High Yield Weeks 1 6

Weeks 1-6

• LG 1.1 Cardiac cycle Physiology Pavlick• Objective: Define and distinguish between each of the following terms:

diastole, systole, heart rate, stroke volume, cardiac output, venous return, EDV, ESV and ejection fraction.

• Objective: Distinguish between the 4 basic heart sounds and explain how each of the sounds is produced.

• Objective: Explain the series of events that occur during each of the following

phases of the cardiac cycle: atrial systole, isovolumetric ventricular contraction, rapid ventricular ejection, reduced ventricular ejection, isovolumetric ventricular relaxation, rapid ventricular filling, and reduced ventricular filling.

– KAPLAN DISK 6-2-03

LG1.1 cardiac cycle

Basic TerminologySystole

– period of contraction and emptying atrial systole and ventricular systole

Diastole – period of relaxation and filling atrial diastole and

ventricular diastole

Stroke Volume (SV) – quantity of blood pumped out of the ventricles per

beat @ rest - 70 ml/beat; maximum - 120 ml/beat

Heart Rate (HR) – # of times the heart beats per minute @ rest 72

beats/min; maximum – 230 beats/min

Cardiac Output (CO) – quantity of blood pumped by the ventricles per

minute @ rest - 5 L/min; maximum - 20-25 L/min – The following relationship exists between CO, HR,

and SV: HR X SV = CO

Venous Return (VR) – quantity of blood returned to the heart per minute

normally, venous return equals cardiac output

End Diastolic Volume (EDV) – quantity of blood remaining in the ventricles at the end

of ventricular diastole average value is around 130 ml

End Systolic Volume (ESV) – quantity of blood remaining in the ventricles at the end

of ventricular systole average value is around 60 ml

Ejection Fraction– the fraction of the EDV that is ejected in one SV

normally around 0.55 or 55% indicator of contractility ejection fraction = SV / EDV

Cardiac Index (CI)– The cardiac output normalized for body surface area– CI = CO SA– Normal = 2.8-4.2 L/min/m2

1/28/2009

anatomy lab

Cardiac cycle• http://www.youtube.com/watch?v=Ge12P7u0a

Qo&feature=PlayList&p=2AA4AF1F5402CE54&index=39

1/27/2009

http://www.youtube.com/watch?v=Ge12P7u0aQo&feature=PlayList&p=2AA4AF1F5402CE54&index=39



LG1.1 cardiac cycle

Right & Left Heart DifferencesAtrial Systole (contraction)

begins and ends earlier in the RA than LA Initiation of ventricular contraction• contractions start earlier on the left side• mitral valve closes before the tricuspid (timing difference is so small that a split is not heard)• pulmonary valve opens before the aortic valve (hence, duration of isovolumetric

ventricular contraction is briefer for the right ventricle)

Ventricular ejection• Ejection from the right ventricle lasts longer than that from left ventricle• The aortic valve, with higher pressure downstream, closes before the pulmonary valve• The pulmonary valve, with its lower pressure downstream, opens first and closes last

Ventricular relaxation• pulmonary valve closes after the aortic valve• isovolumetric ventricular relaxation is briefer in the right ventricle• tricuspid valve opens before the mitral valve• right ventricle fills before the left ventricle

1/28/2009

LG1.1 cardiac cycle

Phases of the

Cardiac Cycle

1/28/2009

LG1.1 cardiac cycle

7 phases of the CARDIAC CYCLEPhase A – Atrial Systole• in order for this event to occur, the left atrium must FIRST be depolarized (notice the location of the P wave just before atrial

systole) • the contribution of atrial contraction to ventricular filling is usually small (approx. 15-20% of the total ventricular volume) • after atrial systole, LVP > LAP and the mitral valve shuts • 1st heart sound (S1) is heard; may be “split” because the mitral valve closes slightly before the tricuspid valve (usually the timing

difference is so small that a split is not heard)• the volume of blood in the left ventricle at this point is the EDV • Important Lesson: AFTER ALL IS SAID AND DONE, THERE ARE 3 PHASES OF VENTRICULAR FILLING

Phase B – Isovolumetric Ventricular Contraction• the left ventricle develops significant pressure after initiation of QRS complex and starts contracting• ventricular volume is constant, as all heart valves are closed

Phase C – Rapid Ventricular Ejection• eventually, the left ventricle develops enough pressure such that LVP exceeds aortic pressure • the aortic semilunar valve opens and blood is ejected quickly

Phase D – Reduced Ventricular Ejection• blood is ejected at a slower rate• the volume of blood remaining in the left ventricle after ejection is the ESV • once blood is ejected, LVP falls below aortic pressure and the aortic semilunar valve shuts • 2nd heart sound (S2) is heard• inspiration delays closure of the pulmonic valve and causes splitting of S2; that is, during inspiration, the pulmonic valve closes

distinctly after the aortic valve • appearance of dicrotic notch on aortic pressure curve• aortic pressure begins to fall as blood flows into distant arteries

1/28/2009

LG1.1 cardiac cycle

7 phases of the CARDIAC CYCLE

Phase E – Isovolumetric Ventricular Relaxation• marks the end of ventricular systole / beginning of ventricular diastole • at the end of a heartbeat, all four chambers of the heart are relaxed and all of its valves are closed • the left atrium is filling with blood that has returned from the pulmonary veins • left ventricular pressure falls because of the blood that was previously ejected • as left atrial volume increases, left atrial pressure (LAP) begins to exceed left ventricular pressure (LVP), resulting in opening of

the mitral valve • Important Lesson: HEART VALVES OPEN AND CLOSE DUE TO DIFFERENCES IN PRESSURE

Phase F –Rapid Passive Ventricular Filling• blood flows quickly past the mitral valve and into the relaxed left ventricle • there is NO contraction of any of the heart chambers• left ventricular volume begins to increase

Phase G -- Slow Passive (Reduced) Phase or diastasis • blood flows slowly past the mitral valve and into the relaxed left ventricle • there is NO contraction of any of the heart chambers• left ventricular volume continues to increase• once blood is ejected, LVP falls below aortic pressure and the aortic semilunar valve shuts • 2nd heart sound (S2) is heard• inspiration delays closure of the pulmonic valve and causes splitting of S2; that is, during inspiration, the pulmonic valve closes

distinctly after the aortic valve• appearance of dicrotic notch on aortic pressure curve• aortic pressure begins to fall as blood flows into distant arteries

1/28/2009

LG1.1 cardiac cycle

The sequence of mechanical and electrical events that repeats with every heartbeat

1/28/2009

Cardiac Cycle

LG1.1 cardiac cycle

EKG

1/28/2009

P wave

Depolarization of the ATRIA

QRS Complex depolarization of the ventricles

T Wave Repolarization of the ventricles

PQ Segment time when the impulse is traveling through the AV node, bundle of His, and bundle branches

PR Interval onset of P wave to middle of QRS complex

ST Segment End of QRS complexrepresents the time from the end of ventricular depolarization to the start of ventricular repolarization.

ST Interval end of QRS complex to end of T wave

QT Interval onset of QRS complex to end of T wave

LG1.1 cardiac cycle1/28/2009

LG1.1 cardiac cycle

Overview of Heart Sounds

S1: this is the first heart sound and is associated with closure of the mitral and tricuspid valves at the onset of ventricular contraction

S2: the second heart sound is shorter and usually of higher frequency than S1 -- it indicates the end of ventricular systole and the beginning of diastole, which is characterized by the closure of the semilunar valves

S3: the third heart sound is associated with the rapid passive filling phase of diastole; iThe third heart sound is sometimes heard in children with thin chest walls or in patients with left ventricular failure. The vibrations occur in early diastole and are caused by the abrupt cessation of ventricular distention and by the deceleration of blood entering the ventricles.

S4: the fourth heart sound is associated with atrial contraction; it is not audible in normal adult; it is usually heard in pathological conditions in which an unusually strong atrial contraction occurs in combination with low compliance (i.e., increased stiffness) of the left ventricle

1/28/2009

• LG 1.2 Coronary circulation Physiology Pavlick• Objective: Explain how the sympathetic and

parasympathetic nervous systems influence CBF.

LG1.2 Coronary Circulation & Myocardial Oxygen

1/29/2009

Coronary Blood Flow (CBF)Heart Rate and CBF:• Changes in heart rate, because they affect the duration of diastole more than that of

systole, also affect coronary blood flow. • During tachycardia, the fraction of the cardiac cycle spent in diastole decreases,

minimizing the time available for maximal left coronary perfusion. • If the heart is healthy, the coronary vessels can adequately dilate in response to the

metabolic signals generated by increased cardiac work (active hyperemia), which offsets the negative effects of the shorter diastole.

• On the other hand, a high heart rate can be dangerous to a patient with severe coronary artery disease.

SNS & CBF:• The primary effect of stimulation of the SNS to the coronary vessels is

VASOCONSTRICTION (via a1-receptors). HOWEVER, the observed effect is a great INCREASE IN CORONARY BLOOD FLOW (via b1-receptors).

• In normal circumstances: Sympathetic stimulation increases coronary blood flow by increasing heart rate

and contractilityIncreases cardiac work and myocardial O2 consumptiondecrease in tissue PO2 increases coronary blood flow by metabolic regulation.

Heart Rate and CBF:• Changes in heart rate, because they affect the duration of diastole more than that of

systole, also affect coronary blood flow. • During tachycardia, the fraction of the cardiac cycle spent in diastole decreases,

minimizing the time available for maximal left coronary perfusion. • If the heart is healthy, the coronary vessels can adequately dilate in response to the

metabolic signals generated by increased cardiac work (active hyperemia), which offsets the negative effects of the shorter diastole.

• On the other hand, a high heart rate can be dangerous to a patient with severe coronary artery disease.

SNS & CBF:• The primary effect of stimulation of the SNS to the coronary vessels is

VASOCONSTRICTION (via a1-receptors). HOWEVER, the observed effect is a great INCREASE IN CORONARY BLOOD FLOW (via b1-receptors).

• In normal circumstances: Sympathetic stimulation increases coronary blood flow by increasing heart rate

and contractilityIncreases cardiac work and myocardial O2 consumptiondecrease in tissue PO2 increases coronary blood flow by metabolic regulation.

• LG 1.6 Atherosclerosis, genetics Biochemistry Gardner• Objective: Discuss the role that each of the following plays in fatty streak formation and

atherosclerosis.• LDLs• Oxidation and Glycation• Monocytes/Macrophages• Scavenger receptors• Foam cells• Inflammation• Smooth muscle cells• Growth factors• Calcium• Fibrous cap• Collagen• Tissue factor• Platelets• Clotting factors• Thrombus

• Objective: Discuss the hypothesized relationship between Lp(a) and increased risk of CHD.

LG1.6 Biochemistry Atherosclerosis, Clotting & Cholesterol

Risk Factors for CHD• Hyperlipidemia • Hypertension• Smoking• Hyperglycemia• Genetics (risk is higher if):

– More affected relatives.– Female relative affected.– Early Onset (before age 55)– Genes involved in lipid metabolism and transport are major area of risk.

Additional Risk Factors for CHD:• Lp (a) is a LDL with a apoplipoprotein called apo(a).• Lp(a) is a risk factor for CHD.• Lp(a) are determined by genetics through trans fats and have been shown to increase Lp(a) levels.• Apo(a) is strucurally homologus to plasminogen.• Plasminogen is precursor to Plasmin, which cleaves fibrin to degrade clots.• α2-antiplasmin found in the blood that inactivates free plasmin.

Take home message:High Lp(a) -> low plasmin and increased clotting (because urokinase and t-Pa bind Lp(a) instead.

1/27/2009


1/27/2009

• Atherosclerosis– The process of build-up of materials on the inner lining of an artery.

• Examples include: cholesterol, triacylglycerol, calcium, machrophages, collagen, elastin, foam cells, vascular smooth muscle and dead cells.

– Process• Fatty streak formation

– LDL particles accumulate in the intima of arteries, if hyperglycemia is present, LDLs become glycated» Oxidation of LDL occurs in the intima» Once this LDLs are oxidized or glycated, they stimulate an inflammatory response

• Monocytes migrate and are transformed into macrophages.• Macrophages (express unregulated scavenger receptors) ingest the oxidized LDLs

• This leads to the formation of foam cells= fatty streak.• Foam cells release factors that stimulate smooth muscle cells to migrate to the

site from the media to the intima (cytokines).• Foam cells die and release their lipid content.• Smooth muscle cells proliferate and produce ECM (eg.collagen, lipids) build-

up.

•

– The fatty streak converts to Atheroma» It’s believed that smooth muscles play a role in the transition by changing the site from a

streak to fibrous/fatty lesion• Growth factors are expressed at the site of the lesion.• PDGF, Multiple Growth factors and TGF-Beta.

» Atheroma often has core of lipid (necrotic core) released from dying foam cells» Calcium deposits from smooth muscle cell death enhances the instability of the

atheroma» Atheroma has a fibrous cap which is very fragile

• This thin fibrous cap surrounding the plaque can rupture (c)• This rupture can expose tissue factor and collagen (d)• Collagen stimulates platelet plug and TF stimulates fibrin clot formation.

• It is the thrombus formation that occludes the artery causing an MI—The clot is what occludes the artery not the atheroma

• If it moves, then it becomes embolism.• Accumulation and swelling in the artery walls that is made up of

macrophages, lipids cholesterol and fatty acids.

• Cardiac Cell death– Two forms of cell death• Necrosis

– Occlusion of a coronary artery leads to oxygen deprivation» If it is within 20 minutes, tissue become necrotic

• Apoptosis– Cells undergo apoptosis before becoming necrotic cells

» The surrounding area of necrosis undergo another type of cell death—apoptosis.

» Inhibiting apoptosis can reduce the severity of cell death.


Urokinase and t-Pa convert plasminogen to plasmin

1/27/2009

• Other Risk Factor for CHD—LIPOPROTEIN (a) or Lp(a)• Lp(a) particles are identical to LDL but have an apoliprotein called apo(a)

associated with apo B-100• Levels of Lp(a) are largely determined by genetics

– Trans fat can increase them as well

• High levels of Lp(a) associated with higher risk for CHD• Mechanism

– Apo is structurally homologous to plasminogen» Plasminogen is incorporated into a clot during its formation and then activated by

plasminogen activators• Anti-plasmin also found in the blood inactivates plasmin

» Plasminogen is converted into plasmin by plasminogen activators such as T-PA or urokinase.• Plasmin then cleaves fibrin into soluble degradation products

(anticoagulant)» THE PROBLEM: T-pa and urokinase bind Lp(a) rather than plasminogen

• This leads to low levels of plasmin and enhanced clotting

• LG 1.5 Cholesterol, lipids Biochemistry Gardner

• Objective: List the functions of the following apolipoproteins: CII, AI, E, B-48 and B-100.

• Diagram how an apo C-II or LPL deficiency could cause elevated chylomicrons and VLDLs

SP1.2 Lipoproteins & Lipid Transport

Lipoproteins & Lipid Transport• From least to most dense: chylomicrons, VLDL, LDL, HDL• Exogenous pathway – metabolism of chylomicrons, which carry dietary fats• Endogenous pathway – transports triacylglycerols synthesized from the liver to the body• Elevated levels of intracellular cholesterol inhibit HMGCoA reductase and therefore reduces LDL receptor

numbers on the cell surface

The apolipoproteinsA1: Produced in the small intestines and liver

Major component of HDLThe protein promotes cholesterol efflux from tissues to the liver for excretion.

B100:Synthesized in the liver

Found in VLDL, IDL, LDLB48: Synthesized in the intestinal epithelium

Found in chylomicronsC II: An activating cofactor for lipoprotein lipaseC III: An inhibitor of lipoprotein lipaseApolipoprotein E:

• Synthesized in the liver• Blocked from interacting with hepatic receptors by the C apolipoproteins• Found on chylomicrons, VLDL and HDL• When present on IDL, apolipoprotein E enhances the interaction of apolipoprotein B100 with the

hepatic LDL-receptors

1/26/2009

– Chylomicrons• They are made in the small intestine and released in the

lymphatic system and then the blood. – Contain protein, phospholipid (hydrophilic layer) and large amounts

of triacyglycerol, cholesterol and cholesteryl esters (hydrophobic layer)

• In the blood HDL gives chylomicrons ApoE and ApoC-II• ApoC-II binds and activates lipoprotein lipase (LPL)-

extracellular protein anchored to the capillary wall by heparan sulfate in different tissues (adipose, cardiac and skeletal muscle.

• LPL degrades the triacyglycerol in the chylomicron to free fatty acids and glycerol

– Hyperchylomicronemia• People with this condition may have:

– A deficiency of ApoC-II or– A deficiency of LPL or both.

• Test for deficiency of LPL or ApoC-II– Heparin competes with heparan sulfate which is bound to LPL

» Adding IV heparin will lead to its binding to LPL and release from the capillary walls into the blood.• Blood is drawn to measure LPL activity

• Low LPL activity=less binding therefore LPL is deficient

• High LPL activity= LPL binds, but ApoC-II activity is low or deficient.

SP1.2 Lipoproteins & Lipid Transport

Atherosclerosis & Hyperlipidemia

• Atherosclerosis is a multifactorial chronic inflammatory disease that is associated with the accumulation of LDLs in the walls of the larger arteries

• Familial hypercholesterolemia generally occurs as a result of a defective (or absent) LDL receptor

• Statins (HMG CoA reductase inhibitors) block cholesterol biosynthesis and consequently increase the number of LDL receptors on hepatocytes, thus reducing LDL levels in the circulation while increasing HDL levels

1/26/2009

• LG 1.7 Coronary artery disease and complications of MI Pathology Fischione

• Objective: Describe the various complications of an Acute Myocardial Infarct

• Objective: Define Sudden Cardiac Death and its cause

Pathology wk1 LG1.7

Too many Big Macs may cause?

Progressive

Acute

1/28/09

Coronary Artery Disease:• Atherosclerosis of the coronaries -> myocardial ischemia • May be chronic progressive ischemia from atherosclerosis • May be acute coronary thombosis due to a sudden occlusion

Results in a MI in an anatomically defined area

Acute MI cause:White thrombus forms when atherosclerotic plaque ruptures. White thrombus is mostly platelets w/ little fibrin.

Pathology wk1 LG1.7

Calcified plaque

1/28/09

• Coronaries -> atherosclerosis -> narrowing of the lumen due to fibrotic plaques and atheromas • Plaques may be covered with fibrinous clots in an acute occlusion• Granulation tissue of the plaque and thrombi in older lesions may

reestablish blood flow via recanalization• Wall contains calcium and cholesterol deposits

Pathology of CAD

Pathology wk1 LG1.71/28/09

Rapid, sudden occlusion of a coronary artery

• Sudden cardiac death in ~25%• Among survivors of the onset: inadequate perfusion -> multisystemic major organ failure• Cerebral ischemia most dangerous• Kidney damage most often

Causes:• Thrombosis of a coronary artery (80-90%)• Ulceration of an embolized atherosclerotic plaque• Prolonged vasospasm

Myocardial Infarction

Pathology wk1 LG1.71/28/09

Anterior wall infarctOcclusion of the Left Anterior Descending (LAD) Artery – over 50%

Lateral wall infarctOcclusion of the Left Circumflex Artery – 30-40%

Infarct of the right ventricle and posterior wall of the left ventricle

Occlusion of the Right Coronary Artery (RCA) – 10-20%

Distribution of MI’s

Pathology wk1 LG.17

Types of MI’s

Transmural:• Most common• All 3 layers of the heart involved• Free wall of the left ventricle and/or

interventricular septum usually involved

• New Q-waves develop1/28/09

Subendocardial or Intramural:• Infarction usually concentric around the subendocardial layer of the left ventricle• Q waves are absent

Transmural Subendocardial

Pathology wk1 LG1.7

Acute with soft yellow & hemorrhagic tissue

Subacute with deposition of granulation tissue1/28/09

Gross Pathology of MI:First 1-2 days• Cannot be definitively

identified• May be pallor of infarcted

myocardium3-5 days • Infarct becomes yellow • Hemorrhagic rim• Soft infarcted myocardium

from hydrolytic enzymes released from neutrophils

1-2 weeks• Granulation tissue imparting a

gray-pink, mottled appearanceChronic infarct• White-tan

fibrosis

Gross Pathology of MI

Pathology wk1 LG1.7

Ventricular rupture with necrosis Hemopericardium due to Rupture Causing Cardiac Tamponade

1/28/09

• COMPLICATION OF MI• Softened necrotic myocardium ruptures• Blood fills the pericardial sac (hemopericardium) -> cardiac tamponade (compression of the heart)

Myocardial Rupture

Pathology wk1 LG1.7

Left Ventricular Aneurysm• COMPLICATION OF MI• MI’s of the left ventricle -> granulation and fibrous tissue

replacement -> bulge under pressure -> ventricular aneurysm• Fibrous tissue does not contract -> heart dilated and contracts

irregularly

1/28/09

Ventricular AneurysmW/ Mural Thrombus

Ventricular Aneurysm With Infarcted Myocardial Wall

Pathology wk1 LG1.7

Mural Thrombus• COMPLICATION OF MI• Endocardium damaged/disrupted• Blood coagulates in contact with the necrotic

endocardium/exposed myocardium -> thrombus attached to the wall

• Complications:– Impede blood flow– Weakens ventricular

contractions– May detach giving rise

to emboli -> cerebral Infarcts

1/28/09

• LG 1.8 Acute coronary syndrome Clinical Thomson

• Objective: Recognize acute changes in an ECG associated with a myocardial infarction.

• Objective: Formulate the pathophysiology of myocardial ischemia in terms of myocardial oxygen demand and supply.

LG1.8 acute coronary syndrome, SP1.1 chest pain

Pulmonary Edema Related to Ischemia

1/28/2009

Chest x-ray may show pulmonary edema. Ischemia changes myocardial stiffness, increasing the resistance to ventricular filling, elevating ventricular filling pressures, and ultimately causing symptoms of pulmonary congestion


Arcus senilis: also known as arcus cornealis, – gray or white arc visible above and below the outer part of the cornea – Eventually the arc may evolve into a complete ring around the cornea. – common in older adults. – caused by fat (lipid) deposits deep in the edge of the cornea. It can be

suggestive of high cholesterol. – Does not affect vision, nor does it require treatment. – suggestive of risk factors for vascular disease

1/28/2009

Arcus Senilis


Xanthomas:• lesions characterized by accumulations of lipid-laden macrophages. • can be a reflection of lipid metabolism alteration or a result of local

cell dysfunction. • common manifestation of lipid metabolism disorders.• suggestive of risk factors for vascular disease (cholesterol level

elevation)

1/28/2009

Xanthomas

Tuberous xanthomas: • firm, painless, red-yellow nodules. • Tuberous xanthomas are particularly

associated with hypercholesterolemia and increased levels of LDL.

• Also seen in dysbetalipoproteinemia and familial hypercholesterolemia.


Classic symptoms of angina:– Sensation of a constriction of the chest– Radiation to the neck, jaw and both arms

Occasionally: Epigastrium or through to the back.– Pain is worse with exertion, especially in cold air; improved by rest and nitrates.– Retrosternal pain in particular (often described by patients as “pressure”) suggests that angina

is the cause. – Pains that are localized elsewhere, described as sharp or stabbing, or reproduced by palpation

are much less likely to be cardiac in origin.

ECG:– Development of pathological Q waves on the electrocardiogram (ECG)– ST-segment elevation or depression on the ECG

Standard Treatment for all 3 types of Angina:Morphine sulfateOxygen Nitroglycerin Aspirin

1/28/2009

Angina


3 Types of AnginaStable Angina:• Most common type of Angina• Caused by coronary artery

atherosclerosis w/ luminal narrowing greater than 75%. No plaque rupture

• Chest pain brought on by exertion or emotional

• EKG: ST segment depression (subendocardial ischemia)

• Relief: Rest and Nitroglycerin

Prinzmetal Variant Angina:• Caused by coronary artery vasospasm and

seems to be independent of atherosclerosis

• Episodic chest pain often occurring at rest• EKG: Transient ST segment elevation

( transmural ischemia)• Relief: Nitroglycerin

1/28/2009

Unstable or Crescendo Angina:• Caused by formation of a non- occlusive thrombus in an area of coronary atherosclerosis. Plaque rupture w/ transient or incomplete occlusion.• Increasing frequency, intensity and duration of episodes• Occurs at rest• lasts longer than 30 minutes• not relieved by several doses of sublingual nitrate• elicited over days or weeks by gradually smaller• amounts of exertion (crescendo angina)• High risk for MI

• LG 1.9 MI Biochemistry Gardner• Objective: Outline the molecular mechanism

of action for each of the following therapies: Aspirin, Heparin, t-PA, Streptokinase, GP IIb/IIIa antagonist

LG1.9 Biochemistry of MI

Treatment of MI

• Immediate Goal: Reperfusion, by eliminating clot.• Accomplished with fibrinolysis (heparin) and platelet

inactivation (aspirin).• Treatments

– Aspirin block formation of thromboxane α2 by blocking COX-1.

– Heparin (IV) – t-PA <- expensive– Streptokinase– Urokinase– GP IIb/IIIa receptor antagonist

1/28/2009

• Aspirin– MOA: Blocks the formation of Thromboxane A2 by inhibiting COX-1– Reduces platelet aggregation and platelet plug formation

• So, it would prevent the extension of the plug

• Platelet glycoprotein (GP)IIb/IIIa-receptor antagonist– It prevents aggregation by binding to the platelet receptor and not allowing it to bind to the

fibrinogen receptor.• Heparin

– Heparin binds to the enzyme inhibitor antithrombin (AT) causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa.

• t-PA—tissue plasminogen activator– It is only active when bound to fibrin in a clot– It catalyzes the conversion of plasminogen to plasmin– It degrades the clot and engages reperfusion and is faster than warfarin– Plasma inhibitor activator keeps t-PA in plasma in an inactive state

• Streptokinase– Streptokinase forms a complex in the plasma with plasminogen to form an activator

complex. This complex then forms plasmin from unbound plasminogen.[3]

– Streptokinase is a bacterial product so the body will build up an immunity to it. It is recommended that this medication should not be used again after four days from the first administration, as it may not be as effective and can also cause an allergic reaction. For this reason, it is usually given only for a person's first heart attack

• aPTT Test (assess clotting time)-- Why is it good for heparin therapy?– Reference range is approximately 29-41 seconds– Values below 25 seconds or over 39 s (depending on local normal ranges) are generally

abnormal. Shortening of the APTT has little clinical relevance. Prolonged APTT may indicate:• Use of heparin• hemophilia

– In other words it takes longer to clot and the test it’s good for heparin because it can monitor the fluctuation and effect of the drug in the blood.• >39s if you’re trying to prevent clot formation especially in people who had a stroke or suffer from

coronary artery syndromes.

http://en.wikipedia.org/wiki/Streptokinase#cite_note-2

• LG1.10 Myocarditis and Pericarditis - Dr. Fischione

• Objective: Identify which virus is responsible for the most cases of Viral Myocarditis

• Objective: Identify the causes of Pericarditis

Pathology wk1 LG1.10

MyocarditisClinical Presentation:• Mild fever• Shortness of breath• Malaise• Signs of heart failure if severe and chronic

– Tachycardia– Peripheral cyanosis– Pulmonary edema

• Males > females

Diagnosis & Treatment:• Diagnosis:

– Endomyocardial biopsy• Treatment:

– Supportive measures1/28/09


MyocarditisAcute inflammation of the myocardium

– Most often due to viral infections• Coxsackie B virus

– Also can be caused by parasites• Toxoplasmosis

– Can be due to a secondary disorder• Rheumatic fever

– Aschoff bodies: granulomas in the myocardium

– Bacteria are a rare cause• Epimyocardial microabscesses

– Other causes:• Radiation• Hypersensitivity• Sarcoidosis

1/28/09

Toxoplasma Myocarditis cyst

Myocardial Aschoff Bodies in Rheumatic Heart Disease


Viral Myocarditis

• Viruses damage organelles -> cell death

• Myocardium invaded by T-lymphocytes -> secrete interleukins, TNF -> destroy virus-infected myocardial cells

• Pathology:– Tiger Effect

• Pale, congested areas with mild hypertrophy

• Biventricular dilatation• Generalized hypokinesis• Flabby, dilated heart

1/28/09Tiger Effect from Acute Viral Myocarditis

Viral (interstitial) myocarditis


Acute Viral Myocarditis• Histology:– Patchy, diffuse infiltrate of T-cells and macrophages

surrounding individual myocytes– Focal or patchy acute myocyte necrosis

1/28/09


Pericarditis• Inflammation of the visceral or parietal pericardial

layers• Most often associated with myocarditis, tuberculosis

Causes of Pericarditis:• Bacteria, viruses, fungi (rarely)• Severe autoimmune diseases (SLE)• Rheumatic Heart Disease• Chronic renal failure -> metabolic waste products in

the blood (uremia)• Trauma, radiation injury, and open-heart surgery

1/28/09


Pathology of PericarditisExudation of fluid into the pericardial sac– Clear yellow with serous pericarditis (viral infections)– Purulent with bacterial infections– Serofibrinous exudate associated with more severe damage

(Rheumatic fever)

1/28/09

Bacterial(Suppurative) Serous

Pathology wk1

Fibrinous Pericarditis• Does not resolve as easily as a serous exudate• Fibrin bridges the space between the two layers of the pericardial sac

– When separated the epicardium and pericardium resemble bread and butter taken apart

• Macrophages invade exudate -> stimulate fibroblasts -> further fibrous adhesion = adhesive pericarditis

• Blood vessels invade exudate -> organization = blood vessels fill space occupied by fibrin and obliterate it

• Fibrous scarring may prevent expansion in diastole = constrictive pericarditis

1/28/09


Non Ischemic Causes:

• Sharp in quality• Anterior in location• Sharp in nature• Non exercise related• Not relieved by NTG

1/28/2009

Pericarditis

http://images.google.com/imgres?imgurl=http://www.pathguy.com/lectures/fibrinous_pericarditis.jpg&imgrefurl=http://www.histopathology-india.net/pericard.htm&usg=__9xFIZ16jGgcVTPXCjpCmV7YEjeI=&h=367&w=556&sz=49&hl=en&start=12&tbnid=RIlJg_aA9xcNnM:&tbnh=88&tbnw=133&prev=/images?q=pericarditis&gbv=2&hl=en&sa=G

• LG 1.11 Anticoagulants, antiplatelets, thrombolytics, antianginals Pharmacology Wendel

• Objective: For each group of Antianginal drugs specify a prototypical agent and describe its mechanism of action, clinical use and adverse effects

• • Objective: For each of the seven agents

(anticoagulants, antiplatelets, thrombolytics) listed previously be able to describe: Mechanism of action, Clinical utilization, Adverse effect

LG1.11, LG1.12

Statins/HMG-CoA reductase InhibitorsMOA:

HMG-Co reductase inhibition:– decreases synthesis of cholesterol in

the liver– Therefore, LDL receptor is up-

regulated in expression and down regulated in clearance, thus uptake of LDL/IDL increases

– Decrease in Cholesterol will also decrease VLDL synthesis

Vasoprotection: – Serves as an antioxidant or anti-

inflammatory agent on blood vessels

Drug Interactions: – Substrates of P450 3A4 and

Substrates of CYP2C9

Clinical Uses:Hypercholesterolemia (Type IIa):– First line choice– Used in combination with resins or niacin

Combines hyperlipidemia (Type Iib). – Used with niacin

Adverse effects:(HeMostat pinches Hepatic tissue and Muscle)– H- hepatic enzyme elevations and hepatic

toxicity. – H- hypersensitivity (rare).– MyOsitis(<1%) and rhabdoMyolysis:

increased risk with P450 inhibitors.– Maternal use should be avoided.

1/30/2009

LG1.11, LG1.12

Bile acid-binding resinsMOA• Increased bile acid excretion in the

jejunum and ileum. • results in increased hepatic

conversion of cholesterol to bile acids.

• The resultant decrease in cholesterol leads to increased expression of LDL receptors and thus increased uptake of LDL and IDL

Adverse effects (CoLestipol)• Constipation and bloating• Less absorption of fat soluble

vitamins. – Decreased vitamin K may lead to

hypoprothrombinemia

Clinical uses• Hypercholesterolemia (Iia)

– 1st line choice• Combined hyperlipidemia(Iib)

– Used with other agents– NOT used in hypertriglyceridemia

(Type 1 of IV) due to increase in VLDL

Drug interactions• Decreased absorption of certain

drugs such as:– Aspirin– Digitalis– Statins– Tetracyclin– warfarin

1/30/2009

LG1.11, LG1.12

Anti-hyperlipidemic FibratesFenofibrate, Gemfibrozil

– This PHENOmenally FABRICATEd GEMstone is made in BRAZIL. It fits in a HanD Large (HDL) that can hold a big Lipstick (Lipoprotein Lipase-LPL)

MOA: • PPAR alpha activation leads to

increased LPL expression, thus decreased plasma TG and VLVL levels by increasing TG hydrolysis.

• increased plams HDL levels by increasing hepatic expression of APoA-I and II

Clinical uses:• The GEMstone is usually worn on

the 4th or the 3rd finger• Hypertriglyceridemia (IV):

– Used in severe or moderate cases.

• Dysbetalipoproteinemia(III)

Adverse effects:• (The Phenomenal GEMstaone

hurts)– G-gallstones due to rise in

cholesterol– E-elevated liver enzyme levels– E-enhanced action of oral

anticoagulants– Myositits and rhabdoMyolysis

1/30/2009

LG1.11, LG1.12

Anti-hyperlipidemic drugs: sterol absorption inhibitor

EZETIMIBE:• Has an Eze time blocking intestinal

sterol absorption

MOA: • decreased sterol absorption• Decreased LDL by inhibiting

intestinal absorption of cholesterol• decreased absorption of

phytosterols

Drug interactions:• Plasma levels decreased by resins

but increased by fibrates

Clinical uses• Hypercholesterolemia.

– Usually used with a statin for synergistic action to decrease LDL

• Phytosterolemia

Adverse effects• (But no EZE time for the liver)• Hepatic dysfunction, reversible

and usually minor

1/30/2009

LG1.11, LG1.12

Niacin (nicotinc acid)

• My NIECE has a very low dental line (VLDL) due to low tooth growth(TG). Although she has small lips (Lp(a)), she likes to use a big lipstick (Lipoprotein Lipase (LPL) with a HanD large (HDL)

Adverse effects:– (my niece likes to FIGHT too)

F - FlushingI - ItchingGI upsetHepatic dysfunctionHyperglycemia & HyperuricemiaTachyarrhythmias

MOA:• Decreases Plasma VLDL• Decreases Lp ()• Increased HDL

Clinical uses:• Hypercholesterolemia(IIB)• Combines hyperlipidemia• Hypertriglyceridemia (IV)• Dysbetalipoproteinemia (III)• Lp(a) hyperlipoproteinemia

1/30/2009

LG1.11, LG1.12

Drugs used for Angina PectorisVASODILATORS

Organic NitratesNitroglycerinIsosorbide dinitrateIsosorbide mononitrateAmyl nitrite

Calcium Channel Blockers (CCBs)Dihydopyridines –dipineNifedipineAmlodipineFelodipineIsradipineNicardipineNisoldipine

PhenylalkylaminesVerapamilBenzothiazepinesDiltiazem

NEGATIVE INOTROPIC DRUGSBeta-blockers (Bbs)

Non-selective -ololPropranololNadololBeta 1-selectiveMetoprololAtenolol

Calcium Channel Blockers (CCBs)

VerapamilDiltiazem

1/30/2009

LG1.11, LG1.12

Drugs used for Angina Pectoris

Antiplatelet AgentsCOX inhibitorAspirinGPIIb/IIIa AntagonistAbciximabEptifibatideTirofiban

Anticoagulants-parinHeparin

Late Na current blockerRanolazine

Mnemonic for angina drugs:A- anticoagulantsB- Bbs C- vasoDilators (CCBs also)D- CCBs

1/30/2009

LG1.11, LG1.12

Angina Pectoris & Anti-anginal Drugs

Pathophysiology for angina pectoris & actions of anti-anginal drugs:

• Anticoagulants & Antiplatelets prevent coagulation, platelet aggregation, and atherosclerotic plaques which in turn increases coronary blood flow

• Vasodilators (venous) decrease myocardial wall tension• Negative inotropic drugs decrease HR and contractility,

which in turn decreases preload• Vasodilators (arterial/arterioles prevent vasospasms and

decrease peripheral vascular resistance, which in turn decreases afterload.

1/30/2009

LG1.11, LG1.12

Nitroglycerin MOA• Nitroglycerin will dilate veins more than arteries,

– decreasing cardiac preload– leading to the following therapeutic effects during episodes of

angina pectoris:• subsiding of chest pain• decrease of blood pressure• increase of heart rate.• orthostatic hypotension

These effects arise because:– nitroglycerin is converted to nitric oxide in the body by

mitochondrial aldehyde dehydrogenase– nitric oxide is a natural vasodilator.

1/30/2009

http://en.wikipedia.org/wiki/Orthostatic_hypotension

http://en.wikipedia.org/wiki/Nitric_oxide

http://en.wikipedia.org/wiki/Aldehyde_dehydrogenase



LG1.11, LG1.12

Nitrates (Nitroglycerin, isosorbide dinitrate)

Delivery:• Administered across the

buccal membrane• should be used for

acute/prophylactic angina pectoris – exertional, variant, or

unstable

MOA:• Decreases oxygen demand

by dilating veins and reducing the preload on the heart

Adverse effects:• Headache, syncope• Flushing, palpitations,

postural hypotension• Rashes, vasospasms on

withdrawal• Contraindicated in:

– constrictive pericarditis– increased intracranial

pressure– severe hypotension – Hyperthroidism– hepatic disease

1/30/2009

LG1.11, LG1.12

Beta Blockers

MOA• Propranolol (nonselective

Beta Blocker)• Metoprolol (Beta 1-

selective Beta Blocker)• BOTH Act to decrease

myocardial oxygen demand by

★ Decreasing HR★ Decreasing

contractility★ Decreasing BP

• Increase diastolic perfusion time (increase coronary vessel perfusion)

Clinical Use• DO NOT USE FOR PRINZMETAL

(VARIANT) ANGINA• Use for chronic angina

treatment (exertional and unstable)

Adverse effects• Decreased tolerance for

exertion• Drowsiness• Rebound angina if

discontinued• Asthma (due to the

presence of Beta receptors in the lungs as well0 1/30/2009

LG1.11, LG1.12

Ca++ Channel BlockersMOA

– Verapamil (Calan)–Decrease force of myocardial contraction (decrease Ca in myocardial cells)–Decreased BP due to decreased Ca in vascular smooth muscle

Clinical Use–Chronic treatment of angina pectoris (all forms)–Alternative to beta blockers–Other uses (Arrhythmia, hypertension, migraine, myocardial infarction, etc)

Adverse effects: –Headache, dizziness–Flushing, hypotension, tachycardia, arrhythmias–Constipation, gingival hyperplasia, nausea, abdominal pain–Contraindicated:

• hypotension• GI reflux disease• ventricular tachycardias• Wolfe Parkinson White Syndrome

“I get dizzy and constipated when I drink Jin (gingival hyperplasia) in the Car (calcium) but I cant Park (CI for White Parkinson White) this Jeep (GI reflux)”

1/30/2009

WEEK 2

• LG 2.1/2.2 Pavlick cardiac muscle excitation/pacemaker• Objective: Sketch a typical action potential in a ventricular muscle

cell and a pacemaker cell, labeling both the voltage and time axes accurately. Describe how ionic currents contribute to all phases of the cardiac action potential. Use this information to explain differences in shapes of the action potentials of different cardiac cells. Describe the ion channels that contribute to each phase of the cardiac action potential. Explain how differences in channel population influence the shape of the action potential in the nodal, atrial muscle, ventricular muscle, and Purkinje fiber cardiac cells.

• Objective: Define the Frank-Starling Law of the Heart.

LG2.1, LG2.2

Intercalated DiscsThe plasma membranes of adjacent

cardiac muscle cells inter-lock at dark-staining junctions called INTERCALATED DISCS – see arrows in picture– Subdivided into two distinct structures:

• Desmosomes - prevent cells from separating during contraction

• Gap Junctions - allow ions to pass freely from cell to cell, directly transmitting the depolarizing current across the entire heart

Entire myocardium behaves as a single coordinated unit or FUNCTIONAL SYNCYTIUM – allows synchronous myocardial

contractions)2/2/2009

LG2.1, LG2.22/2/2009

Cardiac Action Potentials

AP Duration: • Neuron (green) – 1 msec; • Skeletal Muscle Cell – 2-5 msec; • Non-Pacemaker or “Fast Response” Cardiac Myocyte (red) – 200-400 msec

Two Types CAP:Non-Pacemaker or “Fast Response:”• Occur in atria, ventricles, Purkinje

fibers• undergo rapid depolarization

(steeper slope during Phase 0)

Pacemaker or “Slow Response:” • Occur in the SA node and AV node• undergo slow depolarization

(less steep slope during Phase 0)

LG2.1, LG2.22/2/2009

Summary of Ion Conductance & Channel Involvement

LG2.1, LG2.2

Calcium InfluxKey Points:

• Excitation-Contraction coupling in skeletal muscle does NOT require influx through L-type Ca+2 channels, but cardiac contraction has an absolute requirement for Ca+2 influx through these channels during the action potential

• The amount of calcium entering the cardiac muscle cell during an action potential is small and does NOT promote actin-myosin interaction

• The influx of calcium during an action potential serves as a trigger to induce calcium release from the sarcoplasmic reticulum, which then promotes actin-myosin interaction and hence contraction

• Neurotransmitters and drugs can alter calcium conductance (e.g. NE , whereas Ach, b-blockers & Ca+2-channel blockers )

2/2/2009

LG2.1, LG2.2

Calcium Extrusion Mechanisms

3 Mechanisms:• Sarcoplasmic Reticulum

Ca+2 pumps (SERCA)– Utilize ATP

• Sarcolemmal Ca+2 pumps– Also ATP driven

• 3Na+/1 Ca+2 anti-porters

All 3 mechanisms restore the normal intracellular Ca+2 level

2/2/2009

LG2.1, LG2.22/2/2009

Conduction VelocitySpeed at which excitation spreads throughout cardiac tissue• Depends on size of inward current during

the upstroke (phase 0); • the larger the inward current, the

higher the conduction velocity

Purkinje fibers – fastestAV node – slowest* *Allows time for ventricular filling before ventricular contraction

The conduction system permits a rapid and organized depolarization of ventricular myocytes that is necessary for the efficient generation of pressure during systole.

LG2.1, LG2.2

Phases of Non-Pacemaker “Fast Response” Cardiac APs

Phase 0 (Rapid Depolarization)– Upstroke; – “Fast” Na+-channels open (iNa); – Several types of K+-channels closed (iK)

Phase 1 (Early/Initial Repolarization)– Transient outward current as K+ channels open (iKto);

– “Fast” Na+-channels are closed

Phase 2 (Plateau Phase)– Long-lasting (L-type) Ca+2 channels open leading to inward

calcium movement [iCa(L)]; – Efflux of K+ through several– types of K+-channels (iK, iK1, even iKto to a degree)

Phase 3 (Late or Final Repolarization)– Continual efflux of K+ through several channels; – Ca+2-channels eventually close

Phase 4 (Resting Membrane Potential)– K+-channels (iK1) remain open; – Calcium extrusion mechanisms become highly active

2/2/2009

LG2.1, LG2.2

Phases of Pacemaker “Slow Response” Cardiac APs

Phase 0– Upstroke caused by an increase in Ca+2

conductance • (NOT an inward Na+ current)

Phase 3– Repolarization caused by an increase in K+

conductance;– results in an outward K+ current causing

repolarization of the membrane potentialPhase 4

– Slow depolarization– Accounts for the pacemaker activity of the

SA node (automaticity)– Is caused by an increase in Na+ conductance,

• which results in an inward current called If

– If is “turned on” by repolarization of the membrane potential during the preceding AP

2/2/2009

LG2.1, LG2.2

Conduction Velocity

Sympathetic activation – conduction velocity (positive dromotropic effect) in nodal and non-nodal

tissues by the slope of phase 0 (more rapid depolarization of adjacent cells)

– Results from NE binding to 1b -receptors; • drugs that block 1b -receptors (i.e., b-blockers) conduction velocity

and can produce AV block.Parasympathetic (vagal) activation

– conduction velocity (negative dromotropy) in nodal and non-nodal tissues by decreasing the slope of phase 0 (slower depolarization of adjacent cells)

– Ach binds to muscarinic receptors– excessive vagal activation can produce AV block– drugs such as digoxin

• which increase vagal activity• used to reduce AV nodal conduction in patients that have tachycardia

due to atrial flutter or fibrillation.Because CV depends on the rate of tissue depolarization (which is related to the slope

of phase 0 of the AP)– conditions (or drugs) that alter phase 0 will affect conduction velocity. – Examples

• Conduction can be altered by changes in membrane potential, which can occur during myocardial ischemia & hypoxia

• Anti-arrhythmic drugs such as quinidine (a Class IA anti-arrhythmic) block “fast” sodium channels and cause a in conduction velocity in non-nodal tissue 2/2/2009

Non-nodal

Nodal

LG2.1, LG2.2

Cardiac EC CouplingAction potential spreads from the sarcolemma into the T-tubules

During plateau phase:– Ca+2-conductance – ECF Ca+2 enters cell

Large release of Ca+2 from Sarcoplasmic Reticulum (SR) is triggered

Ca+2 binds to troponin C and tropomyosin is moved out of the way– removing the inhibition of actin & myosin binding

Thick and thin filaments slide past each other– myocardial cell contracts

• the magnitude of the tension that develops is proportional to the ICF concentration of Ca+2

Relaxation occurs:– when Ca+2 is re-accumulated by the SR (via SERCA) – or moved to the ECF (via Sarcolemmal Ca+2 pumps and antiporters)

2/2/2009

LG2.1, LG2.2

Refractory Periods

2/2/2009

Once a fast response has been initiated, the depolarized cell is no longer excitable until the cell is partially repolarized.

EFFECTIVE (or ABSOLUTE) REFRACTORY PERIOD (c d) = a 2nd action potential

absolutely cannot be initiated, no matter how large a stimulus is appliedRELATIVE REFRACTORY PERIOD

(d e) = a 2nd action potential may be evoked only when the stimulus is sufficiently strong (supra-threshold)

TETANYThe electrical and mechanical events in cardiac muscle overlap (see pic →) • it is impossible to produce the

summation and tetanus found in skeletal muscles during high frequency stimulation in cardiac muscles.

LG2.1, LG2.2

Contractile Force

Intrinsic Control of Contractile Force:– Frank-Starling Law:

• within physiological limits, the more ventricles fill during diastole, the more blood they eject during systole

Extrinsic Control of Contractile Force:– INOTROPISM:

• modification of cardiac contractility independent of Frank-Starling Law (“normal” curve shifts up or down)

• Positive inotropism (↑ contractile force) occurs with sympathetic (NE) or hormonal (EPI) stimulation

KEY POINT

• Heart is a functional syncytium;

• it is NOT possible to increase the force of contraction via RECRUITMENT2/2/2009

• LG 2.3 Pong ECG• Objective: Describe and identify in a Lead II

ECG: T wave• LG 2.4 and 2.7 EKG clinical Thomson• Objective: Distinguish among the major

tachyarrhythmias and bradyarrhythmias • Objective: Recognize shockable rhythms

LG2.3 ECG/EKG

Atrial Fibrillation

Normal

Ventricular Fibrillation

2/2/2009

Arrhythmias by Chris

Atrial Fibrillation

• Multiple ectopic foci in the atria causing rate of 350-450/min

• Irregular baseline without P-waves since no single impulse depolarizes the atria completely

• Irregular ventricular (QRS) rhythm since only random impulses get through AV node

EKG (LECOM)

A fibVentricular rate is 75QRS is normal. No LVH. ST and T changes could be due to digoxin effect.

LG2.7 Clincal EKG

Atrial Fibrillation

• characterized by the presence of an irregularly irregular rhythm in the absence of P waves.

• Undulations in the baseline (known as "fib waves") may sometimes be seen . A Fib is therefore described as having one of the following: – rapid ventricular response,

• rate averages over 120 beats/minute. – controlled (moderate) ventricular response

• rate averages between 70-110 beats/minute. – slow ventricular response

• rate averages less than 60 beats/minute. • Common Causes:

– Hyperthyroidism– Alcohol use (Holiday heart)– Pulmonary embolism– Pneumonia. – Most commonly, atrial fibrillation occurs as a result of some

other cardiac condition (secondary atrial fibrillation). • Heart valve disease• Left ventricular hypertrophy• Coronary heart disease• High blood pressure• Cardiomyopathy• Sick sinus syndrome• Pericarditis

2/4/2009

EKG (LECOM)

Atrial FlutterAtrial flutter is like A-fib but there is a single foci that is re-entrant.

– That focus conducts repetitively. – The atrial rate is:

• between 240 and 350 beats per minute for type I • Between 350 to 430 for type II; • this information is not very useful in the prehospital setting.

As seen here, the atrial waves are wider and move further from the isoelectric baseline. – What is the rate here?

• 7*10.


Atrial Flutter

• Ectopic focus in the atria fires at 250-350• Each P-wave looks identical to all the others– Not really P-waves = flutter waves– “Saw tooth” baseline

• Only occasional atrial stimulus will penetrate the AV node– Few flutter waves in series before a QRS

EKG (LECOM)

Atrial TachycardiaAtrial tachycardia is similar to sinus tachycardia except the sinus node

is not the primary focus. – The normal rate is 150 - 250 bpm for atrial tach. – We can see there is still a P wave for the QRS complexes; although small.

What is the rate here? – About 21*10 bpm.

EKG (LECOM)

Left Bundle Branch Block (LBBB)• Also notice the “M” pattern seen in lead V5 (or V6). • These are “left side” leads, implying LBBB; “WilliaM”

*

EKG (LECOM)

Right Bundle Branch Block (RBBB)

*

Also notice the “M” pattern seen in lead V2 (or V1). These are “right side” leads, implying RBBB; “MarroW”


Right Bundle Branch Block

• R,R’ in V1 or V2 (right chest leads)

Conduction Issues

LG2.3 ECG/EKG

Conduction Block

2/2/2009

*Most likely at the AV node– First degree AV block:

• PR interval is prolonged, slow conduction in AV node– AV node becomes depressed (from

anoxia etc) so the AV node cannot respond to a high rate of incoming impulses.

– Second degree AV block: • atrial excitation does not lead to

ventricular excitation. P waves but no QRS complexes. – Alternate waves can be blocked. – Ratios of waves to blocked waves

can be 2:1, 3:1, 3:2, 4:1 etc.

– Third degree or complete AV block: • AV node or common bundle is

unable to conduct impulses.

• Block can occur anywhere from sinus node to ventricles

Bundle Branch Block:• Failure in either right or left bundle

branch.• Usual cause is myocardial damage.• Creates a prolonged QRS complex

– 60 to 100 ms is normal– Up to 120 ms (incomplete block)– Longer than 120 ms (complete block)

• T wave has reversed polarity to QRS complex

EKG (LECOM)

First Degree Heart Block

Here we can see that the PR interval is larger than 0.20s. – AV node is stalling for longer than it should. – Remember the PR interval should be between 0.12 and 0.20s.

This may not cause immediate problems for the patient, but could progress to 2nd degree or 3rd degree block. – Second degree Type II block and 3rd degree block require rapid

intervention, which may include an electrical pacemaker

.


1st degree AV Block

• Prolongs the PR interval more than one large square (0.2s)

• PR interval is prolonged the same amount in every cycle

• Normal P-QRS-T• Asymptomatic


2nd degree AV Block: Mobitz I “Wenckebach”

• PR interval becomes progressively longer until the final P wave does not elicit a QRS

• Not pathologic

EKG (LECOM)

Second Degree Block Type I

Type 1: Also called Wenckebach or Mobitz I.

Here the PR interval becomes longer and longer until a beat is eventually missed. – Notice after the 4th QRS here there is a T-wave then a p-wave for the next

beat. However, the ventricles are in refractory so they do not depolarize.

These patients may need treatment but it is not immediate; there is a good prognosis here.

*


2nd degree AV Block: Mobitz II

• QRS is dropped after a normal P wave • Generally there are normal, uniform PR

intervals• Pathologic

EKG (LECOM)

Second Degree Block Type IIType 2: Also called Mobitz II.

Here there is a dropped QRS for a given P wave at regular intervals. – For example, there may be 4 p-waves for every 3 QRS complexes. (4:3 block)– Here you can see 2 p-waves for every 1 QRS complex (2:1 block).

• The p-wave after the T-wave does not cause a QRS.

These patients may need treatment more quickly, which may be an VVI pacemaker that senses and paces in the ventricles as the atrium (SA node) is working properly.

LG2.3 ECG/EKG

What’s the difference?

2/2/2009

AV block 2nd degree


3rd degree “Complete” AV Block

• None of the atrial depolarizations penetrate through to the ventricles

• Ventricles must be paced independently by a ectopic (junctional or ventricular) focus

• AV dissociation– Atrial rate independent of ventricular rate

• Usually treated with a pacemaker

EKG (LECOM)

Third Degree Heart BlockAlso called complete heart block. • Another description of this type of block would be sinus rhythm 3rd degree

block with ventricular escape (or junctional escape).• This has a very poor prognosis if treatment is not given quickly. These patients

will become pacemaker dependent.

Here the p-waves are separate from the QRS complexes, signifying that they are not coordinated. – You can see that in the middle the p-wave occurs during the QRS and is masked.

EKG (LECOM)

Supraventricular Tachycardia (SVT)Supraventricular tachycardia (SVT) can also be paroxysmal (PSVT), meaning it occurs intermittently.

– SVT is the same as Atrial Tachycardia (AT), except AT may use an accessory pathway. – SVT uses the normal pathway (SA, AV) so QRS complexes are narrow. – It looks like a box of crayons if the ECG is held upside down.

These are initially treated with vagal maneuvers: – having the patient bear-down (adult) – ice water pack on the face (child, mammalian diving reflex)

Drugs such as adenosine may be given as well. – Adenosine has a half-life <10 seconds so it is important to administer rapid push (RIVP) followed by a saline

bolus as the drug will be metabolized quickly in the body.

Atrioventricular nodal reentry tachycardia (AVNRT) is the most common type of reentrant supraventricular tachycardia (SVT).


Supraventricular Tachycardia

• Tachycardia that originates above the ventricles– Both atrial and junctional tachycardia


Wolff-Parkinson-White Syndrome

• Accessory bundle of Kent provides ventricular “pre-excitation” bypassing AV node

• Premature ventricular depolarization represented as a delta wave

• Shortened PR interval• Lengthened QRS• Patients may have

supraventricular tachycardia of 2 mechanisms:– Re-entry

• Ventricular depolarization may immediately restimulate the atria in a retrograde fashion

– Rapid conduction• Supraventricular tachycardia may be

rapidly conducted to the ventricles via this accessory pathway

EKG (LECOM)

Ventricular FibrillationBlood is not circulated throughout the system and the patient will die quickly

– losing 10% chance of survival for every minute in arrest. – Along with pulseless ventricular tachycardia these rhythms are treated with drugs

(epinepherine) and “Edison medicine” (shocking). – Emergency personnel follow the ABCDs for basic life support and CPR:

• Airway, Breathing, Circulation, and Defibrillation

Here, multiple foci in the ventricles fire causing the heart to quiver uncontrollably. – This is a cardiac arrest rhythm.


Ventricular Fibrillation• Numerous ventricular ectopic foci producing a rate of 350-450• Erratic twitching because so many foci firing at once, each only depolarizing a small area• No identifiable waves• No effective cardiac pumping

– A type of cardiac arrest– Fatal without CPR and defibrillation


Ventricular Flutter• Single ventricular ectopic focus firing at 250-350• Smooth sine wave appearance• No cardiac output -> deteriorates into ventricular

fibrillation

EKG (LECOM)

Ventricular TachycardiaThis rhythm is marked by very wide QRS complexes occurring rapidly.

– The problem is blood cannot fill into the atria quick enough and thus is not oxygenated well.

– It is important to check a pulse before defibrillating this patient. The patient will die without treatment.

Here, an irritable focus in the ventricles fires at 150 to 250bpm causing the heart to beat too quickly.

EKG (LECOM)

Torsade de PointesTorsade de Pointes (tōr-sad’ dĕ pwant’) literally means “twisting of the points”

– giving a twisted ribbon or party streamer look. – The “R on T” phenomenon occurs when a PVC R-wave lands on a T-wave, causing ventricular arrhythmia. – Ventricular fibrillation is induced in patients receiving implantable cardioverter defibrillators (ICDs) using

a similar “T-Shock”. – TdP is facilitated by prolonged QT interval (QTc) due to drugs or heredity.

• http://qtdrugs.org/

• LG 2.6 Fischione Cardiac tumors• Objective: Describe the pathologic findings of

a Cardiac Myxoma

LG2.6 Pathology

Cardiac Tumors

• Rare• Usually benign and pedunculated• Three types:– Cardiac myxomas– Rhabdomyomas– Metastatic tumors

2/4/2009

LG2.6 Pathology

Cardiac Myxomas• The most common primary adult tumor (35-50%)• Most arise from the left atrium (90%)• Complications:

– “Ball-valve” effect may obstruct the mitral valve orifice in over half of patients with myxomas of the left atrium• Blocks diastolic filling of the ventricle, stimulating mitral valve stenosis -> may cause syncopal

episodes

– One third of these patients die of embolization of the tumor to the brain• Dx: transesophageal ultrasound

2/4/2009

Right atrial With stalk

LG2.6 Pathology

Histology of Cardiac Myxomas• Loose myxoid matrix• Abundant proteoglycans with stellate cells

within the matrix

2/4/2009

Stellate cells and fibroblasts Amorphous extracellular matrix

LG2.6 Pathology

Rhabdomyomas• Most common primary cardiac tumor in infants and children

– Major association with tuberous sclerosis• Forms hamartomas in the myocardium• Almost all are multiple

– Involve both the left and right ventricles, and the atria in 1/3 of cases– Projects into the cardiac chamber in ½ of cases

• Grossly:– Pale gray masses, up to several centimeters

• Histologically:– Derived from striated muscle cells with abundant glycogen

2/4/2009

Striated muscle (“Spider”) cellsGrossly

• LG 2.8 Antiarrhythmics Pharmacology Szarek• Objective: Explain the molecular mechanism

of action of antiarrhythmic drugs.

Cardio Drugs for BOARDS more than test

Adenosine (a-den-oh-seen)• Therapeutic class

– Antiarrhythmic agent

• Pharmacologic class– Purine nucleoside

• M.O.A.– Activates adenosine receptors ->

Gi coupled ↓ in cAMP = opens K channels and blocks T-type Ca influx

– ↓SA, AV nodal activity by ↓slope of phase 4

• Clinical Use– DOC for terminating paroxysmal

supraventricular tachycardias, AV nodal arrhythmias

– Emergency use

• Special Considerations– IV – Half life < 10 seconds

• Adverse Effects– Bronchospasm in

asthmatics– Hypotension– Facial flushing

• Interactions– Antagonized by

theophylline– Dipyridamole ↓uptake

and ↑ its effects

Drugs

Adenosine

• Antiarrhythmic• Purine nucleoside, cardiac

node membrane stabilizer

• Opens K channels & blocks Ca influx in SA & AV nodes

• Slows AV conduction• ↑ AV refractory period

– Terminate SVT

– Transient asystole


Amiodarone (am-ee-oh-da-rone)• Therapeutic class


• Pharmacologic class– Class III antiarrhythmic– Mimics classes I, II, III, IV

• M.O.A.– Blocks K, Na, Ca and B-receptors– Slows phase 3 (repolarization),

increases refractory periods, slows HR, increases PR and QT intervals = ↑APD and ERP

• Clinical Use– Supraventricular and ventricular

arrhythmias, including V-tach and V-fib– Oral and IV

• Special Considerations– Very long half-life (>80 days)– Safe to use in Wolff-Parkinson-White

• Adverse Effects– Pulmonary fibrosis– Hypo/hyperthyroidism– Hepatotoxicity– Blue pigmentation of

the skin (“smurf skin”)– Photosensitivity– Corneal deposits

• Interactions– ↑digoxin levels

Drugs

Amidarone

• Antiarrhythmic• Cardiac ion channel blocker

• Blocks K, Na, Ca channels & β receptors– Prolongs repolarization– ↑ refractory period– Slows HR– ↑ PR & QT intervals

– SVT, VT, VF

– Hypo/hyperthyroidism– Photosensitivity– Blue-gray skin– Corneal microdeposits– Pulmonary fibrosis


Atenolol (a-ten-oh-lol)• Therapeutic class

– Sympatholytic; antihypertensive

• Pharmacologic class– Selective B1 receptor antagonist– Class II antiarrhythmic

• M.O.A.– Competitively blocks B1 receptors =

↓cAMP, ↓Ca currents– ↓phase 4 slope in pacemakers = ↓SA and

AV nodal activity = ↑PR interval

• Clinical Use– Supraventricular tachycardias via ↓ AV-

conduction– Angina– Hypertension– Post-MI– Oral and IV

• Special Considerations– C/I in Wolff-Parkinson-White, vasospasm,

bronchospasm, and diabetes– Less lipophilic; fewer CNS effects

• Adverse Effects– Bronchoconstriction due to B2

blockade– Heart block– Bradycardia

• Interactions– Additive hypotensive effect with

nitrates and antihypertensives– Additive bradycardia with digoxin– Unopposed α-adrenergic stimulation

with epinephrine and in pt’s with excess sympathetic stimulation (pheochromocytoma) = severe hypertension/arrhythmias

• Similar Drugs– Acebutolol– *Esmolol* (IV): used in acute SVT’s;

very short half life– Metoprolol: may cause dyslipidemia


Atropine (at-roe-peen)

• Therapeutic class– Anticholinergic agent

• Pharmacologic class– Muscarinic receptor antagonist

• M.O.A.– Competitively blocks all

muscarinic receptors

• Clinical Use– Acute MI– Bradycardia and AV block– Irritable bowel symptoms– Anticholinesterase poisoning

• Special Considerations– Can slow HR when 1st

administered

• Adverse Effects– Tachycardia– Mydriasis– Cycloplegia– Delirium and hallucinations

• Interactions– Additive anticholinergic effects

with antihistamines and tricyclic antidepressants

– Slows absorption of other drugs by delaying gastric empying

• Similar Drugs– Dicyclomine– Ipratropium


Digoxin

• Therapeutic class– Cardiac stimulant

• Pharmacologic class– Digitalis glycoside

• M.O.A.– Inhibits Na/K ATPase– ↑intracellular Ca and cardiac

contractility from indirect inhibition of Na/Ca exchanger

– ↓AV conduction

• Clinical Use– Heart failure (↑contractility)– Atrial fibrillation (↓AV

conduction and depression of SA node)

• Special Considerations– Metabolized in stomach by

intestinal bacteria– Most of drug is eliminated

unchanged in the urine - ↓dose in renal failure

– C/I in Wolff-Parkinson-White

• Adverse Effects– Proarrhythmic– GI: nausea, vomiting, diarrhea– Blurred vision, yellow vision

• Interactions– Amiodarone, quinidine,

cyclosporine, diltiazem, and verapamil increase serum levels

– Hypokalemia increases effects and toxicity

Drugs

Digoxin

• Cardiac stimulant• Digitalis glycoside

• Inhibits Na/K ATPase– ↑ IC Ca & cardiac contractility– ↓ AV conduction– ↑ AV refractory period

– Heart failure– Serum levels assess dosage &

toxicity

– Arrhythmias– N, V– Blurred vision– Yellow vision


Lidocaine (lye-doe-cane)• Therapeutic class

– Local anesthetic

• Pharmacologic class– Amide-type local anesthetic– Class IB antiarrhythmic

• M.O.A.– Blocks inactivated Na channels– ↓APD due to block of the slow Na

“window” currents

• Clinical Use– Ventricular arrhythmias– IV because of 1st pass metabolism– Post-MI due to preference for

tissues partly depolarized = ↑threshold for excitation and ↓excitability of hypoxic heart muscle

– Open-heart surgery

• Special Considerations– Rapid onset of action and immediate

duration– Metabolized in liver - ↓ in liver disease– Inducers/inhibitors of liver enzymes

alter metabolism

• Adverse Effects– Rarely: cross-hypersensitivity with

other amide-type anesthetics– CNS toxicity: confusion, dizziness,

seizures– Least cardiotoxic of conventional

antiarrhythmics

• Interactions– Additive effects with other local

anesthetics and class I antiarrhythmics

• Similar drugs– Mexiletine, tocainide = oral analogues


Magnesium

• M.O.A.– Unknown

• Clinical Use– Torsades– Digoxin-induced

arrhythmias


Procainamide• Therapeutic class


• Pharmacologic class– Class IA sodium channel blocker

• M.O.A.– Blocks Na channels in the open or

activated state and K channels in cardiac tissue, slowing conduction

– ↑action potential duration (APD) and the effective refractory period (ERP)

– Less M2 block than Quinidine, no α1 block = less ANS side effects

• Clinical Use– Supraventricular and ventricular

arrhythmias– Oral and IV

• Special Considerations– Metabolized in liver to NAPA (N-

acetyl-procainamide), a K channel blocker with class III antiarrhythmic effects

– NAPA and parent drug excreted by kidney = caution in pt’s with renal failure

• Adverse Effects– Hypotension– Systemic Lupus Erythematosus

(SLE)-like syndrome more likely with slow acetylators

– Torsades caused by NAPA prolonging refractoriness and lengthening the QT interval

– Hematotoxicity (thrombocytopenia, agranulocytosis)


Propafenone (proe-paff-e-none)• Therapeutic class


• Pharmacologic class– Class IC sodium channel

blocker

• M.O.A.– Blocks fast Na channels,

especially His-Purkinje tissue = marked ↓ in slope of phase 0

– No effect on APD– No ANS effects

• Clinical Use– Supraventricular

arrhythmias

• Special Considerations– Metabolized in liver = reduce in liver

disease– Monitor ECG when starting therapy;

most proarrhythmic events occur in 1st 2 weeks

• Adverse Effects– Proarrhythmic: can aggravate existing

arrhythmias or precipitate new ones; may prolong QT interval

– Bronchospasm in asthmatics due to B-blocking effects

– GI disturbances– Dizziness

• Interactions– Increases digoxin levels

• Similar drugs– Flecainide: most proarrhythmic drug

of class I


Propranolol (proe-pran-oh-lol)• Therapeutic class

– Sympatholytic; antihypertensive

• Pharmacologic class– Nonselective B receptor antagonist– Class II antiarrhythmic

• M.O.A.– Competitively and non-selectively

blocks B1 and B2 receptors = ↓cAMP, ↓Ca currents

– ↓phase 4 slope in pacemakers = ↓SA and AV nodal activity = ↑PR interval

• Clinical Use– Supraventricular tachycardias via ↓

AV-conduction– Angina– Hypertension– Post-MI– Oral and IV

• Special Considerations– Highly lipophilic = CNS penetration – insomnia

and depression– Metabolized in liver; extensive 1st pass

metabolism– C/I in Wolff-Parkinson-White, vasospasm,

bronchospasm, and diabetes

• Adverse Effects– Bronchoconstriction– Cold extremities and impotence due to B2

blockade– Heart block– Bradycardia

• Interactions– Additive hypotensive effect with nitrates and

antihypertensives– Additive bradycardia with digoxin– Unopposed α-adrenergic stimulation with

epinephrine and in pt’s with excess sympathetic stimulation (pheochromocytoma) = severe hypertension/arrhythmias

• Similar drugs– Timolol


Quinidine (kwin-i-deen)• Therapeutic class


• Pharmacologic class– Class IA sodium channel blocker

• M.O.A.– Blocks Na channels in the open

or activated state and K channels in cardiac tissue, slowing conduction

– ↑action potential duration (APD) and the effective refractory period (ERP)

• Clinical Use– Supraventricular and

ventricular arrhythmias– Orally effective

• Adverse Effects– Proarrhythmic effects

• M2 receptor blockade: ↑HR and AV conduction, prolongation of QRS and ↑QT interval

• α1 receptor blockade: vasodilation with possible reflex tachycardia

– Cinchonism: GI, tinnitus, ocular dysfunction, CNS excitation due to ANS effects

– Hypotension

• Interactions– Hyperkalemia enhances effects,

worsens risk of arrhythmias– Displaces digoxin from tissue binding

sites, enhancing toxicity– Levels↑ by amiodarone, cimetidine,

diltiazem, verapamil, and grapefruit juice

– Quinidine is a weak base and antacids ↑absorption, thus greatly ↑toxicity


Sotalol (soe-ta-lole)• Therapeutic class


• Pharmacologic class– Class III K channel blocker– Exhibits class II actions

• M.O.A.– Blocks K channels in cardiac

tissue, slowing phase 3 = ↑APD, ERP

– Also blocks B1 receptors = ↓HR, AV conduction

• Clinical Use– Supraventricular and life-

threatening ventricular arrhythmias

– Oral

• Special Considerations– Excreted unchanged in urine =

↓dose,↑dosing interval in pt’s with renal failure

• Adverse Effects– Torsades– Bronchoconstriction due to B-

blockade

• Interactions– Hypotension with

antihypertensives and nitrates– Bradycardia with digoxin– Myocardial depression with

verapamil

• Similar Drugs– Ibutilide– Bretylium


Verapamil (ver-ap-a-mil)• Therapeutic class

– Antihypertensive and antianginal agent– Class IV antiarrhythmic

• Pharmacologic class– Non-dihydropyridine Ca channel blocker

• M.O.A.– Blocks L-type cardiac Ca channels– Primarily affects nodal cells– ↓phase 0 = ↓SA, AV nodal activity

• Clinical Use– Supraventricular tachycardias– Hypertension– Angina– Oral and IV

• Special Considerations– Metabolized in the liver = caution in liver

disease– Inducers of P450 ↑metabolism – ↓P450– Suppresses cardiac contractility more than

other Ca channel blockers

• Adverse Effects– Constipation– Hypotension and bradycardia – Peripheral edema– Gingival hyperplasia– AV block

• Interactions– C/I in Wolff-Parkinson-White– Additive AV block with B-

blockers and digoxin– Displaces digoxin from tissue

binding sites– Cyclosporine, quinidine,

carbamazepine, grapefruit juice ↑serum levels

• Similar Drugs– *Diltiazem*

Drugs

Enalapril

• Antihypertensive• ACE inhibitor

• Inhibits ACE & formation of AT II– Vasodilation– ↓ aldosterone secretion– ↑ CO– ↓ V remodeling– ↑ survival in heart failure

– HTN– Heart failure– Post-MI– ↓ progression of diabetic nephropathy

– Cough & angioedema• Inhibits bradykinin

degradation– Hypotension– Taste disturbances

Drugs

Esmolol

• Antiarrhythmic• Class II• Selective β1 blocker

• Blocks SNS stim. SA & AV nodes– ↓ HR– ↓ AV conduction– ↑ AV refractory period

– Sinus tachycardia & SVT during/after surgery

– Rapidly metabolized by plasma esterase

– Hypotension– Bradycardia

Drugs

Furosemide

• Loop-acting diuretic• Membrane ion transport inhibitor

• Inhibits Na/K/2Cl cotransporter in ascending loop of Henle– Blocks NaCl reabsorption

– Edema– Heart failure– HTN– Hypercalcemia

– ↑ Ca excretion– ↑ Na/K exchange in collecting duct

– Hypokalemia– Metabolic alkalosis– Hyperuricemia– Hypomagnesemia

– ↑ ototoxicity of aminoglycoside ABX

WEEK 3

• LG 3.1/3.2 Pavlick Hemodynamics/Systemic circ• Objective: Explain the relationship between

pressure, flow, and resistance.• Objective: Explain how Poiseuille's Law

influences resistance to flow. Use it and other equations to calculate changes in resistance.

• LG 3.3 Pong VSM control• Objective: Describe the pressure changes

across the cardiovascular system.

• LG 3.4 Pavlick control of BP• Objective: Predict the mechanisms the body

utilizes to restore and maintain arterial pressure under various pathological / clinical scenarios.

• Objective: List all of the anatomical components of the baroreceptor reflex.

• LG 3.7 Shock Pharmacology Szarek • Objective: Explain the mechanism of action of

each drug in each drug class• ..\My Documents\SOMA\Cardiopulmonary m

odule\Tables\LG3_7PharmacologyOfShockMemoryMatrix(1).xls

• LG 3.8 Moticka Immunology• Objective: Describe the mechanism by which

endotoxin can result in the pathophysiology of shock

• LG 3.9 Fischione Hemodynamics• Objective: Differentiate Cardiogenic from

Hypovolemic Shock clinically • Objective: Differentiate Acute vs. Chronic

Hyperemia

• LG 3.11 Pavlick edema• Objective: Explain how edema develops in

response to: venous obstruction, lymphatic obstruction, increased capillary permeability, heart failure, tissue injury or allergic reaction, malnutrition, other clinical scenarios (as discussed in the Berne & Levy assignment or during class)

Week 4

• LG4.3 Normal Cardiovascular Control and Exercise – Dr. Pong

• Objective: Describe the importance of the venous return for cardiovascular control.

•

• LG4.2 Cardiac Performance – Dr. Pavlick AND LG6.2 Compensatory Responses to CHF – Dr. Pavlick

• Objective: Using key cardiac equations, calculate various parameters, including stroke volume, cardiac output, mean arterial pressure, stroke work, ejection fraction, EDV, ESV and cardiac index.

Objective: Describe and predict the impact of changes in preload, afterload, and contractility in determining cardiac performance.

• Objective: Draw a cardiac function curve and explain which factors cause the curve to shift.

• Objective: Draw a ventricular pressure-volume loop and on it label the phases and events of the cardiac cycle.

LG4.2 Cardiac Performance 185

PhysiologyStroke Volume:

SV = EDV-ESV

Cardiac Output (C0)Heart Rate X Stroke Volume CO = HR X SV

Ejection Fraction:– the fraction of the EDV ejected in each stroke volume– is an estimation of contractility is normally ~ 0.55-0.75 or 55%-75%

EF = SV / EDV

Stroke WorkStroke Work = Aortic Pressure X Stroke Volume– fatty acids are the primary energy source for stroke work

Cardiac Output

CO = MAP / TPR

Cardiac index (CI) – Relates heart performance to the size of the individual

CI = CO / BSA2/17/2009

• Objective: Describe and predict the impact of changes in preload, afterload, and contractility in determining cardiac performance.


Factors Affecting Heart RateParasympathetic Nervous SystemThe SA node, atria, and AV node have parasympathetic

vagal innervation, but the ventricles do not.

The neurotransmitter is acetylcholine (Ach) muscarinic

Negative chronotropic effect– Decreases HR by decreasing the rate of phase

4 depolarization– Fewer action potentials occur per unit time

because the threshold potential is reached more slowly and, therefore, less frequently

– The mechanism of the negative chronotropic effect is decreased If, the inward Na+ current that is responsible for phase 4 depolarization in the SA node

Negative dromotropic effect– Decreases conduction velocity through the AV

node– Action potentials are conducted more slowly

from the atria to the ventricles– Increases the PR interval on ECG– The mechanism of the negative dromotropic

effect is decreased inward Ca+2 current and increased outward K+ current

– the negative dromotropic effect reinforces the negative chronotropic effect

Sympathetic nervous systemnorepinephrine is the neurotransmitter, acting at b1 receptors

Positive chronotropic effect– Increases HR by increasing the rate of phase 4 depolarization– More action potentials occur per unit time because the threshold

potential is reached more quickly and, therefore, more frequently– The mechanism of the positive chronotropic effect is increased If,

the inward Na+ current that is responsible for phase 4 depolarization in the SA node.

Positive dromotropic effect– Increases conduction velocity through the AV node– Action potentials are conducted more rapidly from the atria to

the ventricles, and ventricular filling may be compromised.– Decreases the PR interval on ECG– The mechanism of the positive dromotropic effect is increased

inward Ca+2 current– the positive dromotropic effect reinforces the positive

chronotropic effect

Other– Hormones – Epinephrine / NE from the adrenal medulla exert similar effects as

the SNS; these tend to be important during exercise, stress and excitement

– Thyroid hormones (T3 & T4) can elevate HR at rest– Ions– Age, gender, physical fitness and body temperature also influence

resting HR2/17/2009


Factors Affecting Stroke Volume PreloadFrank-Starling Law of the Heart

– Describes the increases in stroke volume and cardiac output that occur in response to an increase in venous return or end-diastolic volume (preload)

– Based on the length-tension relationship in the ventricle; increases in EDV cause an increase in ventricular fiber length, which produces an increase in developed tension

– Is a major mechanism that matches cardiac output to venous return (particularly on a beat-by-beat basis); the greater the VR, the greater the CO

– This type of control of SV is sometimes referred to as heterometric regulation– There is no single Frank-Starling curve (or “cardiac function curve”) on which the ventricle operates; there is actually a family of

curves, each of which is defined by the afterload and inotropic state of the heart.– ↑ afterload or ↓ inotropy shifts the curve down and to the right, whereas ↓ afterload and ↑ inotropy shifts the curve up

and to the leftKey point:

– ANY mechanism that raises cytosolic [Ca+2]• increases the developed force within the myocardial cells.

– ANY mechanism that lowers the cytosolic [Ca+2]• decreases the developed force within the myocardial cells.

2/17/2009


Factors Affecting Stroke Volume Inotropism (Contractility)

2/17/2009

4 things affecting Inotropism Effect

Increased HR Positive

SNS Influence Positive

Cardiac Glycosides Positive

ParaNS influence Negative


Factors Affecting Stroke Volume Inotropism (Contractility)Increased Heart Rate [POSITIVE INOTROPIC EFFECT]

– More action potentials– more Ca+2 enters the myocardial cells during the action potential plateaus– more Ca+2 is released from the SR– greater tension is produced during contraction

This phenomenon is known as:– “positive staircase”– “Bowditch staircase”– treppe.

Increased HR increases the force of contraction– in a stepwise fashion– as the intracellular [Ca+2] increases cumulatively over several beats.

2/17/2009


Factors Affecting Stroke Volume Inotropism (Contractility)Sympathetic stimulation via b1 receptors [POSITIVE INOTROPIC EFFECT]

– Increases the inward Ca+2 current during the plateau of each cardiac action potential

– Increases the activity of the SERCA pumps• as a result, more Ca+2 is accumulated by the SR and

thus more Ca+2 is available for release in subsequent beats

– NE binding to b1-receptors on cardiac muscle cells activates adenylate cyclase• thereby increasing c-AMP• promoting cAMP-dependent phosphorylation of 2

important proteins:– the L-type Ca+2 channels (responsible for the

“trigger” Ca+2) – Phospholamban (protein associated with

SERCA)» The combined action of these

phosphorylations increases the amount of Ca+2 in the SR.

– The net result is that the SR releases more Ca+2 into the cytosol during the next action potential, which promotes more actin-myosin interactions and hence a greater force of contraction.

2/17/2009


Factors Affecting Stroke Volume Inotropism (Contractility)

Cardiac glycosides (e.g., digoxin) [POSITIVE INOTROPIC EFFECT]

Increase the force of contraction:– by inhibiting Na+-K+ ATPase in the myocardial cell membranes

• As a result of this inhibition– the intracellular [Na+] increases– diminishing the Na+ gradient across the cell membrane

Na+-Ca+2 exchange (a mechanism that extrudes Ca+2 from the cell):– depends on the size of the Na+ gradient– thus is diminished, producing an increase in intracellular [Ca+2]

2/17/2009


Factors Affecting Stroke Volume Inotropism (Contractility) & Afterload

Parasympathetic stimulation via muscarinic receptors [NEGATIVE INOTROPIC EFFECT]

– Decreases the force of contraction in the atria (NOT THE VENTRICLES)• by decreasing the inward Ca+2 current during the plateau of the cardiac action

potential– control of SV via inotropism

• sometimes referred to as homometric regulation.– In other words, contractile strength is independent:

• of muscle stretch (Starling's Law)• the EDV

– Instead, it is dependent on things like HR, SNS or ParaNS influence, and drugs.

Afterload– ↑ afterload:

• The ventricle must pump blood against a higher pressure, resulting in a ↓ in stroke volume

– ↓ afterload:• The ventricle pumps blood against a lower pressure, resulting in an ↑ in stroke

volume2/17/2009


Summary

Cardiac performance is ENHANCED by:↑ Preload↑ Inotropy↑ Heart rate↓ Afterload

Cardiac performance is DEPRESSED by:↓ Preload↓ Inotropy↓ Heart rate↑ Afterload

2/17/2009

• Objective: Draw a ventricular pressure-volume loop and on it label the phases and events of the cardiac cycle.


Ventricular Pressure - Volume Loops1 2 (isovolumetric ventricular contraction)

– The cycle begins at the very end of diastole at point 1. • The left ventricle is filled with blood from the left atrium and its volume is about 140ml (EDV).

– Ventricular pressure is low because the ventricular muscle is relaxed. – On excitation, the ventricle contracts and ventricular pressure increases. – The mitral valve closes when left ventricular pressure is greater than left atrial pressure.

• Because all valves are closed, no blood can be ejected from the ventricle (isovolumetric)2 3 (ventricular ejection)

– The aortic valve opens at point 2 when pressure in the left ventricle exceeds pressure in the aorta. • Blood is ejected into the aorta, and ventricular volume decreases.

– The volume that is ejected in this phase is the stroke volume. • Thus, stroke volume can be measured graphically by the width of the pressure-volume loop.

– The volume remaining in the left ventricle at point 3 is the end systolic volume (ESV).3 4 (isovolumetric ventricular relaxation)

– At point 3, the ventricle relaxes. • When ventricular pressure decreases to less than aortic pressure, the aortic valve closes.

– Because all of the valves are closed again, ventricular volume is constant (isovolumetric) during this phase.

4 1 (ventricular filling or ventricular diastole)– Once left ventricular pressure decreases to less than left atrial pressure,:

• the mitral (left AV; bicuspid) valve opens• filling of the ventricle begins.

– During this phase, ventricular volume increases to about 140 ml (EDV).2/17/2009


Changes in the ventricular pressure-volume loop are caused by several factors:

A. Increased Preload– Refers to an ↑ in EDV and is the result of ↑ VR– Causes an ↑ in SV based on the Frank-Starling mechanism– The increase in SV is reflected in increased width of the pressure-volume loop

B. Increased Afterload– Refers to ↑ in aortic pressure (in terms of the left ventricle)– The ventricle must eject blood against a higher pressure, resulting in a ↓ in SV– The decrease in SV is reflected in decreased width of the pressure-volume loop– The decrease in SV results in an increase in ESV

C. Increased Contractility– The ventricle develops greater tension than usual during systole, causing an increase in SV– The increase in SV results in a decrease in ESV2/17/2009

• Objective: Draw a cardiac function curve and explain which factors cause the curve to shift.


Vascular Function Curves / Venous Return CurvesA vascular function or venous return curve depicts the relationship between blood flow through the

vascular system (or venous return) and right atrial pressure (RAP).– As RAP (or PRA) increases, venous return falls.– Venous return to the heart from the venous vascular beds is determined by a pressure gradient

(venous pressure, PV, minus right atrial pressure, PRA). Therefore, ***increases in venous pressure or decreases in right atrial pressure will lead to an increase in venous return.

Mean Systemic Filling Pressure (MSFP)– Point where the vascular function curve intersects the x-axis. – MSFP equals right atrial pressure when there is “no flow” in the cardiovascular system. – It is measured when CO and VR are zero

• pressure is equal throughout the cardiovascular system. – It is often used as a reference point of sorts when looking at a SERIES of vascular function curves

• because just like cardiac function curves can “shift” so too can vascular function curves.

2/17/2009


Shifting of Vascular Function CurvesBlood Volume

– Mean systemic pressure is increased by an increase in blood volume• shift of the vascular function curve to the right.

– Mean systemic pressure is decreased by a decrease in blood volume• shift of the vascular function curve to the left.

Arteriolar Resistance– The slope of the venous return curve is determined by the

resistance of the arterioles.– Clockwise rotation:

• indicates a ↓ in TPR:– When TPR is ↓ for a given right atrial pressure,

there is an ↑ in venous return» i.e., vasodilaton of the arterioles “allows”

more blood to flow from the arteries to the veins and back to the heart

– Counterclockwise rotation: • indicates an ↑ in TPR:

– When TPR is ↑ for a given right atrial pressure, there is a ↓ in venous return to the heart » i.e., vasoconstriction of the arterioles

decreases blood flow from the arteries to the veins and back to the heart2/17/2009


Combining Cardiac Output & Venous Return Curves

Equilibrium or Steady State:– The point at which the 2 curves intersect . – Equilibrium occurs when CO = VR.

Cardiac output can be changed by:– Altering the cardiac output curve, the venous return curve, or both curves

simultaneously. – The superimposed curves can be used to predict the direction & magnitude

of changes in cardiac output.

2/17/2009

CO=VR


Combining Cardiac Output & Venous Return CurvesPositive inotropic agents

– e.g., digoxin– produce ↑ contractility and ↑

cardiac output.

The equilibrium, or intersection, point shifts to:– a higher CO– A correspondingly lower RAP.

• RAP decreases because more blood is ejected from the heart on each beat – Increased SV

2/17/2009


Changes in Blood Volume Change the Venous Return Curve

An ↑ in blood volume ↑ MSFP– shifting the venous return curve to

the right in a parallel fashion.– A new equilibrium, or intersection,

point is established at which both cardiac output and RAP are ↑

A ↓ in blood volume (e.g., hemorrhage) has the opposite effect:– ↓ MSFP and a shift of the venous

return curve to the left in a parallel fashion.

– A new equilibrium is established at which both cardiac output and RAP are ↓.

2/17/2009

LG4.2 Cardiac Performance

Changes in TPR Change Cardiac Function & Venous Return Curves Changes in TPR alter both curves simultaneously:

– therefore, the responses are more complicated than those noted in the previous examples.

↑ TPR:– causes a ↓ in both cardiac output and venous return

A counterclockwise rotation of the venous return curve occurs:– ↑ TPR results in ↓ VR as blood is retained on the arterial side.

A downward shift of the cardiac function curve is caused by the ↑ aortic pressure (↑ afterload) as the heart pumps against a higher pressure.– As a result of these simultaneous changes, a new equilibrium point is established at

which both cardiac output and venous return are ↓.

↓ TPR:– causes an ↑ in both cardiac output and venous return

A clockwise rotation of the venous return curve occurs.– ↓ TPR results in ↑ VR as more blood is allowed to flow back to the heart from the

arterial side.

An upward shift of the cardiac output curve:– is caused by the ↓ aortic pressure (↓ afterload) as the heart pumps against a lower

pressure.– As a result of these simultaneous changes, a new equilibrium point is established at

which both cardiac output and venous return are ↑, but RAP is unchanged.2/17/2009 204

RAP is unchanged

• LG4.5 Aortic Disease – Dr. Fischione• Objective: Describe the basic etiology of

Atherogenesis

LG4.5 & LG4.7 Pathology 206

Etiology of AtherosclerosisEndothelial cell injury -> platelet, LDL

deposition -> macrophage stimulation -> trapped LDL’s transformed into foam cells

Platelets release growth factors -> proliferation of smooth muscle cells -> lipid accumulation within their cytoplasm -> death -> deposition of lipid as cholesterol crystals in the interstitial spaces

Macrophages take up released lipids from smooth muscle death -> secrete cytokines, TNF -> stimulate collagen production -> atheroma2/17/2009


AtheromaSoft core of lipids &

cellular debris– covered by a fibrous

cap of collagen and smooth muscle cells

Major complication is vessel hardening from calcification

2/17/2009Aortic atheroma with foam cells and cholesterol clefts


Risk factors of Atherosclerosis• Age:

– older age• Sex:

– males > females– sex differences less after menopause due to protective effect of estrogens

• Heredity: – i.e. Familial Hypercholesterolemia

• a genetic defect of LDL receptors that does not allow lipoproteins into the liver• Lipid Metabolism:

– elevated serum levels of lipids• Hypertension:

– accelerates atherosclerosis due to:• endothelial defects• ischemic damage• damaged platelets

• Obesity: – causes secondary hyperlipidemia

• Diabetes: – hyperglycemia damages small blood vessels (microangiopathy)– accelerates atherosclerosis

• Cigarette Smoking• Stress2/17/2009


Complications of AtherosclerosisThrombus formation:

due to collagen exposure, plaque rupture, platelet activation and coagulation sequence activation

Aneurysm formation: hypertension develops as blood passes through narrower vessel -> pressure causes dilatation– Most common in the

abdominal aorta2/17/2009

Various forms of Aortic Aneurysms


Dissecting Aneurysm

Major danger of an aneurysm is rupture -> jet of blood dissects through wall -> forms periarterial second lumen in the media = dissecting aneurysm

2/17/2009

Aortic Dissection between the muscle layer (tunica media)

Aortic Dissection Aortic Dissection into Media

Abdominal Aortic Aneurysm


Cerebrovascular DiseaseCerebrovascular

atherosclerosis– Atherosclerosis of the

internal carotids/circle of Willis -> strokes

– 3rd most common cause of death and the most crippling disease in the U.S.

May be gradual from progressive fibrosis/calcification, or sudden from plaque rupture -> thrombosis2/17/2009

Thromboemboli from L heart to cerebral artery causing stroke

Atherosclerosis of Circle of Willis


Atherosclerosis of the ExtremitiesTypically affects legs more than arms

May present as intermittent claudication: chronic ischemia of the lower limbs secondary to narrowing of the femoral or popliteal artery = underperfusion of the leg muscles during walking/running– Treated with surgical plaque removal (endarterectomy)

May present as gangrene from sudden occlusion of the arteries

2/17/2009

Atherosclerosis of the extremity causing gangrene from diabetes


Atherosclerosis of Renal Arteries

Reduced flow of blood through renal arteries -> hypoperfusion of the kidneys -> renal dysfunction -> increased renin release -> hypertension

2/17/2009Renal atherosclerosis


Atherosclerosis of the Intestinal ArteriesCauses ischemia of

gradual onset in the intestines -> nonspecific GI symptoms (constipation, poor digestion, malabsorption)

Acute occlusion, i.e. from embolic thrombic occlusion -> intestinal infarction 2/17/2009

Intestinal infarction

• LG4.6 Peripheral Artery Disease, Ulceration Patterns – Dr. Sharifi

• Objective: Understand the importance of ABI and how to calculate it.

DIAGNOSIS• History taking• Careful examination of leg• Pulse evaluation• Ankle-brachial index (ABI):

SBP in ankle (dorsalis pedis and posterior tibial arteries)SBP in upper arm (brachial artery)

Diagnostic Imaging

2/20/09 LG4.6 216

ABI Calc.

Right Left

Brachial 140/90 130/85

Dorsalis Pedis 120/80 90/70

Posterior Tibial 110/70 115/85

ABI 120/140=0.86 115/140=0.82

Ankle-Brachial Index Values & Clinical Classification

Clinical Presentation Ankle-Brachial Index

Normal > 0.90

Claudication 0.50-0.90

Rest pain 0.21-0.49

Tissue loss < 0.20

2/20/09 LG4.6 217

Values >1.25 falsely elevated; commonly seen in diabetics

• LG4.7 Vasculitis Leading to Skin ulcerations – Dr. Fischione

• Objective: Describe the pathology and ANCA involvement in Churg-Strauss Syndrome


Pathogenesis of VasculitisMay be associated with a

viral infection

Small vessel vasculitides – i.e. Wegener granulomatosis

and Polyarteritis Nodosa– associated with ANCA (anti-

neutrophil cytoplasmic antibodies)• Common patterns are:

– perinuclear immunoflouresnce (P-ANCA)

– cytoplasmic immunoflourescence (C-ANCA)2/17/2009

C-ANCA’s seen in Wegener’s

P-ANCA’s seen in Polyarteritis Nodosa


Churg-Strauss Syndrome• AKA allergic

granulomatosis and angiitis

• Systemic vasculitis in young people with asthma

• Both C-ANCA and P-ANCA are demonstrated in 2/3 of patients

• Microscopic findings:– Granulomas with

intense eosinophilic infiltrate -> fibrinoid necrosis & thombosis2/17/2009

Granulomatous foci around blood vessels

Intense eosinophilic infiltrates

• Objective: Determine which organs and tissues are involved in Kawasaki Disease


3 year old presents w/ a high fever for the past week. Physical exam reveals:

2/17/2009

Mucocutaneous lesions Rash

Peeling of the fingertips Desquamation of the sole of foot


Kawasaki Disease• AKA mucocutaneous lymph

node syndrome• Acute necrotizing vasculitis of

infancy and early childhood• Symptoms:

– High fever, rash– Conjunctival, oral lesions– Lymphadenitis– Desquamation of the

fingertips, soles and palms• In 70%: affects coronary

arteries -> *coronary artery aneurysms*

• Possible association with Parvovirus B192/17/2009Large coronary artery aneurysm

Coronary artery with aneurysmal formations

WEEK 5

• LG5.2 Endocarditis – Dr. Fischione• Objective: Identify the features of

Endocarditis in Intravenous Drug Abusers (IVDA)

• Objective: Describe characteristics of Subacute Bacterial Endocarditis (SBE) and the causative organisms

• Endocarditis in IVDA• Bacteremia from cellulitis or

phlebitis at the injection site or drug contamination is the pathogenesis of this type of endocarditis

• The tricuspid valve is infected in over 50% of all addicts with signs and symptoms of pulmonary emboli and abscesses leading to Pneumonia.

• St. aureus is responsible for 50-60% of cases.

Infective endocarditis

• Acute (staph aureus)

• Subacute (S. viridians)

• LG5.3 Endocarditis – Dr. Kuo• Objective: Identify and contrast the most

common microbial etiologies of endocarditis in native and prosthetic valves.

COMMON MICROBIAL ETIOLOGIES OF ENDOCARDITIS IN NATIVE VALVES

• Most prevalent are staphylococci, streptococci, and enterococci.

• S. aureus is the most common cause.• Acute endocarditis: S. aureus accounts for 60%

of cases.• Subacute endocarditis: α-hemolytic and

nonhemolytic streptococci cause 60% of infection.

COMMON MICROBIAL ETIOLOGIES OF ENDOCARDITIS IN PROSTHETIC VALVE

• First year post-op: often perioperative contamination (nosocomial); 55% staphylococci; mostly β-lactam antibiotic–resistant S. epidermidis

• >1 year post-op: community acquired; streptococci, S. aureus, enterococci, and Gram-negative coccobacilli; : mostly β-lactam sensitive

• LG5.4 Heart Sounds – Dr. Rios• Objective: Describe the pathophysiology of

heart sound abnormalities

• LG5.5 Valvular Disease, Rheumatic Fever, Cardiomyopathies – Dr. Fischione

• Objectives: Describe what Aschoff Bodies are as they relate to RHD; Define the Jones Criteria for the diagnosis of RHD

• Objective: Demonstrate the major diagnostic procedure for the diagnosis of all cardiomyopathies

• LG5.6 Embryology, Congenital Heart Disease – Dr. Fischione (2 hours)

• Objective: Differentiate prenatal vs. postnatal structures in fetal circulation

• • Objective: Define rib-notching and how this

characteristic occurs in Coarctation• • Objective: Illustrate the four characteristics of a

Tetralogy of Fallot

• LG5.7 Murmurs – Dr. Rios• Objective: Discuss the mechanism(s) for heart

murmurs and the physiological principles.

• LG5.8 Drugs for Endocarditis – Dr. SzarekObjective: Differentiate between the uses of these drugs in treating infective

• ..\My Documents\SOMA\Cardiopulmonary module\Tables\DRUG_THERAPY_FOR_INFECTIVE_ENDOCARDITIS.docx

WEEK 6

• LG6.3 Congestive Heart Failure – Dr. Fischione• Objective: Differentiate pathology between

right and left-sided heart failure.

LG6.2 Compensatory Responses to Heart Failure

2643/3/2009

LG6.3 Congestive Heart Failure 265

Congestive Heart Failure

• Failure of the heart as a pump • Characterized by:• forward failure• backward failure• both

3/3/2009


Left Heart FailureEtiology:

– Ischemic heart disease– HTN– Aortic and mitral valve disease– Non-ischemic myocardial disease

Pathology:– LVH with dilation -> secondary enlargement of the left

atrium -> atrial fibrillation -> blood stasis -> thromboemboli– Lungs due to backward failure:

• Pulmonary congestion and edema• **Hemosiderin-laden macrophages (“heart-failure

cells”)**– macrophages phagocytize RBC’s in alveolar sacs

– Kidneys due to forward failure:• ↓CO -> activation of the RAS -> fluid retention ->

pulmonary edema– Brain due to forward failure:

• Hypoxia -> hypoxic encephalopathy -> stupor, loss of consciousness, restlessness, coma

Clinical:– Dyspnea– Orthopnea– Cough– Fatigue– Limb weakness3/3/2009

Lung Hemosiderin-laden macrophages

Pulmonary edema


Right Heart FailureEtiology:

– Most common cause is left heart failure– If isolated: cor pulmonale

Pathology:– Backward failure -> congestion of the

venous system– Hepatomegaly:

• chronic passive congestion of the liver (“Nutmeg liver”)

– Splenomegaly– Ascites (fluid within the abdomen)– Peripheral edema

• Ankle• Sacrum

– JVD– Pleural effusions3/3/2009

Centrilobular passive congestion of the liver (Nutmeg liver)

Pitting ankle (petal) edema

• LG6.4 CHF-pharmacology Szarek• Objective: Explain the molecular mechanism

of action of each drug in each drug class

• ..\My Documents\SOMA\Cardiopulmonary module\Tables\Heart_Failure_Drugs_Martinez.docx

• SP5.3 Syncope – Dr. Sharifi; PW5.3 Syncope – Dr. Sharifi

• Objective: Recognize Diagnostic modalities: Rhythm monitoring, Head Up Tilt

• A test used to determine the cause of fainting spells. The test involves being tilted, always with the head-up, at different angles for a period of time (2 minutes at 30 degrees, then 2 minutes at 45 degrees, then up to 45 minutes at 70 degrees) . Heart rhythm, blood pressure and other symptoms are closely monitored and evaluated with changes in position.

• Purpose– determine the cause of fainting spells – evaluate heart rhythm, blood pressure, symptoms and

sometimes other measurements with change of position

High Yield Weeks 1 6

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