral position tend to deteriorate more rapidly

• The main causes of valve damage are leaflet tears and calcification

• Very low rate of thromboembolism and do not require long term anti-coagulation therapy

• Very low rates of subsequent infection

Patients that need antibiotic prophylaxis

for dental procedures

• Patients with a history of endocarditis

• Patients with prosthetic heart valves

• Patients with a history of recent surgery for a congenital heart disease

• Patients with a history of heart transplant that later developed cardiac

valve abnormalities

Auscultation

Why is there a systolic murmur in aortic

regurgitation

• 1. Valve is abnormal turbulent flow

• 2. Stroke volume is increased by 2 increased flow

Why is diastolic pressure so low in AR?

• By accommodating the large regurgitant volume the aortic diastolic

pressure drops substantially, which in combination with the high LV

stroke volume produces a widened pulse pressure, which is a

hallmark of chronic AR

• Decreased aortic diastolic pressure → decreased coronary artery

perfusion → may produce angina even in the absence of

atherosclerotic disease

Valve Disease

• Mitral Stenosis

• MCC: Rheumatic Fever

• Sx: dyspnea, RHF, A-fib, Thromboembolism

• Px: Diastolic Murmur: opening snap rumble over apex

• Rx: Diuretics (vascular congestion), B blocker/CaCh Blocker (A-fib), Anticoagulants (thromboembolism), Balloon valvuloplasty

• Mitral Regurgitation

• MCC: Myxomatous degeneration, Rheumatic, Ischemic

• Sx: Acute: dyspnea, pulm. edema, Chronic: Fatigue, A-fib, LV dysfunction

• Px: Apical holosystolic murmur that radiates to axilla

• Rx: Diuretics, Vasodilators, Mitral Valve repair

• CAN BE MASKED BY ELEVATED EF

• Aortic Stenosis

• MCC: Calcific and Rheumatic

• Sx: Angina, exertional syncope, CHF

• Px: Systolic ejection murmur @ RUSB Severe: Pulsus parvus et tardus, Late-peaking murmur, Soft or absent A2 sound

• Rx: ACE inhibitors, diuretics, Beta blockers WITH CAUTION and AVR for symptomatic pts.

• Aortic Regurgitation

• MCC: Bicuspid Valve

• Sx: Acute: dyspnea, pulm. edema, Chronic: Fatigue

• Px: Diastolic murmur (LLSB) + systolic murmur, wide pulse pressure

• Sx: Acute: dyspnea, pulm. edema Chronic: Fatigue, LV dysfunction

• Rx: Vasodilators, USE DRUGS WITH CAUTION, Asymptomatic and symptomatic severe AVR

HEART FAILURE

Coronary Artery Disease

Restrictive Cardiomyopathy

Pericardial Constriction/Tamponade

Hypertrophic Myopathy

Hypertension/ LV Hypertrophy

Aortic Stenosis

Frank Starling Relationship

2 Types of Heart Failure

• HF with reduced EF: occurs because of impaired myocardial

contractility or pressure overload; systolic dysfunction

• HF with preserved EF: occurs because of impaired early diastolic

relaxation or because of increased stiffness of the ventricular wall;

causes diastolic dysfunction with reduced ventricular filling

Adrenergic System

• The fall in CO is sensed by baroreceptors in the carotid sinus and

aortic arch they decrease their firing, and the signal is sent through

CN IX and X to the cardiovascular control center in medulla

• This results in increased sympathetic outflow to the heart and

peripheral circulation, and parasympathetic tone is diminished.

• The immediate consequences of this are an increased heart rate,

increased ventricular contractility and vasoconstriction, sweating, skin

vasoconstriction, increased renin release, cardiac deterioration

(fibrosis etc.)

Renin-Angiotensin-Aldosterone

• 1) Decreased renal perfusion, 2) Decreased salt delivery to macula

densa, 3) Direct stimulation of juxtaglomerular β2 receptors by

sympathetic nervous system Renin Secretion

• Renin cleaves angiotensinogen to angiotensin, which is cleaved by

ACE to form angiotensin II (a potent vasoconstrictor).

• constricted arterioles and raises total peripheral resistance

• Angiotensin II also increases intravascular blood pressure by

stimulating thirst and increasing aldosterone secretion.

• Aldosterone promotes sodium reabsorption from the distal convoluted

tubule of the kidney, and increases intravascular volume

ADH Secretion

• Increased ADH hormone production: ADH secreted in response to

arterial baroreceptor signaling and increased circulating angiotensin II

• ADH increases intravascular volume by

• 1) Promoting water retention by the distal nephron

• 2) Contributing to systemic vasoconstriction increased LV preload

increased CO

Eccentric vs. Concentric Hypertrophy

• Eccentric hypertrophy: synthesis of new sarcomeres in series with the old, causing myocytes to elongate; wall thickness enlarges proportionally with radius of the ventricular chamber• Caused by chronic chamber dilatation due to volume overload

• Concentric hypertrophy: synthesis of new sarcomeres in parallel with the old, causing myocytes to thicken; wall thickness increases without a proportional increase in chamber radius, which can reduce wall stress substantially• Caused by chronic pressure overload

• Valvular insufficiency: eccentric hypertrophy

• Aortic stenosis: concentric hypertrophy

• Hypertension: concentric hypertrophy

Triggers of Heart Failure

• Fever/Infection: Increased Metabolic Demand

• Pregnancy: Increased Metabolic Demand

• Ischemia: Increased Metabolic Demand

• Acute PE: Increased afterload

• Excess salt intake: Increased blood volume/preload

• Negative inotropic drugs: Reduced contractility

Sx of Heart Failure

• Left• Dyspnea

• Pulmonary congestion and reduced CO

• Orthopnea

• Redistribution of blood to lungs in supine position

• PND

• Gradual reabsorption of peripheral edema in blood volume

• Fatigue

• Decreased CO

• Right• Abdominal Discomfort

• Engorged liver

• Peripheral Edema

• Increased hydrostatic venous pressures

NY Heart Association Criteria

Physical Findings

Chest Radiographic Findings

• Upper-zone vascular redistribution - LA P > 15mmHg

• Kerley-B lines - LA P > 20mmHg• Interstitial edema

• Alveolar opacification - LA P >25-30mmHg• Alveolar edema

• Cardiomegaly - Cardiothoracic ratio of >0.5 on the PA film

• Pleural effusion - fluid into the pleural cavity

Use serum brain natriuretic peptide,

sodium, and creatinine levels to evaluate

the cause of dyspnea and severity of

heart failure.

• BNP: correlates with degree of LV dysfunction and prognosis. If you

have elevated BNP you know dyspnea is due to heart failure and not

other causes (like primary lung diseases) or use as a baseline

indicator.

• Sodium: reduced serum levels reflect activation of the renin-

angiotensin-aldosterone system and alterations in intrarenal

hemodynamics. Less sodium, worse prognosis.

• Creatinine: indicative of renal failure secondary to CHF

Patients with heart failure get low grade

troponin elevation.

Only take real notice if Troponin is > 1.

Diagnostic Tests

•Ultrasound – tells the ejection fraction

• Below 40% EF, think pathology

• Chest Radiograph

• BNP

Prognosis: HF pts with preserved EF

have similar rates of hospitalization, in

hospital complications, and mortality as

those with reduced EF

Therapy

• Diuretics:• Furosemide and Bumetanide

• Hydrochlorothiazide and Metolazone

• Spironolactone and Eplerenone

• Vasodilators• Nitrates

• ACE Inhibitors: Lisinopril

• Isorbide dinitrate and Hydralazine

• Inotropics for acute HF• Digoxin and Digitoxin

• PDE Inhibitors• milrinone

• Beta Agonists

• Beta Blockers: Carvedilol

Implantable Defibrillators

• There are cardiac arrhythmias that accompany heart failure, such as

Afib. Conversion to a sinus rhythm is beneficial in these patients.

Ventricular arrhythmias can be lethal and lead to sudden cardiac

death. Patients with heart failure with symptomatic or sustained

ventricular arrhythmias or inducible ventricular tachycardia benefit

more from an implantable ICD than medical treatment.

• Many patients with heart failure have intraventricular conduction

abnormalities that have uncoordinated right and left ventricular

contraction. They benefit from biventricular pacing that stimulates

both ventricles simultaneously to resynchronize them. This is

indicated for patients with advanced systolic dysfunction, a prolonged

QRS complex, and continued heart failure symptoms despite medical

management.

Acute Heart Failure

• Urgent and life threatening symptomology precipitated by certain

triggers

LMNOP Algorithm for Acute

Decompensated Heart Failure• L → Lasix (furosemide) is a diuretic that reduces blood volume and venous

return, therefore, removing blood from the pulmonary circulation and reducing

LV pressures

• M → Morphine reduces respiration, reduces distress, reduces sympathetic

activity (causing vasodilation that reduces resistance and therefore afterload),

and is a vasodilator that helps pool blood in the periphery

• N → Nitrates are vasodilators that reduce venous return, which reduces left

heart pressure, leading to reduced congestion in the pulmonary space

• O → Oxygen

• P → Position (sit upright) will help pool blood in the peripheral lower

extremities rather than in the lungs

CARDIOMYOPATHIES

Types

• Dilated cardiomyopathy: ventricular chamber enlargement with impaired systolic contractile function; only mild increased thickness• Ischemic, idiopathic, infectious (myocarditis), genetic, alcoholic

• Hypertrophic cardiomyopathy: abnormally thickened ventricular wall with abnormal diastolic relaxation but usually intact systolic function; hypertrophy often asymmetrically involving the intraventricular septum

• Restrictive cardiomyopathy: abnormally stiffened myocardium (because of fibrosis or an infiltrative process) leading to impaired diastolic relaxation, but systolic contractile function is normal or near normal; usually without ventricular chamber enlargment

• **LA enlargement is common to all three types of CMP

Dilated Cardiomyopathy Etiology

Ischemic Cardiomyopathy is the cause of

70% of DCM

DCM Pathophysiology

DCM Symptoms and PE

• Sx

• Pulmonary Congestion

• Fatigue

• Dyspnea

• Orthopnea

• PND

• Signs

• Rales

• JVD

• Hepatomegaly

• Edema

• S3

• Mitral Regurgitation Murmur

DCM Therapy

• Standard Rx for Heart Failure

• ACE inhibitor, diuretic, beta blocker

• Arrhythmia prevention

• Amiodarone

• ICD

• Warfarin for thromboembolic events

• Cardiac transplantation

DCM and Mitral Regurgitation

• 3 Serious Consequences

• 1) Excessive volume and pressure loads are placed on the atria,

causing them to dilate, often leading to atrial fibrillation

• 2) Regurgitation of blood into the left atrium further decreases

stroke volume into the aorta and systemic circulation

• 3) Regurgitant volume returns to the LV during each diastole

leading to an even greater volume load on the dilated LV

Compensatory Mechanisms of DCM

• 1) Frank–Starling mechanism: ↑ventricular diastolic volume = ↑

stretch of myofibers = ↑ stroke volume

• 2) Neurohormonal activation: sympathetic nervous system = ↑ heart

rate and contractility

• 3) Renin-angiotensin-aldosterone axis: ↓cardiac output = ↓ renal

blood flow

• ↑ renin secreted by kidneys

• ↑peripheral vascular resistance (via angiotensin II)

• ↑ intravascular volume (via aldosterone)

• Help buffer fall in cardiac output

Decompensation in DCM

• 1) Arteriolar vasoconstriction + ↑ systemic resistance

• Difficult for the LV to eject blood in the forward direction

• 2) ↑ intravascular volume

• ↑ ventricular filling pressures pulmonary and systemic congestion

• 3) Chronically ↑ levels of angiotensin II and aldosterone

• Directly contributes to pathological myocardial remodeling and fibrosis

• 4) Ventricular enlargement over time

• Mitral and tricuspid valves may fail to close during systole leading to

valvular regurgitation

DCM Survival Based on Etiology

• From best to worst survival:

• Peripartum > Idiopathic > Ischemic > HIV

HCM Etiology

• Genetic

• HCM follows autosomal dominant inheritance with variable

penetrance.

• 100’s of genes all having to do with sarcomere complex

• buzzword favorites: B-myosin heavy chain (B-MHC), cardiac troponin, myosin-

binding protein C

• Random mutant incorporation into sarcomere impairs contractile

function myocyte stress compensatory hypertrophy + fibroblast

proliferation

Histology of HCM

1/3 of patients with HCM develop outflow

obstruction

Compare and contrast the LV-Aortic

pressure gradient in patients with HCM

with that seen in severe AS.

• In both HCM with obstruction and aortic stenosis, the LV has to

contract with extra force to overcome the obstruction. So the LV

pressure is higher than the aortic pressure during systole. However, in

aortic stenosis, the “obstruction” is in the aorta, whereas in HCM, the

obstruction is before the aorta, in the outflow tract.

• Post extra systolic potentiation increased force of contraction

• Both show angina and syncope.

HCM Symptoms• Dyspnea:

• Due to elevated diastolic LV pressure, which backs up in to the LA and the pulmonary circulation

• For patients with outflow obstruction, dyspnea is exacerbated by high systolic pressure and mitral regurgitation.

• Angina:

• 1) Narrowing of the small branches of the coronary arteries b/c of the hypertrophied ventricular wall.

• 2) High oxygen demand d/t increased muscle mass.

• Syncope:

• May be caused by arrhythmias, which can develop because of the structurally abnormal myofibers in HCM.

• Orthostatic lightheadedness in patients w/ outflow obstruction:

• Venous return drops d/t gravitational pooling, which causes LV to decrease in size and intensify outflow obstruction transient reduction in CO and cerebral perfusion.

HCM Physical Exam

• Dyspnea

• Angina

• Syncope

• LLSB Systolic Murmur

• S4

• Mitral Regurgitation

HCM Therapy

• Beta Blockers are standard therapy

• Calcium channel antagonists

• Antiarrhythmics

• Amiodarone

• Disopyramide

• No Extreme Physical Exertion

• Pacemaker

• Myomectomy

• Percutaneous septal ablation

Risks for Sudden Cardiac Death in HCM

• Risk factors:

• Prior ventricular arrhythmias

• History of syncope, especially unexplained episodes

• Family history of sudden death

• Certain high-risk HCM mutations b/c different mutations confer a

vastly different risk

• Extreme hypertrophy of the LV wall (>30 mm)

Restrictive Cardiomyopathy Etiology

Endomyocardial Biopsy can help to

distinguish between restrictive

cardiomyopathy and constrictive

pericarditis.

RCM Pathophysiology

RCM Symptoms and PE

• Systemic congestion

• JVD

• Peripheral edema

• Engorged liver

• Fatigue

• Decreased exercise tolerance

• Arrhythmias

• Conduction blocks

• Kussmaul sign

RCM Therapy

• Very poor prognosis

• Salt restriction and cautious use of diuretics

• No vasodilators

• Amyloidosis: chemotherapy, bone marrow stem cell transplantation

Work Up

Cardiac Catheterization and MRI

• Use cath for hemodynamics and CAD investigation

• Use MRI for investigating intramuscular/pericardial inflammation

• Cardiac Catheterization

• Patients with angina or possible prior MI

• Inspect coronary arteries for disease

• Confirm pressure changes in uncertain diagnosis

• Elevated diastolic in Dilated CM

• LV pressure gradient in Hypertrophic CM

• Cardiac MRI

• Separate constrictive pericarditis from Restrictive CM

• Diagnose myocarditis

Dilated Cardiomyopathy causes systolic

heart failure and S3 while hypertrophic

and restrictive cardiomyopathy causes

diastolic heart failure and S4

ARRHYTHMIAS

Sinus Bradycardia/SSS

• Rate <60bpm

• Causes• Normal at rest or during sleep

• Depressed automaticity due to ischemic heart disease or cardiomyopathy

• Beta Blockers, Calcium channel blockers

• Hypothyroidism

• High vagal tone in highly trained athletes

• Sx• Usually asymptomatic

• Can result in low CO with dizziness, confusion, or syncope

• Rx• Atropine (anticholinergic)

• Isoproterenol (Beta adrenergic)

• Pacemaker

• Susceptibility to Bradycardia-Tachycardia Syndrome

Escape Rhythms

• Junctional Escape Rhythm

• Narrow QRS and rate of 40-60bpm

• No normal P waves, but retrograde P waves maybe seen after QRS and

inverted in II, III and avF

• Ventricular Escape Rhythms

• Widened QRS and rate of 30-40bpm

• Can cause RBBB or LBBB

• Sx: often asymptomatic

AV Blocks• First Degree:

• PR >0.2, with preserved 1:1 relationship of P to QRS

• Usually benign asymptomatic treatment that does not require Rx.

• Second Degree: • Mobitz Type I (Wenckebach): degree of AV delay increases with each beat until a QRS is

dropped.

• Impaired conduction in the AV node with narrow QRS

• Usually benign and temporary

• Rx: Atropine, isoprotenerol or pacemaker

• Mobitz Type II: sudden loss of QRS without lengthening of interval

• Impaired conduction in bundle of His or Purkinje system with wide QRS

• Usually indicates Severe Disease

• Third Degree: Complete Heart Block• MCC: acute MI

• AV dissociation, QRS of normal width or widened

• Lightheadedness and syncope due to slow rate

• Pacemaker almost always necessary

• Slow heart rate does not accommodate exercise

Supraventricular Arrhythmias

Sinus Tachycardia

• Rate >100bpm

• Causes

• Increased sympathetic tone and/or decreased vagal tone

• Exercise

• Fever, hypoxemia, hyperthyroidism, hypovolemia, anemia

APBs

• Causes

• Automaticity or reentry in an atrial focus outside the SA node and are

exacerbated by sympathetic stimulation

• ECG:

• Premature abnormal P wave followed by normal QRS

• Sx:

• Typically asymptomatic, but may cause palpitations

• Rx:

• Beta Blockers

• Address caffeine, alcohol and emotional stress

Atrial Flutter

• Rapid regular atrial activity at rate of 180-350bpm

• Cause: • Reentry over a large anatomically fixed circuit

• ECG:• Sawtoothed atrial activity

• Sx: • Rate < 100 usually asymptomatic

• Rate > 100 can cause palpitations, dyspnea, weakness

• Antiarrhythmics can worsen condition by increasing ventricular rate

• Predisposition to atrial thrombus formation

• Rx• Electrocardioversion + anticoagulation

• Pacemaker

• 1. Beta blockers/ Calcium Channel blockers/ Digoxin

• 2. Class IA, IC, or III for sinus rhythm and longer term prophylaxis

Atrial Flutter

Atrial Fibrillation

• Irregularly irregular rhythm of 350-600bpm

• Ventricular rhythm 140-160

• Causes• Multiple wander reentrant circuits within the atria

• Associated with atrial enlargement due to heart failure, hypertension, CAD and pulmonary disease

• ECG:• Discrete P waves are not visible, baseline shows low amplitude undulations punctuated by QRS

complexes and T waves

• Sx• Rapid ventricular rates low CO pulmonary congestion and hypotension

• Stasis risk of thrombus formation

• Rx• Adenosine, Beta blockers/ Calcium channel blockers (digitalis only for ventricular dysfunction)

• Systemic Anticoagulation for at least 3 weeks

• Type IA, IC, III antiarrhythmics or electical cardioversion

CHA2DS2VAS2

• Algorithm for Anticoagulation

• Congestive Heart Failure

• Hypertension

• >75 (2)

• DM

• Stroke/TIA (2)

• Vascular disease

• >65

• Sex category

Surgical Procedures for Afib

• Maze procedure: incisions in right and left atria to prevent reentry

circuits

• Percutaneous catheter ablation: left atrium around pulmonary veins is

cauterized to interrupt reentry circuits

• High risk of stroke or tamponade

• Catheter ablation of AV node with insertion of pacemaker

Paroxysmal Supraventricular

Tachycardias

• 1. Sudden onset and termination

• 2. Atrial rates between 140 and 250 bpm

• 3. Narrow QRS complex

• Cause

• Reentry involving AV node, atrium or accessory pathway

PVSTs

• AVNRT• Slow and Fast AV nodal pathways Reentry

• Regular tachycardia with normal width QRS complexes

• Retrograde inverted P waves in QRS complex

• Presents in teenagers or young adults and is well tolerated

• Rx: Vasalva, IV adenosine

• Preventative Calcium Channer Blockers/Beta blockers

• Catheter ablation

• AVRT – Wolff-Parkinson-White• Shortened PR interval with a delta wave on the upstroke of widened QRS

• Due to conduction through an accessory pathway

• If patient enters AF high risk of VF

• Rx: 1) Cardioversion 2) IA and IC antiarrhythmics (IV procainimide or ibutilide) 3) Ablation

• Caution with beta blockers and calcium channel blockers

AVNRT

AVRT

Focal Atrial Tachycardia

• Cause:

• Automaticity of atrial ectopic site or reentry

• Digitalis toxicity

• Excess sympathetic tone

• ECG:

• Sinus tachycardia with P wave preceding each QRS but P wave

morphology differs from sinus rhythm

• Rx:

• Vagal maneuvers may have no effect

• Beta blockers, Calcium channel blockers and IA, IC, and III

antiarrhythmics can be effective

• Catheter ablation

Multifocal Atrial Tachycardia

• Cause

• Abnormal automaticity in several foci within the atria or triggered activity in the setting of pulmonary disease and hypoxemia

• ECG:

• Irregular rhythm with at least 3 P wave morphologies and avg. atrial rate is >100bpm

• Isoelectric baseline distinguishes MAT from AF

• Sx:

• High mortality rate due to underlying disease

• Rx:

• Verapamil

Ventricular Arrhythmias

VBPs

• Cause:• Ectopic ventricular focus

• Common asymptomatic and benign

• ECG:• Widened QRS complex

• Ectopic beat is not related to a preceding wave

• May appear in repeating patterns

• Sx: • Can be used to track structural heart disease

• Rx: • Symptomatic control using Beta blockers

• ICD in high risk patients

Ventricular Tachycardia• Series of 3 or more VBPs

• Sustained or nonsustained

• Cause: • Structural heart diesase: MI, heart failure, ventricular hypertrophy, valvular heart disease, long QT

syndrome, congenital cardiac abnormalities

• ECG:• Wide QRS with a rate of 100-200 bpm

• Monomoprphic: reentry circuit due to old infarct or cardiomyopathy

• Polymorphic: QRS complex changes in shape and rate varies• Torsades de Pointes or MI most common causes

• Also consider LQTs and Brugada

• Sx: • Sustained: low CO syncope, pulmonary edema, cardiac arrest

• HEMODYNAMICALLY UNSTABLE!

• Rx: • Electrical Cardioversion

• Amiodarone, Procainimide, Lidocaine

• W/ structural heart disease ICD

• Idiopathic Beta blockers, Calcium channel blockers, Ablation

VT can be distinguished from SVT by the

width of the QRS complex*

*Except in SVT with aberrancy

SVT is more probable if vagal

maneuvers affect rhythm

Torsades de Pointes• Cause

• Afterdepolarizations in patients with prolonged QT

• Hypokalemia or hypomagnesemia

• Drugs: Quinidine, Procainimide, disopyramide, sotalol, ibutilide, erythromycin, methadone

• Congenital QT elongation

• ECG:• Polymorphic VT with varying amplitudes of QRS

• Sx: • Lightheadedness or syncope

• Usually self-limited

• Can precipitate Vfib

• Rx:• IV magnesium

• Beta adrenergic stimulating agents or artificial pacemaker to shorten QT

• Beta blockers for congenital long QT decrease sympathetic tone!!!

Ventricular Fibrillation

• Disordered rapid stimulation of ventricles coordinated contractions

leading to cessation of CO and death

• Cause:

• Initiated by episode of VT which degenerates into multiple smaller

wavelets of reentry

• ECG:

• Chaotic irregular appearance without discrete QRS waveform

• Rx:

• IMMEDIATE DEFIBRILLATION

• IV antiarrhythmics: Amiodarone

• ICD

REGULATION OF BP

Overview

• SV * HR = CO

• MAP = (SVR*CO) + CVP

• CVP is affected by Blood

volume, Vessel compliance and

Skeletal muscle contraction

Neural Control• Arterial baroreceptors are found in the carotid

sinus and aortic arch. Afferent fibers from the carotid sinus travel in CN IX up to the brainstem and synapse on the nucleus of the solitary tract (NTS). Aortic arch baroreceptors travel to the NTS via the vagus nerve.

• Inhibitory interneurons from the NTS project to other medullary regions containing cell bodies of sympathetic nerves.

• Excitatory interneurons from the NTS project to medullary regions containing cell bodies of parasympathetic/vagal nerve.

• Peripheral baroreceptors respond to stretching of vessel walls by increasing their firing rate. The net result is increased vagal tone, decreased sympathetic tone, and vasodilation.

Regulatory Mechanisms

• Baroreceptors: located in the carotid

sinus and aortic arch

• Monitor stretch

• Influence HR and MAP

• Chemoreceptors: small carotid bodies

located in the external carotid near the

bifurcation with the internal carotid;

aortic bodies in the aortic arch; central

chemoreceptors in the medulla

• Monitor blood PO2, PCO2, or pH

• Influence respiration

Orthostatic Hypotension

• OH is frequently induced by drugs that lower vascular reactivity and/or impair the CNS (CNS depressants e.g. sleeping pills or alcohol) or by drugs that have alpha-1 adrenergic blocking properties (many antipsychotics, many antidepressants) and by a variety of antihypertensive drugs (examples: ARBs, ACEIs, alpha-1 blockers; especially upon initiation of the treatment (first dose effect)).

• OH is exacerbated by a low blood volume (could be due to bleeding, heat or exercise or consumption of diuretics).

• OH is of special concern in the elderly that have more sluggish baroreflexes and might suffer most from falling.

• OH is common in advanced diabetes. Diabetic neuropathy (DN) produces loss of sensory afferents, especially in the lower limbs

3 Factors that affect postural hypotension:

Age

Diabetes

Atherosclerosis

Orthostatic MOA• The pooling of blood in the lower part of body reduces central venous pressure

and, the lower central venous pressure reduces right ventricular filling pressure.

• The reduced right ventricular filling causes CO to go down as a consequence of the Frank-Starling effect

• BP = CO * TPR and reactive mechanisms of TPR take time to set in, so there is a rapid drop in BP with standing.

• Baroreceptors sense lowered stretch and reduce firing which increases SNA/decreases PSA vasoconstriction and increased cardiac contractility

• In a hypovolemic state (lack of volume from things such as heat, stress, dehydration): SNS is already working really hard to keep up these mechanisms and cannot compensate

• Fainting is a beneficial mechanism to restore cerebral perfusion

• ** Angiotensin and aldosterone DO NOT contribute

Low Pressure Baroreceptors

• Low-pressure baroreceptors encode the degree of stretch of

the upper vena cava, the right atrium and the ventricles

• Low-pressure baroreceptors regulate blood volume via release

of ANF and by controlling renal fluid excretion. Their effect is

too slow to contribute to the orthostatic reflex

• By controlling BV they have a role in the long-term adaptations.

• In 0 gravity or bed rest situations, stretch of baroreceptors is

increased as central venous pressure increases, causing a

long term reduction in blood volume. This can lead to

orthostatic hypotension.

Exercise Regulation

• The cardiovascular responses to exercise are designed to

increase O2 delivery to the more metabolically active

tissues (skeletal muscles and heart)

• The increase in O2 delivery to the muscles occurs via:

• Increased cardiac output

• Vasodilation due to local factors (low pH, K, lactate etc.)

• Increased O2 dumping from Hb due to increased muscle temp.

• Increased O2 dumping from Hb due to increased muscle pCO2

Beta Blockers and Exercise Capacity

• Beta blockers decrease a person’s exercise capacity

because they reduce the ability to increase sympathetic

innervation.

• This prevents the heart from increasing its HR, SV AND

CO

• Beta blockers don’t have much effect during rest because

there is low endogenous beta-agonist to antagonize.

Pulse Pressure

• Pulse pressure (PP)= systolic P – diastolic P

• Mean blood pressure = diastolic pressure + 1/3 (systolic P

– diastolic P)

• Pulse pressure increases during exercise:

• If stroke volume increases, then why doesn’t diastolic

pressure increase?

• Because of the release of epinephrine in blood

• Because of the increased muscle conductance

• Because of reduced resistance in the pulmonary circulation

• Because of the increased skin blood flow

During exercise, skin blood flow goes

from low to high according to the change

in the body’s core temperature

Circulatory Shock

• Circulatory Shock is a condition in which decreased blood flow causes decreased tissue perfusion and O2 delivery. Untreated, shock can lead to impaired tissue and cellular metabolism and, ultimately, death.

• Causes:• Decrease in circulating blood volume: Hypovolemic shock

•

• Myocardial impairment: Cardiogenic shock

• Brain impairment: Neurogenic shock

• Leaky capillaries: Septic or anaphylactic shock

Mechanisms of Compensation

• Activate sympathetic nervous system to stimulate the heart and

constrict systemic vascular beds.

• Increase vasopressin (ADH) and activate the RAAS system to

increase blood volume and reinforce vasoconstriction caused by

sympathetic nervous system.

• Increased lactic acid (acidosis) and stagnant hypoxia (due to

decreased carotid body blood flow) activate chemoreceptors to further

stimulate SNA increased respiratory rate

• Capillary fluid reabsorption can increase intravascular fluid volume, at

the expense of O2 carrying capacity (decreased hematocrit) and

osmotic pressure (dilute plasma proteins)

Mechanisms of Decompensation• Reduced contractility and SV: coronary artery vasoconstriction → myocardial

hypoxia → myocardial dysfunction

• Vasodilation: prolonged reduction in perfusion to organs→ tissue hypoxia → vasodilation (aka “Sympathetic Escape”) caused by release of vasodilator metabolites by the organs. Eventually hypoxia-induced vasodilation overcomes vasoconstrictive compensatory mechanisms→ BP falls

• Acidosis: prolonged hypotension and hypoxia leads to acidosis as organs begin to generate ATP anaerobically (via lactate) → cardiac and smooth muscle contraction impaired → decreased inotropy and BP

• Cerebral ischemia/hypoxia: enhances sympathetic tone at first, but eventually results in depression of all autonomic outflow → BP falls etc

• Blood viscosity: vasoconstriction→ decreased flow rates in the microvasculature → increased blood viscosity via RBC-RBC adhesion (increased ESR), leukocyte-endothelial adhesion, and platelet-platelet adhesion → disseminated intravascular coagulation → more ischemic damage → worse acidosis & vasodilation

SYNCOPE

Syncope

• A sudden, transient loss of consciousness (LOC) and postural tone

that fully resolves spontaneously without specific intervention (as in:

CPR, or electrical or chemical cardioversion).

• Pathophysiology

• A transient reduction in cerebral blood flow (CBF), leading to cerebral

hypoperfusion.

• Reduced CBF is usually attributable to cardiovascular and

neurocardiogenic causes.

• Note that even when CBF is normal, a reduced delivery of essential

cerebral nutrients (O2, sugar) can occasionally cause LOC.

Causes

• Orthostasis: decreased blood volume

• Neurogenic: baroreceptor mediated

• Vasovagal (failed baroreceptor reflex in response to standing)

• Carotid Sinus Hypersensitivity (too much baroreceptor activation)

• Situational (Vagus activation due to fear, peeing, pooping, valsalva)

• Bradyarrhythmia: decreased CO decreased MAP

• Tachyarrhythmia: decreased preload decreased SV decreased

MAP

Etiologies

CausePrevelence Mean

%

Vasovagal 21.2

Orthostatic 9.4

Cardiac 9.5

Seizure 4.9

Medication 6.8

Stroke 4.1

Other 7.5

Unknown 36.6

Neurocardiogenic Syncope

• Vasovagal:

• Carotid Sinus Hypersensitivity:

• Situational:

Medications that Cause Bradycardia

• Beta Blockers

• Don’t forget the eye drops!

• Calcium Channel Blockers

• Antiarrhythmic Medications

• Digoxin

Medications that Cause Hypotension

• Beta Blockers• Don’t forget the eye drops!

• Calcium Channel Blockers

• Antiarrhythmic Medications

• Digoxin

• ACEI

• ARB

• Opiates

• Benzodiazepines

• Lots More!

Syncope- High Risk Features

• Structural Heart Disease

• VT, VF, Bradyarrhythmia, Valvular Heart Disease

• Symptoms Characteristic of Ischemia or Arrhythmias

• VT, VF

• Abnormal ECG

• VT, VF, Bradyarrhythmias

• Neurologic Disease

• Stroke

• Intracranial hemorrhage

History

• Precipitating factors (micturition, cough, exertion),

• Premonitory symptoms (aura)

• Onset (sudden or slow)

• Associated symptoms (palpitations, chest pain, headache),

• Activity (at rest or with exercise)

• Position (standing, sitting, changing position)

• Other systemic illnesses

• Family history of cardiac illness, arrhythmias, syncope, sudden

death, or pacemaker implantation.

• Medications and recreational drugs

Carotid Sinus Massage

• R and L carotid independently.

• 5-10 secs of pressure.

• Postive:• >50 mmHg drop in BP

• >3 sec pause

• Contraindications: • Carotid bruits.

• MI, TIA, Stroke within 3 months.

Treatment

• Orthostatic

• Increase blood volume

• Tachyarrhythmias

• Medical therapy is the primary treatment for SVTs

• Implantable defibrillators are primarily targeted toward VT

• Bradyarrhythmias

• Pacemakers are generally used for bradyarrhythmias.

• Neurocardiogenic

• Pacemakers for carotid sinus hypersensitivity

• Medical therapy in all other cases

Rx for Neurocardiogenic Syncope

DIURETICS AND

EDEMATOUS STATES

Body Fluid Compartments

• The largest compartment by far is comprised of water that is inside of cells – this is the intracellular compartment.

• The extracellular compartment consists of water in the blood vessels (plasma water) and the interstitial space

• The membranes between these distinct spaces are porous to different substances.

• Water moves freely between all compartments; however, sodium movement is highly restricted between the intracellular and extracellular space.

• All body fluid compartments have the same osmolality, that is, the concentration of solutes (electrolytes, proteins, etc.) is the same across all compartments: roughly 290 milliosmoles / liter. However, the concentrations of individual solutes can be very different.

Describe the effect of sodium loading on

extracellular fluid volume.

• Increase of sodium → increase in concentration of sodium for a given

extracellular fluid volume (higher osmolarity) → compensatory

measures: release of arginine vasopressin (AVP / ADH / vasopressin)

→ 1) Increased thirst and 2) Decreased water excretion from kidneys

→ increase in extracellular fluid volume with normal sodium

concentration.

Describe the renal response to decreased

effective circulating volume.

• Decrease in effective circulating volume → decreased renal perfusion

→ increase RAA system and Arginine Vasopressin (AVP) → 1) Thirst ,

2) Sodium retention, 3) water retention in the kidneys → increase in

ECF volume.

Describe each variable of Starling’s law.

• Net driving force = (Pcap - Pi) – σ (πcap - πi)

• Pcapis the capillary hydrostatic pressure

• Hydrostatic pressure driving fluid out the capillary.

• Pi is the interstitial hydrostatic pressure

• Hydrostatic pressure in the interstitium that opposes Pcap.

• πcap is the capillary oncotic pressure

• Osmotic pressure exerted by the presence of proteins in the capillary that opposes filtration and promotes reabsorption.

• πi is the interstitial oncotic pressure

• Osmotic pressure exerted by proteins in the interstitium and opposes πcap

• σ is the reflection coefficient of the membrane.

• It is a correction factor used to account for permeability to proteins within capillaries, which lowers the effective oncotic pressure since some of the proteins can diffuse down their gradient.

Describe how changes in variables of

Starling’s law may promote or inhibit

edema formation

• Promote Edema (increase net driving force)

• Hydrostatic pressure : Increase Pcap or decrease in Pi

• Oncotic pressure: Increase in i or decrease in cap

• Oncotic permeability: Decrease

• Inhibit Edema (decrease net driving force)

• Hydrostatic pressure : Decrease Pcap or increase in Pi

• Oncotic pressure: Decrease in i or increase in cap

• Oncotic permeability: Increase

Four basic mechanisms of edema

Describe the mechanism of diuretic

resistance.

• 2 Types:

• Renal Failure

• Increase dose

• DCT Hypertrophy

• Give Thiazide

Starlings Law and CHF

• Main alteration to Starling’s law is Pcap (hydrostatic capillary pressure)

increases due to low cardiac output & backup of fluid pressure in

veins, venules & capillaries

Electrolyte Effects of Diuretics

• Delivery of large amounts of sodium to the distal nephron (the

collecting tubule) interferes with normal potassium handling and leads

to potassium wasting.

• Also, blockade of Cl absorption in the medulla alters the electrical

gradient between the tubular lumen and the tubular cells which can

lead to wasting of Magnesium and Calcium.

• Finally, lasix activates the renin-angiotension-aldosterone system.

Increased aldosterone activity results in hypokalemia and enhanced

proton secretion resulting in metabolic alkalosis.

HYPERTENSION

Identify the global magnitude and impact

of hypertension on health.

• Approximately 60 million Americans and 1 billion people worldwide

have hypertension.

• 90% of individuals over the age of 55 will develop hypertension in

their lifetime.

• Hypertension is a major risk factor for:

• Coronary artery disease

• Stroke

• Heart failure

• Renal disease

• Peripheral vascular disease

• About 2/3rds of individuals are unaware of their high blood pressure.

Screening is an important aspect of clinical care.

Maintenance of Blood Pressure

• Short term: Baroreceptor reflex. Baroreceptors in carotid sinus and

aortic arch stretch, send afferent impulse to medulla (CS--

glossopharyngeal, AA--vagus). Tractus solitarius → increase PNS

tone → vasodilate and reduce CO

• Long term: Renin-angiotensin-aldosterone axis regulates Na+ and

intravascular volume.

SNS Regulation

• The kidneys do not work in isolation

• Extrinsic factors include aldosterone and the sympathetic nervous

system.

• Increased sympathetic nervous system activity produces a right-shift

in the pressure-natriuresis curve

• Sympathetic activity promotes volume expansion via the kidneys by

• (1) Promoting renin release by JGG cells

• (2) Directly stimulating Na reabsorption at the tubules

• (3) Causing decreased renal blood flow via vasoconstriction to

indirectly cause Na reabsorption.

Major determinants of blood pressure

regulation • Adrenal Gland:

• Control circulating levels of catecholamines and aldosterone

• Kidneys:

• Maintenance of blood volume and electrolyte balance

• The renin–angiotensin–aldosterone axis is an important hormonal regulator. Renin levels in EH patients are above normal

• Heart:

• CO depending on stroke volume, heart rate and contractility

• Blood Vessels contribute to peripheral vascular resistance:

• Sympathetic activity

• Regulation of vascular tone by local factors, including nitric oxide, endothelin, and natriuretic factors

• Contractile vascular smooth muscle

• Autonomic Nervous System:

• Balance of sympathetic and parasympathetic inputs to heart and peripheral blood vessels

Essential vs. 2° Hypertension

• 90% of Cases are Essential with an unknown cause

• Likely results from multiple defects of blood pressure regulation that

interact with environmental stressors. The regulatory defects may be

acquired or genetically determined and may be independent of one

another.

• Secondary Hypertension: the cause of the high blood pressure

has a definable cause

• More likely if patient develops HTN before age 20 or after age 50

• Often causes BP to rise dramatically

• Often presents abruptly in a patient who was previously normotensive,

rather than gradually progressing over years as in EH

• May have other characteristic abnormalities

• Occurs more sporadically, so may lack a family history

Hypertension + Hypokalemia

Think Renovascular Hypertension or

Primary aldosteronism

To distinguish Primary Aldosteronism from

Renal Stenosis, check Renin

In Stenosis Renin will be high, and in

Hyperaldosteronism Renin will be low.

Do not use ACE Inhibitors with bilateral

renal stenosis

Criteria for Hypertension

Basic Patient Evaluation

461

History and physical examination

ECG: look for LVH and LAE, also assess for CAD

Lab tests

Urinalysis: proteinuria/renal dysfunction

BUN and creatinine: renal function

Serum potassium: renal, aldosterone secreting tumor

Blood glucose: metabolic syndrome

Cholesterol: metabolic syndrome

Initial Laboratory Evaluation of the

Hypertensive Patient

• Urinalysis – evidence of renal damage especially albumin/microalbuminuria

• Blood chemistry for electrolytes and renal function, especially potassium and creatinine with eGFR

• Lipids – LDL, HDL, TG preferably fasting.

• Fasting blood sugar and, if there are concerns about diabetes mellitus, hemoglobin A1c

• ECG

462

Common Symptoms of Hypertension

• There are no common symptoms of hypertension until

you develop end organ damage!

• Headache

• Epistaxis

• Dizziness

• Palpitations

• None

463

Hypertensive patients depend on atrial

kick for efficient filling and can often

decompensate into A-fib

Heart Sequelae

• Left Ventricular hypertrophy

• High arterial pressure increases wall tension

• Typically concentric

• May cause eccentric with chamber dilation

• Diastolic dysfunction pulmonary congestion

• Degree of LVH one of strongest predictors of morbidity

• Systolic dysfunction

• Elevated pressure is too much to handle

• See reduced cardiac output and pulmonary congestion

Vascular Sequelae

• 1. Smooth muscle hypertrophy

• 2. Endothelial cell dysfunction

• 3. Fatigue of elastic fibers

• Promotes atherosclerosis and ultimately coronary artery disease

• Myocardial infarction/ischemia

• Higher risk of complications: rupture of ventricles, LV aneurysm formation, congestive heart failure

• Formation/rupture of aneurysm

• Post MI

• Abdominal aortic aneurysm

• Aortic dissection

• Weakened aorta wall exposed to high pressure tearing of intima

Stroke Sequelae

• Hemorrhagic

• Microaneurysms in cerebral parenchymal vessels

• Atherothrombotic

• Portions of atherosclerotic plaque break off and embolize to smaller

vessels

• Intracerebral vessels may be occluded by local plaques also

• LACUNAR INFARCTS

Renal Sequelae

• Vasculature becomes thickened (hyaline arteriolosclerosis)

• smooth muscle hypertrophy fibrinoid necrosis ischemic atrophy

of tubules

• Malignant hypertension may inflict permanent damage leading to

chronic renal failure

• WITH RENAL FAILURE BP can no longer be regulated

Retinal Sequelae

• Hypertensive retinopathy

• Acute hypertension leads to hemorrhages, exudation of plasma lipids and

areas of local infarction

• Ischemia of optic nerve blurred vision

• Papilledema from increased ICP

• Arterial sclerosis appears as “copper/silver wiring” in the opthalmoscope

Hypertensive Retinopathy

Keith Wagner Classification

Grade I – Arteriolar narrowing, tortousity, irregular caliber with copper/silver wiring.

Grade II – Arteriovenous nicking/nipping.

Grade III – flame-shaped and blot. haemorrhages, cotton wool spots and hard exudates.

Grade IV – Papilledema

472

When to Treat – JNC 7

473

No RF, No TOD At least 1 RF TOD, CCD or DM

No CCD No TOD, CCD, DM (+ or - RF’s)

Prehypertensive

(120-139/80-89)

Stage I

Stage II

(>160/100)***

Life style Life style Drug Rxmodification modification

Life style Life style

mod x 12 m mod x 6m Drug Rx

Drug Rx Drug Rx Drug Rx

(classification based on highest systolic or diastolic BP)

JNC VII. JAMA 2003 or http://www.nhlbi.nih.gov/guidelines/hypertension/

Risk A Risk B Risk C

Mechanisms of Treatment

• Fundamental concept 1: Recall that BP = CO * TPR, so to reduce

BP, a drug needs to be able to reduce CO or TPR.

• Note that most anti-hypertensives reduce TPR (including diuretics),

but Beta Blockers reduce BP primarily via a reduction in CO.

• Fundamental concept 2: Under normal conditions (no drugs), any

sustained drop in BP is eventually negated by the kidneys via volume

expansion. This is because CO = HR * SV, and an increase in volume

can lead to increased CVP increased preload increased SV.

• Thus, an anti-HTN agent must also be able to reduce the ability of the

kidney to retain fluids.

6 Important Consequences

• 1. Some degree of volume expansion via renal compensation typically occurs with the antihypertensives that target the heart and blood vessels primarily i.e pure vasodilators > alpha-1 adrenergic antagonists > CCBs.

• 2. The magnitude of the volume expansion depends on their ability to also reset the renal P/natriuresis relationship.

• 3. The addition of a diuretic as second drug (e.g. a thiazide) usually helps to achieve greater reductions in BP.

• 4. All diuretics cause some reduction in plasma volume

• 5. Most other antihypertensive except ACEIs and ARBs cause a small increase in BV (all sympatholytics, CCBs, arteriolar vasodilators).

• 6. ACEIs and ARBs do not increase BV because they are the most effective at resetting the renal pressure natriuresis relationship

Antihypertensive drugs

• AngII-related drugs: ACEIs = ARBs >> Renin inhibitor• ACE Inhibitors first line

• Diuretics:• 1. Thiazides (and related drugs)

• 2. Potassium-sparing diuretics

• Ca2+ channel blockers• 1. Vascular smooth muscle (VSM)-selective (dihydropyridines)

• 2. Non-selective (diltiazem, verapamil).

• Sympatholytic drugs: • 1. selective α1-adrenergic antagonists

• 2. ß1-adrenergic antagonists

• Aldosterone Receptor Antagonist

ACE Inhibitors

• Prime consideration in patients with concurrent heart failure, diabetes,

or LV dysfunction.

• MOA: 1) Inhibits Angiotensin Converting Enzyme to inhibit

transformation of angiotensin I to angiotensin II

• Inhibits vasoconstriction and aldosterone production TPR falls and sodium

retention declines

• Decreases degradation of bradykinin vasodilation

• Use: CHF, post MI, Hypertension and diabetic nephropathy,

IMPORTANT FOR DIABETICS!

• SE: Dry cough, hyperkalemia, azotemia, teratogen

ARBs

• MOA: block Angiotensin II receptor decrease in peripheral

resistance and decrease in effective circulating fluid volume

• Use: Hypertension, CHF, diabetic nephropathy

• SE: NO COUGH, hyperkalemia, teratogen

Thiazide Diuretics• Thiazide diuretics are the most commonly used diuretics in patients with mild-

moderate HTN with normal renal function.

•

• MOA: They block reabsorption via a Na+/Cl- cotransporter on distal tubule and collecting segment of the renal tubules. • Hydrochlorothiazide, chlorthalidone, indapamide, metolazone

• SE: Elevated triglycerides and glucose, hypokalemia, hyperuricemia, decreased sexual function, metabolic alkalosis. HYPER GLUC + alkalosis and hypokalemia

• Short term effect: reduction in circulatory volume, CO, and mean arterial pressure. The baroreflex kicks in & stimulates sympathetic nervous system, causing transient TPR increase.

• Long term effect: CO returns to normal and TPR decreases. • 1. Baroreceptor resetting and decrease in sympathetic system may cause TPR

reduction

• 2. Thiazide is also a direct smooth muscle relaxant and vasodilation decreases TPR

Beta Blockers

• MOA: Lower blood pressure by decreasing HR and contractility and

decreasing secretion of renin in the kidney which causes a decrease

of TPR

• B1 and B2 – Propanolol, Nadolol, Pindolol, Timolol

• NOT FOR DIABETICS

• B1 – Metoprolol, atenolol, esmolol, acebutolol, bisoprolol, betaxolol

• Less bronchoconstriction

• A1 and B1 – Labetalol

• Vasodilation

• Use: Hypertension, CAD, tachyarrhythmias, migraines, CHF

• SE: Hypotension, bradycardia, bronchoconstriction, arrhythmias,

sexual dysfunction, fasting hypoglycemia

α1 and α2 agonists are not commonly

used anymore except for prazosin which

can be used for prostatic hyperplasia.

Calcium Channel Blockers

• MOA: block voltage gated L-type calcium channels of cardiac and vascular smooth muscles leading to decreased muscle contraction• Decreased myocardial contractility

• Peripheral vasodilation

• Dihydropyridines• Verapamil and Diltiazem

• Use: Hypertension, Prinzmetal angina, Raynaud disease, supraventricular tachycardias

• SE: bradycardia and heart block (verapamil, diltiazem), hypotension, peripheral/pedal edema

• WATCH OUT FOR BETA BLOCKERS bradycardia

Aldosterone Antagonists

• MOA: Compete for the cytoplasmic aldosterone receptor, inhibiting

the Na+ sensitive channel in the kidney which decreases the lumen

negative potential to drive K+ and H+ ion excretion, thus K+ and H+ are

retained in the circulation. Also shows beneficial cardiac

antiremodeling effects

• Spironolactone, Eplerenone

• Use: Primary or secondary hyperaldostonerism, CHF, and to reduce

loss of potassium caused by other diuretics

• SE: hyperkalemia, antiandrogenic activity (not in eplerenone)

Lifestyle Modifications

• Low Sodium diet• Limit intake to < 2 gm Na or <5 gm NaCl per day.

• Less Alcohol• Women no more than 1 drink per day, men no more than 2

• Exercise• 30 minutes aerobic activity 3-5x / week

• Weight loss• 10kg loss will lower BP about 10/8 mmHg

• Stress reduction• Meditation, martial arts, prayer reduce stress and BP

• CPAP treatment for sleep apnea• Associated with risk for CAD

• Avoid decongestants (phenylephrine, etc) and NSAIDS (like ibuprofen)• All NSAIDs may raise blood pressure and diminish the antihypertensive efficacy of

all classes of antihypertensive drugs, except calcium channel blockers.

• Treating dyslipidemia will lower BP about 5 mmHg

Determining Salt Sensitivity

• Salt sensitivity is an independent risk for Cardiovascular Disease

• How to determine salt sensitivity

• Method 1:

• Administer 2 L of normal saline over 4 hours

• Measure BP before infusion, after infusion, and on the next day

• On the second day, give patient diuretic and again remeasure their BP at multiple

timepoints

• Salt sensitivity defined as decrease in MABP >10mmHg on the second day

• Salt Resistant defined as decrease <6 mmg Hg

• Intermediate = 6-9mm Hg

• Method 2:

• Controlled Na+ diet (50 - 250 mmol/day)

• Measure MAP rise of > 4mm Hg

• Controlled Na+ diet (100 – 250 mmol/day)

• Measure MAP rise of >3 mm Hg

J-Shaped Sodium Curve

Salt Sensitivity

• 11% Inverse Salt Sensitivity

• 72% Salt Resistant

• 17% Salt Sensitive

• African American and Japanese at high risk

DEVELOPMENT OF THE

HEART

Describe the developmental basis of

dextrocardia and atrial septal defects.

• On day 23, the heart tube undergoes a characteristic, right-sided

bending that transforms it into a form referred to as the “cardiac loop”.

• Dextrocardia-This developmental abnormality in which the heart lies on the

right side of the thorax occurs when the heart tube bends to the left instead

of the right.

• Formation of septum primum and secundum occurs as endocardial

cushions begin to fuse.

• Atrial Septal Defect (ASD)-A congenital abnormality caused by either

excessive resorption of tissue around the foramen secundum or

hypoplastic/insufficient growth of the septum secundum.

List the embryonic structures involved in

the formation of the interventricular

septum.• Most of the interventricular septum is made up of a muscular septum

• Superiorly, the interventricular septum develops in close coordination with the outflow tract and it is during this process that a large portion of congenital heart defects arise.

• Separation of the outflow tract into aortic and pulmonary channels occurs via the aorticopulmonary septum which arises in a spiral pattern, resulting in the twisted configuration of the aorta and pulmonary artery.

• The septum extends inferiorly into the ventricle to form the top part of interventricular septum

• 3 components of IV septum:

• Muscular wall

• Aorticopulmonary septum

• Endocardial cushions (membranous)

• Pathology: VSDs, persistent truncus arteriosus, transposition of the great vessels, tetralogy of Fallot.

Describe the underlying basis of cyanosis

in congenital heart disease

• Cyanosis occurs when a right-to-left venous shunt mixes venous

blood with systemic blood.

• Deoxygenated/blue blood is being pumped into the systemic

circulation

Identify adult remnants of the fetal

circulation.

• Closure of the ductus arteriosus

• Occurs immediately after birth by contraction of its muscular wall.

• Muscular contraction mediated by bradykinin released by the lungs during initial inflation.

• Ligamentum arteriosum is your obliterated ductus arteriosus

• Patent ductus arteriosus is a failure in closure seen in pregnancies complicated by rubella or hypoxia.

• Closure of the foramen ovale

• Caused by an increase in pressure in the left atrium

• Pressure changes come with the first breath and press septum secundum against septum primum (LO#1 again) with fusion of the two layers becoming complete around 1 year.

• In first days of life, newborn can reverse closure and shunt blood from right-to-left causing cyanotic period

• Closure of the umbilical arteries

• Occurs within minutes of birth by contraction of the smooth muscle

• Caused by thermal and mechanical stimuli and change in oxygen tension

• Permanent closure through fibrous proliferation • Distal portions converted into the medial umbilical ligaments.

• Proximal converted into vesical arteries to bladder

• Closure of the umbilical vein and ductus venosus

• Occurs shortly after closure of the umbilical arteries

• After obliteration, forms the ligamentum teres in the falciform ligament of the abdominal cavity.

• Obliterated ductus venosum forms the ligamentum venosum

List in sequence the vessels involved in

bypassing a postductal coarctation of the

aorta.

• Aorta subclavian a internal thoracic artery intercostal arteries

• Or internal thoracic artery→ superior epigastric artery→ inferior

epigastric artery→ external iliac arteries

CONGENITAL HEART

DEFECTS

Flow Physiology

• Blood will flow down the path of least resistance

• While a pressure difference will dictate blood flow, blood

will travel to the area of least resistance, even if the

physical pressures are equal.

Fick Principle

3 Fetal Structures

• Ductus Venosus: Vascular connection between the placenta and the

heart

• Foramen Ovale: Normal connection between the two atria designed

to allow appropriate shunting

• Ductus Arteriosus: Vascular structure between the PA confluence and

the aorta designed to shunt blood away from the lungs

Atrial Septal Defect

• 1:1500

• Most commonly occur at foramen ovale, also in ostium primum

• Pathophysiology: High pressure in left ventricle leads to a left-right

directed shunt volume overload and enlargement of RA and RV

• Sx: Typically asymptomatic, dyspnea and fatigue, recurrent lower

respiratory infections

• PE: Systolic impulse at LLSB (RV heave), S2 with widened fixed

splitting pattern

• Dx:

• Enlarged heart on radiograph

• RVH, RAE, and RBB on ECG

• Echo for definitive diagnosis

• Rx: Elective surgical repair with suture closure, synthetic patch or

percutaneous closure device

In ASD, atria are compliant, so shunting

depends on ventricular pressures and

resistance

Ventricular Septal Defect

• 1.5-3.5:1000

• Most often in membranous (70%) and muscular (20%) parts of septum

• Pathophysiology: After birth, left-right shunt volume overload on RV, Pulmonary circulation, LA, and LV• Over time can result in chamber dilatation and systolic dysfunction

• Also Eisenmenger Syndrome

• Sx: Large VSDs will cause CHF, tachypnea, poor feeding, failure to thrive and lower respiratory infections• Fall off growth chart after 4 weeks.

• PE: Harsh holosystolic murmur at LSB, systolic thrill

• Dx: • Cardiomegaly and pulmonary vascular markings on radiograph

• LAE, and LVH on ECG

• Echo for definitive diagnosis

• Rx: By age 2 – 50% small VSDs undergo closure, surgical correction within first months for severe disease

Babies are not symptomatic for the first

few weeks due to slow decrease of

pulmonary vascular resistance

Patent Ductus Arteriosus

• 1:2500-5000

• Ductus arteriousus typically closes with decrease in PGE1/bradykinin

• Pathophysiology: After birth blood is shunted from aorta to left pulmonary artery LA, LV, and Pulmonary circulation become volume overloaded• Eisenmenger syndrome

• Sx: Large shunts early CHF, tachycardia, poor feeding, slow growth, recurrent lower respiratory infections, Atrial fibrillation, endarteritis

• PE: Continuous machine-like murmur at left subclavicular

• Dx: • Enlarged cardiac silhouette on radiograph, calcification of ductus may be seen

• LAE and LVH on ECG

• Echo for definitive diagnosis

• Rx: High risk of endarteritis even small/asymptomatic PDA is referred for surgical closure, Prostaglandin synthesis inhibitors may be used prior to surgery

PREMATURITY and rubella are big risk

factors for PDA

AVSD: most common CHD in Trisomy 21

Congenital Aortic Stenosis

• 5:10,000, 4X more common in males

• Typically bicuspid leaflet structure is seen

• Pathophysiology: LV systolic pressure increases to pump blood

across valve LVH and aortic dilatation

• Sx: Typically asymptomatic, dyspnea, angina, syncope, fatigue in

adulthood

• PE: crescendo-decrescendo systolic murmur, systolic ejection click

• Dx:

• Enlarged LV and dilated aorta on radiograph

• LVH on ECG

• Echo for definitive diagnosis

• Rx: Transcatheter baloon valvuloplasty for severe cases, often

followed with later repair

Pulmonic Stenosis

• Congenitally fused valve commissures, fused RV outflow tract or

stenotic pulmonary artery

• Valvular is most common

• Pathophysiology: Increased RV pressure and hypertrophy Right

sided heart failure

• Sx: Mild or moderate: asymptomatic, Severe: dyspnea, exercise

intolerance, abdominal fullness, pedal edema

• PE: Jugular venous a wave, RV heave, crescendo-decrescendo

systolic murmer @ ULSB, widened splitting of S2

• Dx:

• Enlarged RA and RV on radiograph

• RVH on ECG

• Echo for diagnosis

• Rx: Transcatheter balloon valvuloplasty for severe cases

Aortic Coarctation

• 1:6000

• Discrete narrowing of aortic lumen

• Often with Turner Syndrome or bicuspid valve

• Pathophysiology: LV faces increased afterload diminished flow to lower

extremities LVH, dilatation of intercostal arteries erode ribs

• Sx: Heart failure, differential cyanosis w/ PDA, claudication, upper extremity

hypertension

• PE: weak, delayed femoral pulses, elevated BP in arms or right arm > left

arm

• Dx:

• Notching of ribs on radiograph + indented aorta

• LVH on ECG

• Echo for dx and MRI for severity

• 20 mmHg gradient

• Rx: Prostaglandin infusion to maintain PDA, elective repair in children,

excision and anastomosis or transcatheter procedures

Conotruncal Malformations

• The Bulbus cordis, or Conus cordis, will become the right ventricle

and the left & right outflow tracts (membranous portion).

• Neural crest cells migrate to the conotruncal area that becomes the

outflow tracts and abnormal migration or proliferation of these cells

can result in congenital malformations of the septum/outflow area.

Neural crest cells are also involved in craniofacial development and,

so, heart malformations are often associated with facial malformations

(22q11 deletions/Velocardiofacial Syndrome/DiGeorge Syndrome)

Tetralogy of Fallot: CYANOTIC

• 5:10,000, microdeletion 22q11

• Cephalad displacement of infundibular portion of interventricularseptum• VSD

• Subvalvular pulmonic stenosis

• Overriding aorta receives blood from RV and LV

• RVH

• Pathophysiology: Right-Left shunt due to pulmonic stenosis deoxygenated blood to systemic circulation hypoxemia and cyanosis

• Sx: dyspnea, cyanosis, hyperventilation, syncope

• PE: mild cyanosis, clubbing, palpable heave at LLSB, systolic ejection murmur at LUSB

• Dx: Boot shaped heart on radiograph, RVH on ECG, Echo for diagnosis

• Rx: Elective surgical repair @ 6-12 months

Bundle of His runs in this area and is often

displaced. This puts these children at risk

pre- and post-operatively for dysrhythmia.

The conotruncal malformations are very

highly associated with 22q11 deletions,

also termed Velocardiofacial Syndrome or

DiGeorge Syndrome

Consists of the findings of the

aforementioned cardiac anomalies,

thymic aplasia and immunodeficiency,

cleft palate, and hypocalcemia

Transposition of Great Arteries

• 40:100,000, most common in neonates

• Pathophysiology: pulmonary and systemic circulation in

parallel desaturated blood flows to systemic circulation

LETHAL without PDA

• Sx: BLUE

• Dx: RVH on ECG, echo for diagnosis

• Rx: MEDICAL EMERGENCY, prostaglandin infusion,

Jatene procedure (arterial switch)

Truncus Arteriosus

• If the aorticopulmonary septum truncal swellings fail to fuse, a Ventricular Septal Defect arises.

• A persistent truncus arteriosus results in a common outflow tract that receives blood from both ventricles (deoxygenated from right and oxygenated from left). This is classified as a cyanotic disorder.

• We term this an admixture lesion and it means that in a perfectly balanced world equal parts blue blood mixes with equal parts red blood (Qp=Qs) and the saturations are the average of 100% (normal oxygenated blood) and 70% (normal mixed venous blood) or about 85%

Eisenmenger Syndrome

• Severe pulmonary vascular obstruction caused by chronic left-right shunting

• Leads to reversal of shunt and systemic cyanosis

• Pulmonary arteriolar media hypertrophies and intima proliferates reducing cross sectional area of vascular bed

• Vessels thrombose increased resistance

• Sx: dyspnea, erythrocytosis, hyperviscosity, fatigue, headaches, stroke, hemoptysis

• PE: cyanosis, clubbing, JV a wave, loud P2

• Dx: • Proximal pulmonary artery dilatation on radiograph, calcification

• RVH and RAE on ECG

• Echo for diagnosis

• Rx: avoidance of strenuous activity, high altitude, peripheral vasodilators, pregnancy, treatment of infections, management of arrhythmias, phlebotomy for erythrocytosis, pulmonary vasodilators

PATHOLOGY AND

RADIOLOGY

Benign Cardiac Tumors

• Myxomas are the most common primary cardiac tumor.

• Occur in middle aged patients, more common in women

• Patients may have peripheral embolization of the tumor, obstruction of

an AV valve, or sx of a systemic disease (fever, malaise, etc).

• Typically pedunculated masses located in the LA

• T1-weighted images show a mass with intermediate signal intensity

similar to myocardium. However, this signal may be variable due to

calcifications that are hypointense or hemorrhage that is hyperintense

to myocardium. Myxomas typically enhance heterogeneously.

• Lipomas are the second most common primary cardiac tumor

• Have a high intensity on T1-weighted images that darkens on fat

suppressed sequences.

Myxoma

• Clinicopathologic:• Most common primary cardiac tumor.

• 90% in atria, 80% on left side. LEFT ATRIUM

• Mean age is 50. ADULTS

• Clinical manifestations:• “Ball-valve” obstruction of “wrecking-ball” destruction of valve.

• Tumor embolization.

• Systemic symptoms due to cytokine production.

• Gross Morphology:• Often at site of fossa ovalis.

• 1-10 cm in size.

• May be sessile or pendunculated, hard or gelatinous texture.

• Microscopic Appearance:• Stellate myoxoma cells embedded in myxomatous mucopolysaccharides substance.

• Prominent vessels, hemorrhage and inflammation common.

Lipoma

• Pathogenesis: • Benign tumors composed of mature fat cells

• Adults

• Most often occur in left ventricle, right atrium or atrial septum.

• Clinical manifestations:• Typically asymptomatic; incidental finding on imaging.

• May cause ball-valve obstruction or arrhythmias

• Gross Morphology:• May occur in the subendocardium (bulge into the chamber), myocardium (wall

thickening), or subepicardium (bulge into pericardial space).

• Cut section show yellow, glistening, adipose tissue.

• Microscopic Appearance:• Mature adiopose tissue with entrapped myocardium.

Papillary Fibroelastoma

• Pathogenesis:• Benign tumor of adult.

• Typically occur on valves

• May occur on endocardial surface

• Clincial manifestations:• Often incidental finding.

• May break off and embolize.

• Aortic tumors may prolapse into coronary ostia.

• Gross Morphology: • Compared to sea anemone

• Distinctive cluster of yellow-white hairlike projections covering large portions of valvular surface

• Microscopic Appearance:• Narrow, elongated and branching papillary fronds composed of collagen.

• Lined by endothelium.

Rhabdomyoma

• Pathogenesis: • Most common cardiac tumor of CHILDREN

• Benign tumor of cardiac myocytes.

• Frequently associated with tuberous sclerosis

• Most commonly occur in ventricles; often multiple.

• Clinical manifestations:• May result in arrhythmias or chamber obstruction

• Natural history is regression.

• Gross Morphology:• Myocardial tumor that may bulge into ventricular chamber.

• Cut section shows tan-white homogenous solid tissue.

• Microscopic Appearance:• Enlarged, atypical myocytes with abundant cleared out cytoplasm (glycogen).

• Cytoplasm strands to connect nucleus to cell membrane (spider cells).

Cardiac Fibroma

• Pathogenesis: • Typically tumor of CHILDREN, most often in first year of life.

• Benign tumor of fibroblasts; may be locally infiltrative.

• Most often in ventricles (left>right) or ventricular septum.

• Clinical manifestations:• Heart failure, cyanosis, syncope or arrhythmias.

• Gross Morphology:• Myocardial tumor that may bulge into cardiac chamber.

• Nearly always solitary.

• Cut surface is firm, white with whorled appearance.

• Microscopic Appearance:• Bland spindle cell lesion with collagen production.

• May infiltrate into surrounding myocardium.

Malignant Cardiac Tumors

• Metastatic tumors are the most common tumors found in the heart. The most common cardiac metastases include lung, breast, melanoma, and lymphoma. • Metastases often induce a pericardial effusion.

• Angiosarcoma: the most common primary malignancy of the heart• Usually located in the right atrium.

• Characterized by heterogenous signal on T1-weighted images with areas of elevated signal representing hemorrhage.

• Angiosarcomas demonstrate hyperenhancement after the administration of gadolinium contrast agents.

• Other primary malignant tumors are liposarcoma, leiomyosarcoma, and lymphoma.

• Malignant tumors are more likely to be necrotic, have associated nearby edema, be vascular, demonstrate invasion into adjacent tissues, and have an inhomogeneous appearance.

Angiosarcoma

• Pathogenesis: • Most common malignant cardiac tumor of ADULTS.

• Usually in RIGHT ATRIUM

• Clinical manifestations:• Arrhythmias, heart block, CHF, angina, or infarction.

• Cardiac tamponade.

• Vast majority are metastatic at presentation.

• Highly aggressive tumor with poor response to therapy.

• Gross Morphology:• Large, infiltrating dark brown, necrotic mass.

• Infiltration of inferior vena cava or tricuspid valve common.

• Microscopic Appearance:• Highly atypical, malignant cells with enlarged nuclei, and prominent nucleloli

• Rudimentary vascular channels.

• Hemorrhage and necrosis.

Metastatic Tumors

• Direct consequences of tumor:• Pericardial and myocardial metastases

• (melanoma, carcinoma, leukemia/lymphoma).

• A cardiac mass is 40x more likely to be a metastasis than a primary tumor

• Large vessel obstruction

• Pulmonary tumor emboli.

• Indirect consequences of tumor• Nonbacterial thrombotic endocarditis (mucinous adenocarcinoma).

• Carcinoid heart disease (neuroendocrine carcinoma).

• Effect of tumor therapy• Chemotherapy

• (dilated cardiomyopathy).

• Radiotherapy

• (pericarditis, coronary artery disease, restrictive cardiomyopathy).

Myocarditis

• The most common cause of myocarditis is viral infection

• Coxsackievirus B.

• Inflamed myocardium hyperenhances on early gadolinium enhanced

T1 weighted images due to increased inflow of blood. T2 weighted

images will be bright due to edema.

• Delayed enhanced imaging will demonstrate enhancement in the mid-

myocardium, often in a patchy pattern.

Necrosis and LGE

• In the case of myocardial necrosis (e.g acute myocardial infarction),

the rupturing of myocytes expands the extracellular space. This

results in a delay transit of contrast media into and out of the

extracellular space. A delay of 12-15 minutes for imaging capture the

contrast media in the abnormal myocardium, resulting in a relative

increase in enhancement of necrotic myocardium as compared to

normal myocardium.

• This same process occurs in areas of myocardial fibrosis, where the

dense collagen fiber results in a slow transit of contrast media in and

out the extracellular space

Restrictive Cardiomyopathy• Diastolic Heart Failure

• MCC: amyloidosis, hemochromatosis, and sarcoidosis.

• Often difficult to differentiate from constrictive pericarditis, Cardiac MRI is key

• Hypereosinophilic endomyocardial is a type of RCM in which there is extensive endomyocardial fibrosis, often accompanied by an apical thrombus containing eosinophils. The fibrosis itself may be seen as a dark apical rim on gradient echo sequences.

• Sarcoidosis of the heart may appear as focal bright signal in the myocardium on T2 weighted images. Sarcoid granulomas typically demonstrate late hyperenhancement in a patchy midwall and epicardial distribution.

• Amyloidosis involves the myocardium in nearly all cases of primary amyloidosis, but is less common in secondary amyloidosis. The imaging characteristics of cardiac amyloidosis include ventricular wall thickening and DHE. Amyloidosis typically demonstrates extensive midwall DHE. There may be thickening of the atrial septum or right atrial posterior wall as well.

• Hemochromatosis is characterized by iron deposition in tissues throughout the body, including the heart. Iron deposition in the heart is predominantly subepicardial. Due to the paramagnetic nature of the iron deposits, signal loss is seen on both T1 and T2 weighted images.

Pericarditis

• Pericardial effusion is fluid in the pericardial space.

• Patients can present with pain, dyspnea, pericardial friction rub, and hemodynamic compromise.

• Common causes include neoplasm, uremia, autoimmune disease, inflammation, viral infection, tuberculosis, and hemopericardium.

• Large or rapidly accumulating effusions can cause tamponade.

• Cardiac MRI can be used to characterize pericardial effusions and assess the pericardium

• On spin-echo imaging:• Simple effusions have:

• Low signal intensity on T1-weighted imaging

• High signal intensity on T2-weighted imaging.

• Chylous and hemorrhagic effusions have higher signal on T1

Constrictive Pericarditis

• Thickened pericardium.

• Etiology: tuberculosis, radiation, viral pericarditis, or prior surgery.

• Diastolic dysfunction due to a non-compliant pericardium

• Symptoms often mimic restrictive cardiomyopathy, MRI is key

• Normal pericardium is less than 3 mm thick. In CP pericardium is often thickened heterogeneously with bi-atrial enlargement.

• A diastolic septal bounce can be seen with constrictive pericarditis.

• Images may show a lack of pericardial slippage during the cardiac cycle due to the tight adhesion between the pericardium and epicardium.

• In effusive constrictive pericarditis, there is both thickening of the pericardium with adhesions to the epicardium as well as loculatedpericardial effusions.

Aortic Aneurysm

• A vascular aneurysm is a localized abnormal dilation of a blood; most are acquired but they can be congenital.

• Predisposing Factors:• Atherosclerosis and Hypertension

• Cystic Medial Necrosis• Balance of collagen degradation and synthesis is altered.

• Inflammatory cells produce proteolytic enzymes (MMP) which degrades ECM

• Vascular wall is weakened through loss of smooth muscle and elastic fibers.

• Atherosclerotic intimal thickening caused ischemia of inner media.

• Hypertensive changes of vasa vasorum cause ischemia of outer media

• Intrinsic quality of the vascular wall connective tissue is poor

• In some genetic conditions, scaffolding proteins or collagen synthesis are abnormal (Marfan, Ehler-Danlos)

Cystic Medial Necrosis

Abdominal Aneurysm

• Abdominal Aortic Aneurysm (AAA): usually atherosclerotic related.

• Most below the renal arteries and above the aortic bifurcation

• Saccular or fusiform

• >5 cm is BAAAADDDD

• Intimal surface of the aneurysm shows severe complicated atherosclerosis with destruction and thinning of the media; frequently contains a laminated, poorly organized mural thrombus that may fill some or all of the dilated segment.

• Clinical consequences of AAA :• Rupture into the peritoneal cavity or retroperitoneal tissues with massive, potentially

fatal hemorrhage

• Obstruction of a branch vessel resulting in ischemic injury of downstream tissues

• Embolism from atheroma or mural thrombus

• Impingement on an adjacent structure

• Presentation as an abdominal mass that simulates a tumor

Thoracic Aneurysm

• Thoracic Aortic Aneurysm: related to hypertension, tertiary syphilis or

genetic disorders.

• Most are between the aortic valve and innominate artery

• Clinical consequences of thoracic aneurysm :

• Dilatation of aortic root aortic insufficiency

• Respiratory difficulties due to encroachment on the lungs and airways

• Difficulty in swallowing due to compression of the esophagus

• Persistent cough due to irritation of recurrent laryngeal nerves

• Thrombosis, Embolism or Rupture

Aortic Dissection• Aortic dissection occurs when blood splits the laminar planes of the media to form a blood-

filled channel within the aortic wall.

• Pathogenesis:• Hypertension is the major risk factor

• Arteriosclerosis of vaso vasorum leads to smooth muscle hypertrophy and weakening of wall

• Also due to inherited defects from Marfan syndrome, Ehlers-Danlos syndrome, vitamin C deficiency

• The trigger for dissection is an intimal tear blood flow under systemic pressure dissects through the media, fostering progression of the medial hematoma.

• Gross Morphology:• In the vast majority the intimal tear is found in the ascending aorta within 10 cm of the aortic valve.

• The dissection can extend along the aorta retrograde toward the heart as well as distally

• Spreads along the laminar planes of the aorta, usually between the middle and outer thirds.

• Clinical consequences of aortic dissection:• Rupture through the adventitia causing massive hemorrhage or cardiac tamponade

• Extension of dissection along coronary or cerebral arteries causing myocardial infarction or stroke.

• Compression of spinal arteries resulting in transverse myelitis.

• The dissecting hematoma may reenter the lumen of the aorta through a second distal intimal tear, creating a new vascular channel and forming a “double-barreled aorta” with a false channel.

Stanford Type A vs. Type B

• Type B is below the brachiocephalic arteries and suggests medical management

• Type A is above the brachiocephalic arteries and suggests surgical intervention

• Medical management: BP and HR control (Beta blockade)

• Surgical: open surgery or endoscopic procedures

• Complications

• Rupture surgical intervention

• Branch organ malperfusion

• Aneurysmal degeneration

True vs. False Lumen

True lumen in aortic dissection is typically

smaller.

PERICARDIAL DISEASE

Acute Pericarditis Presentation

• Symptoms: Sharp, pleuritic, and positional chest pain in dermatomes

C3-C5 Fever, Non-exertional dypsnea

• PE: Friction rub

• EKG findings

• Abnormal in 90% of patients with acute pericarditis

• Diffuse ST segment elevation

• PR segment depression

• Labs: Lymphocytosis, elevated ESR/CRP

Etiologies of Pericarditis

Infectious Non-infectious

Viral

•Coxsackie B

•Echovirus

•Influenza

•Varicella

•Mumps

•HepB

•EBV

Post-MI

•Immediately post-MI

•Dressler’s Syndrome

Uremic

Neoplastic

Post-Radiation

Associated with Connective

Tissue Disease

•SLE

•RA

•Systemic Sclerosis

Tuberculous

Non-tuberculous bacterial

(purulent)

•S. pneumo

•S. aureus

Drug-induced

•Procainamide

•Hydralazine

Rx for Pericarditis

Etiology Treatment

Viral NSAIDs

Colchicine

Steroids

Post-MI (both types) Aspirin

Purulent Catheter drainage, antibiotics

Tuberculous Multi-drug TB treatment

Uremia Dialysis

Neoplastic Palliative

Pericardial Effusion and Tamponade

• Pericardial effusion is an increase in the fluid in the pericardial space

• Pericardial tamponade occurs when pericardial fluid accumulates under high pressureand severely limits filling of the heart SV and CO decline, leading to hypotensive shock and death

• Physical findings• Beck’s Triad

• Jugular venous distention

• Systemic hypotension

• “Small, quiet heart” on physical exam

• Sinus tachycardia, dyspnea, tachypnea

• Pulsus paradoxus: A decrease in systolic blood pressure of more than 10 mm Hg during normal inspiration.

• Rapid development symptoms of profound hypotension• Confusion

• Agitation

• Slower development of tamponade (e.g., over weeks)• Fatigue due to low CO

• Peripheral edema due to right-sided heart failure

Water Bottle Heart

Electrical Alternans on ECG

Inspiration and Hemodynamics

• Normal hemodynamics• Inspiration → expansion of the thorax → intrathoracic pressure

becomes more negative → increased CVP→ increased RV filling

• Increased RV filling → interventricular septum shifts to the left → decreased LV filling

• Decreased LV filling → decreased SV and decreased systolic BP

• The normal decrease in systolic blood pressure is <10 mm Hg

• Cardiac tamponade• The situation is exaggerated.

• Both ventricles are compressed by the increased fluid in the pericardium, so the bulging of the interventricular septum to the left leads to an even greater decrease in left ventricular volume.

• The decrease in LV filling leads to a decrease in systolic blood pressure >10 mm Hg.

• This is pulsus paradoxus

Treatment for pericardial tamponade is

pericardiocentesis

Etiology of Constrictive Pericarditis

• Chronic pericarditis

• Idiopathic

• Post surgical

• Radiation induced

• Tuberculosis

Constrictive Pericarditis

• Pathophysiology – develops over months to years• Fluid undergoes organization and fusion to the pericardial layers fibrous

scar formation

• Rigid, scarred pericardium inhibits diastolic filling Right sided heart failure

• Impaired filling (reduced preload) decreased SV, CO

• Sx: Fatigue, hypotension, reflex tachycardia

• PE: JVD, hepatomegaly with ascites, peripheral edema, pericardial knock, Kussmaul sign

• Dx:• Chest radiograph – normal or mildly enlarged cardiac silhouette with

calcifications

• ECG – non specific ST and T wave abnormalities, atrial arrhythmias are common

• CT or MRI is superior to echocardiography in assessment of pericardial thickness (pericardial thickness >2mm)

• Definitive diagnosis – cardiac catheterization

Diastolic Bounce

• The dense, fibrous pericardium restrict normal diastolic filling of the

ventricle. However, unlike restrictive disease, the compliance of the

myocardium is not effected.

• When the ventricle reach a certain volume, the pericardium restricts

further filling and the pressure in the ventricle rapidly rises.

• Since both ventricle are subject to this limitation, the only direction for

pressure to equalize is across the interventricular septum, resulting in

this bouncing motion.

• Distinguishes constrictive pericarditis from effusion

Cardiac

Tamponade

Constrictive

Pericarditis

Pericardial

calcification Absent Common

Kussmaul’s signAbsent Common

Pulsus paradoxusPresent Rare

Pericardial knockAbsent Common

Atrial fibrillationRare Common

Rx for Constrictive Pericarditis

• Only effective therapy: surgical removal of the pericardium

• Signs and symptoms maybe not resolve immediately

because of associated stiffness of outer walls of the heart,

but “subsequent clinical improvement is the rule in

patients with otherwise intact cardiac function”

Gross features of Pericarditis

Serous - mild inflammation with small effusion - uremia, autoimmune

Fibrinous - serosanguinous effusion with “bread & butter” fibrin – viral, MI, radiation

Suppurative - pus laden transudate – bacterial

Hemorrhagic - grossly bloody serous effusion - tumor, TB

Caseous - necrotizing caseous necrosis - TB

Fibrinous Hemorrhagic Suppurative

Microscopic Features of Pericarditis

• Parietal and visceral pericardium shows an infiltration of

white blood cells

• Exudate of fibrin (amorphous eosinophilic material)

admixed with white blood cells.

• Serous - mild inflammation with little to no fibrin,

• Fibrinous – Extensive fibrin and moderate mixed inflammation.

• Suppurative – Abundant neutrophilic inflammation.

• Hemorrhagic – Similar to fibrinous but with blood or hemosiderin

laden macrophages.

• Caseous - necrotizing caseous necrosis with granulomatous

inflammation.

ENDOCARDITIS

Bacterial Portals

Predisposing Factors

Structural Other

Rheumatic Heart Disease IV Drug Use

Mitral Valve Prolapse Elderly (>60)

Degenerative Calcific Stenosis Male Predominance

Bicuspid Aortic Valve Poor Dentition

Prosthetic Valves HIV Infection

Congenital Heart Disease Chronic Hemodialysis

Intracardiac Devices Hypercoagulable state

Single most common bacteria causing

endocarditis?

• Staphylococcus Aureus (31%)

Classifications of Endocarditis

• Native Valve

• Prosthetic Valve

• Early: Staph

• Late: Strep

• IVDA

• Right sided heart valves

• Nosocomial

• Health care acquired

• Acute vs. Subacute• Acute endocarditis is a hectically febrile illness that rapidly damages cardiac structures,

hematogenously seeds extracardiac sites, and, if untreated, progresses to death within

weeks.

• Subacute endocarditis follows an indolent course; causes structural cardiac damage only

slowly, if at all; rarely metastasizes; and is gradually progressive unless complicated by a

major embolic event or ruptured mycotic aneurysm.

Bacterial Mechanisms for Survival

• 1. Surface adhesion molecules called microbial surface components recognizing adhesion matrix molecules (MSCRAMMs)• travel to nonbacterial thrombotic endocarditis (NBTE) or injured endothelium

• EXCEPTION: S. aureus – so virulent it does not need injured epithelium

• NOTE on NBTE: often a result of hypercoagulable state → maranticendocarditis (uninfected vegetations seen in patients with malignancy and chronic diseases)

• 2. Other Adherence Mechanisms• Gram positives – fibronectin binding proteins

• S. aureus clumping factor

• streptococci – glucans or FimA

• 3. Ability to survive in bloodstream (gram + more resistant to destruction by complement system)

• 4. Fibrin deposition combines with platelet aggregation and microorganism proliferation to generate an infected vegetation.

HACEK

• H: Haemophilus aphrophilus

• A: Actinobacillus actinomyetemcomitans

• C: Cardiobacterium hominis

• E: Eikenella corrodens

• K: Kingella kingae

• These are all slow growing, fastidious, gram-negative bacilli that

account for 5-10% of native-valve endocarditis in non-drug using

individuals.

Pathogenesis

• 1. Endocardial injury

• 2. Focal adherence of platelets and fibrin

• 3. Platelet fibrin nidus becomes colonized with bacteria

• 4. Further activation of coagulation system via extrinsic

clotting pathway and tissue factor

• 5. Adherent monocytes and cytokines

• 6. Activated endothelial cells express further local

deposition of fibronectin

• 7. Bacterial growth occurs within matrix of fibronectin

which shields it from the host immune response

Clinical Signs

Vegetations• Vegetative lesions are masses of platelets, fibrin, microcolonies of

microorganisms, and scant inflammatory cells

• Vegetation morphology differs with different types of endocarditis

• Rheumatic heart disease; infectious endocarditis; nonbacterial thrombotic endocarditis; Libman-Sacks endocarditis (non-bacterial endocarditis seen in SLE)

Complications

• CHF develops in 30-40% of patients

• Emboli:

• leading to stroke or encephalopathy

• leading to MI

• leading to renal infarcts and flank pain/ hematuria

• Glomerulonephritis

• Neurologic complications: stroke, encephalopathy, hemorrhagic

infarcts, ruptured mycotic aneurysms, seizures, purulent meningitis

• Heart block: Myocardial abscesses burrow through ventricular septum

and conduction system.

• Chordae rupture leading to severe mitral regurgitation

• Pericarditis: Myocardial abscesses burrow through epicardium.

Diagnostics

• History: Congenital defects, IV drug use, Hx of valve disease, Hx of valve replacement or repair, prior endocarditis

• PE: Murmurs, Fever, Petetchiae, Osler’s nodes, Janeway lesions, Roth spots, Splenomegaly

• Blood Count: Low HCT and elevated ESR, C-reactive Protein and WBC, Serum Rheumatological Factor

• Blood Cultures

• ECG

• Echocardiogram: TTE or TEE

Diagnostics: Echocardiography

• Transthoracic echocardiography (TTE) is noninvasive and exceptionally specific

• Cannot image vegetations <2 mm in diameter, and in 20% of patients it is technically inadequate because of emphysema or body habitus.

• TTE detects vegetations in only 65% of patients with definite clinical endocarditis.

• Moreover, TTE is not adequate for evaluating prosthetic valves or detecting intracardiac complications.

• Transesophageal echocardiography (TEE) is safe and detects vegetations in >90% of patients with definite endocarditis

• Studies may be false-negative in 6–18% of endocarditis patients. When endocarditis is likely, a negative TEE result does not exclude the diagnosis but rather warrants repetition of the study in 7–10 days.

• TEE is the optimal method for the diagnosis of PVE or the detection of myocardial abscess, valve perforation, or intracardiac fistulae.

Dx: Duke Major Criteria• Major Criteria

• 1) Blood culture positive for IE• A.Typical microorganisms consistent with IE from 2 separate blood cultures:

• 1) Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus;

• 2) Community-acquired enterococci, in the absence of primary focus; or

• B. Microorganisms consistent with IE from persistently positive blood cultures, defined:• 1) At least 2 positive cultures from blood samples drawn >12 hours apart

• 2) All 3 or a majority of >4 separate cultures of blood

• C. Single positive blood culture for Coxiella burnetii or antiphase I IgG ab titer > 1:800

• 2) Evidence of endocardial involvement

• 3) Echocardiogram positive for IE• A. Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets,

or on implanted material in the absence of alternative anatomic explanation

• B. Abscess

• C. New partial dehiscence of prosthetic valve

• 4) New valvular regurgitation

Diagnosis: Duke Criteria

• 1. Definitive infective endocarditis

• (1) 2 major criteria

• (2) 1 major criterion and 3 minor criteria

• (3) 5 minor criteria

• 2. Possible infective endocarditis

• (1) 1 major criterion and 1 minor criterion

• (2) 3 minor criteria

• 3. Rejected infective endocarditis

• (1) Firm alternate diagnosis explaining evidence that was attributed to IE

• (2) Resolution of “infective endocarditis syndrome” with antibiotic therapy for 4 days or less

• (3) No pathologic evidence of IE at surgery or autopsy, with antibiotic therapy for 4 days or less

• (4) Does not meet criteria for possible endocarditis

Vegetations and Therapy

• Vegetations protect bacteria from host defenses and the metabolically

inactive bacteria within them are difficult to kill with antibiotics

• To cure endocarditis, all bacteria in the vegetation must be killed

• This means antimicrobial therapy must be bactericidal and prolonged

• Vegetation size and position can be determined by transthoracic or

transesophageal echocardiography

• Large vegetations (>10 mm in diameter) may indicate surgical removal

• Vegetation obstructing valve may indicate surgical removal

Subtleties of Endocarditis

• Protean = displaying great diversity or variety

• Symptoms are very nonspecific and endocarditis is rare; however it is

extremely serious. Even though the symptoms are nonspecific, you

can hear a heart murmur in many cases...

• Patients may present with symptoms more indicative of other disease

processes, such as: hematuria, back pain, or bronchitis

• Also, if patients are treated with antibiotics before blood is drawn for

cultures, the ability to grow and identify bacteria may be lost, which is

not good since knowing the causative microorganism is an important

step in diagnosing and treating endocarditis.

It is difficult to eradicate bacteria from the

vegetation because local host defenses

are deficient and because the largely non-

growing, metabolically inactive bacteria

are less easily killed by antibiotics. To cure

endocarditis, all bacteria in the vegetation

must be killed; therefore, therapy must be

bactericidal and prolonged.

Antibiotic TherapyOrganism Antibiotic

Susceptible Streptococcus 1) 4 weeks Penicillin

2) 4 weeks Ceftriaxone

3) 4 weeks Vancomycin

4) 2 weeks Penicillin + 2 weeks

Gentamycin

Resistant Streptococcus 1) 4 weeks Penicillin + 2 weeks

Gentamycin

2) 4 weeks Vancomycin

Susceptible Enterococcus 1) 4 weeks Penicillin + 4-6 weeks

Gentamycin

2) 4 weeks Ampicillin + 4-6 weeks

Gentamycin

3) 4 weeks Vancomycin + 4-6 weeks

Gentamycin

Resistant Enterococcus 1) 6 weeks Vancomycin + 6 weeks

Gentamycin

Susceptible Staphylococcus 1) 4-6 weeks Nafcillin + 2 weeks

Gentamycin

Resistant Staphylococcus 1) 6 weeks Vancomycin + 2 weeks

Gentamycin

HACEK 1) 4 weeks Ceftriaxone

2) 4 weeks Amp sulfbactam

For Culture Negative Endocarditis give 4-

6 weeks Vancomycin + 4-6 weeks

Gentamycin

Aminoglycoside Synergy

• Aminoglycoside Synergy (source: handout on antibiotics)

• Enterococci are intrinsically resistant to low to moderate levels of

aminoglycosides

• Synergy occurs when enterococci with a low level of

aminoglycoside resistance are exposed to a combination of

aminoglycosides and a ‘cell wall active’ antibiotic (i.e. penicillin,

vancomycin)

• The cell wall-active antibiotic facilitates intracellular uptake of the

aminoglycoside, which then acts bactericidally

• Efficacy in Endocarditis

• Need to kill the bacteria

• Appears to be the only effective bactericidal rx of enterococci

Surgical Indications

• Class I - Surgery Absolutely Indicated

• Causative organism is resistant or fungal

• In the setting of Congestive Heart Failure

• AV block (burrowing abscess severing conduction system)

• Abscess seen on echo

• Class II - Surgery Possibly Indicated

• Recurrent emboli or persistent vegetations

• Mobile vegetations >10mm in size

• Class III - Surgery Contraindicated/unnecessary

• Uncomplicated prosthetic valves

• Organism sensitive to antibiotic therapy

Prophylactic Antibiotic Treatment

• Rationale - give to patients who would have adverse outcome if

endocarditis is contracted

• Amoxicillin in pill form 30 minutes before procedure

• Criteria

• Prosthetic valve placed

• Previous endocarditis

• Congenital heart defect

• Unrepaired cyanotic defect

• Repaired defect with placement of prosthetic material (i.e. mesh in ASD)

• Repaired defect with residual deficiency

• Cardiac transplant patients who develop valvulopathy

Prosthetic Valve Infections

• Prosthetic valve endocarditis (PVE) arising within 2 months of valve

surgery is generally nosocomial, the result of intraoperative

contamination of the prosthesis or a bacteremic postoperative

complication.

• Etiology: Time of onset post-op is related to the likely bacterial source

• Within 2 months - nosocomial (S. aureus, CoNS, facultative gram-

negative bacilli, diphtherioids, fungi)

• 2-12 months - considered a delayed-onset nosocomial infection

• >12 months - organisms similar to community-acquired endocarditis

Catheter Infections

• Incidence of 1.65 infections per 1,000 central line days in the US

• Frequent source of infection in patient populations that require long-term

catheterization, including hemodialysis, oncology, total parenteral nutrition patients

• Site of catheter infection impacts rate of infection, subclavian the

lowest risk

• Endocarditis complicates 6–25% of episodes of catheter-associated

S. aureus bacteremia

Mistreated Endocarditis and prior

exposure to antibiotics causes negative

cultures