B4M1C2: Cardiovascular System

Question 1

What is the algorithm in the evaluation of chest pain?

Answer 1

1. Believed to be non-coronary (low CAD probability). No further work-up needed.
2. Believed to be non-coronary (low CAD probability). Further work-up needed. –> Non-coronary work-up
3. Believed to be coronary. No further work up needed.
4. Believed to be coronary. Further work-up needed. –> Non-invasive testing (threadmill exercise or nuclear imaging) –> 1.) Neg 2.) Pos 3.) Intermediate (if pos – medical mngt & coronary angiography; if intermediate – coronary angiography)
5. Not certain of the cause (intermediate probability of CAD). Further work up needed. –> Non-invasive testing (threadmill exercise or nuclear imaging) –> 1.) Neg 2.) Pos 3.) Intermediate (if pos – medical mngt & coronary angiography; if intermediate – coronary angiography)

Question 2

How do you categorize a patient?

Answer 2

Based on:
- History
- Physical examination
- 12-lead ECG

Question 3

What is an indication for coronary angiography?

Answer 3

A highly positive exercise ECG

Question 4

If stress ECG is equivocal, what may be requested because of its higher sensitivity in detecting coronary artery disease (CAD)?

Answer 4

a stress thallium examination

Question 5

What remains the gold standard for diagnosis?

Answer 5

Coronary angiography

Question 6

What is the algorithm for the management of Chronic Stable Angina?

Answer 6

Chronic Stable Angina –> Risk Stratify –> High risk? No, then medical mngt; Yes, then amenable to invasive procedures –> Coronary angiography –> Suitable for PTCA? if YES, PTCA –> medical mngt; if NO, suitable for CABG –> Yes then CABG then medical mngt; if not then medical mngt only

Question 7

RISK STRATIFICATION SHOULD BE BASED ON THE
FOLLOWING HIGH RISK PARAMETERS

Answer 7

● Canadian chest pain classification III or IV

● Poor LV function

● High-risk treadmill exercise test
○ Duration of symptom-limiting exercise <6 mets
○ Provocation of angina pectoris during exercise
○ Failure to increase SBP > 120 mmHg or a sustained decrease > 10 mmHg during progressive exercise
○ ST-segment depression of > 2 mm, downsloping type
of ST-segment depression, ECG changes starting at < 6 mets (early positive test), involving > 5 leads or
persisting > 5 min into the recovery period
○ Exercise-induced ST-segment elevation (aVR excluded) in a non-Q wave lead
○ Reproducible sustained (> 30 sec) or symptomatic ventricular tachycardia

● High-risk thallium test
○ Multiple severe initial thallium defect
○ Multiple areas showing thallium distribution
○ Increased lung/heart thallium ratio
○ Transient ischemic left ventricular dilation on stress thallium

● Medical treatment failure

Question 8

What is the algorithm for the management of unstable angina?

Answer 8

Clinical Features for Unstable Angina:

1) High risk
>/= 1 of the ff:
- prolonged (>20 min) rest angina, ongoing
- cardiac failure, S3, new systolic murmur, hypotension
- dynamic ST changes >/= 1 mm or new deep T inversions
- positive markers (Troponin I or T, CK-MB)
ADMIT TO CCU

2) Intermediate risk
No high risk feature but >/= 1 of the ff:
- rest angina, now resolved
- nocturnal chest pain
- new onset CCSC III angina (walking <2 blocks) or IV (minimal exertion or rest) angina in past 2 weeks
- ST depression </= 1mm in multiple leads
- age >65 years
ADMIT TO MONITORED BED

3) Low risk
No high intermediate risk but may have any of the ff:
- increased chest pain frequency, severity or duration
- chest pain provoked at lower threshold
- new onset angina <2 months
ADMIT TO MONITORED BED AND OUT PX MNGT

CHECK PAGE 1 DIAGRAM FOR FULL ALGORITHM

Question 9

What are the structures forming the coronary circulation and arterial blood supply of the heart?

Answer 9

• RCA
• LCA
• Circumflex Artery

Question 10

What arises from the anterior aortic sinus of the ascending aorta. And it runs forward between the pulmonary trunk and right auricle then descends in the right AV groove then it goes to the inferior border of the heart posteriorly to anastomose with the coronary artery?

Answer 10

RCA

Question 11

The right coronary artery supplies the:

Answer 11

The right coronary artery supplies all of the right ventricle (except for the small area to the right of the anterior interventricular groove), the variable part of the diaphragmatic surface of the left ventricle, the posterior inferior third of the ventricular septum, the right atrium and part of the left atrium, and the sinoatrial node and the atrioventricular node and bundle.

The LBB also receives small branches.

Question 12

What are the branches of the RCA?

Answer 12

• Right Conus Artery
• Anterior Ventricular Branches (Marginal Branch)
• Posterior Ventricular Branches
• Posterior Interventricular (Descending) Artery
• Atrial Branches

Question 13

What supplies the anterior surface of the pulmonary conus (infundibulum of the right ventricle) and the upper part of the anterior wall of the right ventricle?

Answer 13

Right conus artery

Question 14

What are 2 or 3 in number, and supply the anterior surface of the right ventricle?

Answer 14

Anterior ventricular branches

Question 15

What is the largest and runs along the lower margin of the costal surface to reach the apex?

Answer 15

Marginal Branch

Question 16

What are usually 2 in number, and supply the diaphragmatic surface of the right ventricle?

Answer 16

Posterior ventricular branches

Question 17

What runs toward the apex in the posterior interventricular groove. It gives off branches to the right and left ventricles, including its inferior wall. It supplies branches to the posterior part of the ventricular septum but not to the apical part?

○ A large septal branch supplies the AV node
○ In 10% of individuals this artery (post interventricular artery) is replaced by a branch from the left coronary artery.

Answer 17

Posterior interventricular (descending) artery

Question 18

What supplies the anterior and lateral surfaces of the right atrium. One branch supplies the posterior surface of both the right and left atria?

○ The artery of the SA node supplies the major part of the heart, the node and the left and right atria; in 35% of individuals it arises from the left coronary artery.

Answer 18

Atrial Branches

Question 19

What supplies most of the left ventricle, a small area of the Right ventricle to the right of the interventricular groove, the anterior two-thirds of the ventricular septum, most of the left atrium, the RBB, and the LBB?

Answer 19

LCA

Question 20

● Usually larger than the right coronary artery, supplies the major part of the heart, including the greater part of the left atrium, left ventricle and ventricular septum.

● It arises from the left posterior aortic sinus of the ascending aorta and passes forward between the pulmonary trunk and the left auricle, then enters the atrioventricular groove and divides into branches

Answer 20

LCA

Question 21

Branch of LCA

Answer 21

Anterior interventricular (descending) branch

Question 22

○ Runs downward in the anterior interventricular groove to the apex of the heart and enters the posterior interventricular groove and anastomose with the terminal branches of the right coronary artery.

○ It supplies the right and left ventricles with numerous branches that also supply the anterior part of the ventricular septum.

Answer 22

Anterior interventricular (descending) branch

Question 23

What may arise directly from the trunk of the left coronary artery?

Answer 23

Left diagonal artery

Question 24

What supplies the pulmonary conus?

Answer 24

Left conus artery

Question 25

● The same size as the anterior interventricular artery.
● Winds around the left margin of the heart in the atrioventricular groove.

Answer 25

Circumflex artery

Question 26

What is a large branch that supplies the left margin of the left ventricle down to the apex?

Answer 26

Left marginal artery

Question 27

What supplies the left ventricle?

Answer 27

Anterior ventricular and posterior ventricular
branches

Question 28

What supplies the left atrium?

Answer 28

Atrial branches

Question 29

A. Posterior view of the heart showing the origin
and distribution of the posterior interventricular
artery in the light dominance.

B. Posterior view of the heart showing the origin
and distribution c/ the posterior interventricular
artery in the left dominance.

C. Anterior view of the heart showing the
relationship of the blood supply to the conducting
system.

Answer 29

See page 2

Question 30

Veins and Areas Drained:

Answer 30

Coronary Sinus
Tributaries:
- Great cardiac vein
- Small cardiac vein
- Middle cardiac vein
- Posterior vein of the left ventricle
- Oblique vein of the left atrium

Anterior Cardiac Vein
- Anterior part of the right ventricle
- Right cardiac border
- Right marginal vein
- Right atrium

Venae Cordis Minimae (Thebesius’ Veins)
- Right atrium and veintricle
- Lesser extent: Left atrium and ventricle

Question 31

What drains blood to the right atrium from the whole heart (including its septa) except the anterior region of the right ventricle and small, variable parts of both atria and left ventricle?

Answer 31

Coronary Sinus

Question 32

How long is the coronary sinus?

Answer 32

It is about 2-3 cm long, lying posterior in the coronary sulcus (atrioventricular groove) between the left atrium and ventricle (Fig 10.152)

Question 33

Where does the coronary sinus open?

Answer 33

It opens into the right atrium between the opening of the inferior vena cava and the right atrioventricular orifice, and its opening is guarded by an endocardial fold (semilunar valve of the coronary sinus)

Question 34

This begins at the cardiac apex, ascends in the anterior interventricular sulcus to the coronary sulcus and follows this to the left and round posterior to the heart to enter the coronary sinus at its origin.

It receives tributaries from the left atrium and both ventricles, including the large left marginal vein ascending the left aspect (obtuse border) of the heart.

Answer 34

Great cardiac vein

Question 35

This lies posterior in the coronary sulcus between the right atrium and ventricle and opens into the coronary sinus near its atrial end.

It receives blood from the back of the right atrium and ventricle.

Answer 35

Small cardiac vein

Question 36

Beginning at the cardiac apex, it runs back in the posterior interventricular groove to end in the coronary sinus near its atrial end.

Answer 36

Middle cardiac vein

Question 37

What is found on the diaphragmatic surface of the left ventricle a little left of the middle cardiac vein, it usually opens into the center of the coronary sinus but sometimes into the great cardiac vein?

Answer 37

Posterior vein of the left ventricle

Question 38

What descends obliquely on the back of the left atrium to join the coronary sinus near its end, it is continuous above with the ligament of the left vena cava; the two structures are remnants of the left common cardinal vein. #1-4 have valves on their orifices, #5 has none?

Answer 38

Oblique vein of the left atrium

Question 39

● Drain on anterior part of the right ventricle and a region around the right cardiac border when the right marginal vein joins this group, ending principally in the right atrium.

● There are usually 2 or 3, sometimes even 5, they ascend in subepicardial tissue to cross the right part of the atrioventricular sulcus, passing deep or superficial to the right coronary artery. They end in the right atrium, near the sulcus, separately or in variable combinations.

Answer 39

Anterior cardiac vein

Question 40

What opens into the right atrium and ventricle and, to a lesser extent, the left atrium and sometimes left ventricle?

Answer 40

Venae Cordis Minimae (Thebesius’ veins)

Question 41

PHYSIOLOGY OF CORONARY CIRCULATION

Answer 41

The Coronary Circulation Receives 5% of the Resting Cardiac Output from the Left Heart, and Mostly Returns it to the Right Heart

Question 42

The heart receives approximately 5% of the resting cardiac output, although it represents how much of the total body weight?

Answer 42

Less than 0.5% of total body weight

Question 43

What does the heart usually use to generate the adenosine triphosphate (ATP) required for pumping blood?

Answer 43

Oxidative phosphorylation

However, of all the 02 that the heart consumes, no more than 40% reflects the oxidation of carbohydrate.
More than 60% of myocardial 02 consumption in the fasting state is due to the oxidation of fatty acids.

Question 44

What readily oxidizes ketone bodies, which can provide considerable energy during starvation or during diabetic ketoacidosis?

Answer 44

Myocardium

Question 45

When the 02 supply is adequate, the heart takes up and oxidizes what?

Answer 45

both lactate and pyruvate, as do red (i.e., oxidative) skeletal muscle fibers, although the arterial concentration of pyruvate is usually low.

Question 46

When the energetic demand for ATP exceeds the supply of 02, the heart can no longer take up lactate, but instead releases lactate by:

Answer 46

By breaking down its own glycogen stores

In this manner, the heart can continue to function for a short time when deprived of 02. If hypoxia develops in the myocardium, nociceptive fibers trigger the sensation of referred pain, known as angina pectoris.

○ More severe or prolonged insults damage the myocardial tissue, which eventually becomes necrotic (myocardial Infarction).

Question 47

The entire blood supply to the myocardium derives from the right and left coronary arteries, which originate at the:

Answer 47

root of the aorta behind the cusps of the aortic valves

Question 48

Although anatomy is subject to individual variation

Answer 48

right coronary artery generally supplies the right
ventricle and atrium, and the left coronary artery
supplies the left ventricle and atrium

Question 49

The left coronary artery divides near its origin into two principal branches:

Answer 49

The left circumflex artery sends branches to the left atria and ventricle, and the left anterior descending artery descends to the apex of the heart and branches to supply the interventricular septum and a portion of the right as well as the left ventricle

○ These arteries course over the heart, branching into segments that penetrate into the tissue, and dividing into capillary networks.
○ Capillary density in histologic sections of the human heart exceeds 3000/mm2 (skeletal muscle has only ~400/mm2).
○ The small diameter of cardiac muscle fibers «20 m), less than half that of skeletal muscle (~50 m), facilitates 02 diffusion into the cardiac cells, which have a high energetic demand.

Question 50

Once blood passes through the capillaries, it collects in venules, which drain outward from the myocardium to converge into the:

Answer 50

Epicardial veins

Question 51

○ These veins empty into the right atrium via the coronary sinus. Other vascular channels drain directly into the cardiac chambers.

○ These include the thebesian veins, which drain capillary beds within the ventricular wall.

○ Because the deoxygenatedblood carried by the thebesian veins exits predominantly into the ventricles, this blood flow bypasses the pulmonary circulation.

○ Numerous collateral vessels among branches of the arterial vessels and throughout the venous system act as anastomoses; these provide alternative routes for blood flow should a primary vessel become occluded.

Answer 51

Epicardial veins

Question 52

Extravascular Compression Impairs Coronary Blood Flow During Systole

Answer 52

● In other systemic vascular beds, blood flow roughly parallels the pressure profile in the aorta, rising in systole and falling in diastole.

○ However, in the coronary circulation, flow is somewhat paradoxical: Although the heart is the source of its own perfusion pressure, myocardial contraction effectively compresses its own vascular supply.

○ Therefore, the profile of blood flow through the coronary arteries depends on both the perfusion pressure in the aorta (Fig. 23-4, top panel) and the extravascular compression provided by the contracting ventricles, particularly the left ventricle.

● Blood flow in the left coronary artery may actually reverse transiently in early systole (see Fig. 23-4, middle panel), as the force of the left ventricle’s isovolumetric contraction compresses the left coronary vessels, while the aortic pressure has not yet begun to rise (i.e., aortic valve is still closed).

○ As aortic pressure increases later during systole, flow increases, but never reaches very high values.

● However, early during diastole, when the relaxed ventricles no longer compress the left coronary vessels but aortic pressure is still high, left coronary flow rises to extremely high levels.
○ All told, approximately 80% of total left coronary blood flow occurs during diastole.

● In contrast, the profile of flow through the right coronary artery (see Fig. 23-4, lower panel) is very similar to the pressure profile of its feed vessel, the aorta.

○ Here, systole contributes a greater proportion of the total flow, and systolic reversal does not occur.

○ The reason for this difference is the lower wall tension developed by the right heart, which pumps against the low resistance of the pulmonary circulation.

● The impact of systolic contraction on the perfusion of the left coronary vessels is highlighted by the effect of ventricular fibrillation (see Fig. 20-131).

○ At the onset of this lethal arrhythmia, left coronary perfusion transiently increases, reflecting the loss of mechanical compression of the vasculature.

● Changes in heart rate, because they affect the duration of diastole more than that of systole, also affect coronary 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, 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.

● Coronary blood flow not only varies in time during the cardiac cycle, it also varies with depth in the wall of the heart.

○ Blood flows to cardiac myocytes through arteries that penetrate from the epicardium toward the endocardium.

○ During systole, the intramuscular pressure is greatest near the endocardium and least near the epicardium.

○ All things being equal, the perfusion of the endocardium would therefore be less than that of the epicardium.

● However, total blood flows to the endocardial and epicardial halves are approximately equal because the endocardium has a lower intrinsic vascular resistance, and thus a greater blood flow during diastole.

○ When the diastolic pressure at the root of the aorta is pathologically low (e.g., aortic regurgitation) or coronary arterial resistance is high (e.g., coronary artery occlusion), endocardial blood fow falls below the epicardial flow.

○ Thus, the inner wall of the left ventricle often
experiences the greatest damage with atherosclerotic heart disease.

Question 53

MYOCARDIAL BLOOD
Flow Parallels Myocardial Metabolism

Answer 53

● A striking feature of the coronary circulation is the nearly linear correspondence between myocardial 02 consumption and myocardial blood flow.
○ This relationship persists in isolated heart
preparations, emphasizing that metabolic signals are the principal determinants of 02 delivery to the
myocardium.
○ In a resting individual, each 100 g of heart tissue receives 80 to 70 ml/min of blood flow.
○ Normally, the heart extracts 70% to 80% of the Oz content of arterial blood (normally ~20 ml/dI blood), thereby producing an extremely low venous 02 content (~5 ml/ dl).
○ Therefore, the myocardium cannot respond to increased metabolic demands by extracting much more Oz than it already does when the individual is at rest.
○ The heart can meet large increases in O2 demand only by increasing coronary blood flow, which can exceed 250 ml/min per 100 g with exercise.

● Because blood pressure normally varies within fairly narrow limits, the only way to substantially increase blood flow through the coronary circulation during exercise is by vasodilation.
○ The heart relies primarily on metabolic mechanisms to increase the caliber of its coronary vessels.
○ Adenosine has received particular emphasis in this regard. An increased metabolic activity of the heart, an insufficient coronary blood flow, or a fall in myocardial Poz results in adenosine release.
○ Adenosine then diffuses to the vascular
smooth-muscle cells, activating purinoceptors to
induce vasodilation by lowering [Ca] (see Table 19-7).
○ Thus, inadequate perfusion to a region of tissue would elevate interstitial adenosine levels, causing
vasodilation and restoration of flow to the affected
region.

● When cardiac demand outstrips the blood supply, a transient rise in [K+] may also contribute to the initial increase in coronary perfusion (see Table 19.8).
○ However, it is unlikely that K+ mediates sustained elevations in blood flow.
○ An elevation of the Pcoz and a fall in the Poz may also lower coronary vascular resistance.

● Coronary blood flow is relatively stable between perfusion pressures of approximately 70 mm Hg and more than 150 mm Hg.
○ Thus, like the brain, the blood flow to the heart exhibits autoregulation.
○ In addition to the myogenic response, metabolites such as adenosine and O2 contribute to coronary autoregulation.

Question 54

MYOCARDIAL BLOOD
Although Sympathetic Stimulation Directly Constricts Coronary Vessels, Accompanying Metabolic Effects Predominate, Producing an Overall Vasodilation:

Answer 54

● Sympathetic nerves course throughout the heart, following the arterial supply. Stimulating these nerves causes the heart to beat more frequently and more forcefully.
○ Beta-1 adrenoceptors on the cardiac myocytes mediate these chronotropic and inotropic responses.
○ As discussed in the previous section, the increased metabolic work of the myocardium
leads to coronary vasodilation, via metabolic pathways.
○ However, during pharmacologic inhibition of the B receptors on the cardiac myocytes, which prevents the increase in metabolism, sympathetic nerve stimulation causes a coronary vasoconstriction.
○ This response is the direct effect of sympathetic nerve activity on alpha-adrenoceptors on the VSMCs of the coronary resistance vessels.

● Thus, blocking B receptors “unmasks” adrenergic constriction. However, under normal circumstances (i.e., no B blockade), the tendency of the metabolic pathways to vasodilate far overwhelms the tendency of the sympathetic pathways to vasoconstrict.

● Activation of the vagus nerve has only a mild vasodilatory effect on the coronary resistance vessels.
○ This muted response is not due to insensitivity of the VSMCs to acetylcholine, which elicits a pronounced vasodilation when administered directly.
○ Rather, the release of acetylcholine from the vagus nerve is restricted to the vicinity of the sinoatrial node.
○ Thus, the vagus nerve has a much greater effect on heart rate than on coronary resistance.

Question 55

MYOCARDIAL BLOOD
Collateral Vessel Growth Can Provide Blood Flow to Ischemic Regions

Answer 55

● When a coronary artery or one of its primary branches becomes abruptly occluded, ischemia can produce necrosis (i.e., a myocardial infarct) in the region deprived of blood flow.
○ However, if a coronary artery narrows gradually over time, collateral blood vessels may develop and at least partially ameliorate the reduced delivery of 02 and nutrients to the compromised area, preventing or at least diminishing tissue damage.
○ Collateral vessels originate from existing branches that undergo remodeling with the proliferation of endothelial and smooth-muscle cells.
○ Stimuli for collateral development include angiogenic molecules (p. 481) released from the ischemic tissue and changes in mechanical stress in the walls of vessels supplying the affected region.

Question 56

MYOCARDIAL BLOOD
Vasodilator Drugs May Compromise Myocardial Flow Through “Coronary Steal”

Answer 56

● A variety of drugs can promote vasodilation of the coronary arteries. These are typically prescribed for patients suffering from angina pectoris, the chest pain associated with inadequate blood flow to the heart (see box titled Treating Coronary Artery Disease).

● If the buildup of atherosclerotic plaque - which underlies angina pectoris -occurs in the large epicardial arteries, the increased resistance lowers the pressure in the downstream micro vessels.
○ Under such conditions, the physician should be
cautious in using pharmacologic agents to dilate the coronary vessels: In an ischemic area of the
myocardium, downstream from a stenosis, metabolic stimuli may have already maximally dilated the arterioles.
○ Administering a vasodilator can then only increase the diameter of blood vessels in nonischemic vascular beds that are parallel to the ischemic ones.
○ The result is coronary steal, a further reduction in the pressure downstream from site of stenosis, and further compromise of blood flow to the ischemic region.
○ When vasodilator therapy relieves angina, the
favorable result is more likely attributable to the
vasodilation of the noncoronary systemic vessels.

Question 57

What is a graphic recording of electric potential generated by the heart?

Answer 57

ECG

Question 58

What is a triangle with the heart at its center, can be approximated by placing electrodes on both arms and on the left leg?

Answer 58

Einthoven’s triangle

Question 59

This states that if the electrical potentials of any two of the three bipolar limb leads are known at any given instant, the third one can be determined mathematically from the first two by simply summing the first two (but note that the positive and negative signs of the different leads must be observed when making the summation.)

Answer 59

Einthoven’s Law

○ Example:
■ Lead I - (+) 0.5 mV (millivolts)
■ Lead III - (+) 0.7 mV
■ Lead II: (+) 0.5 + (+) 0.7 = (+) 1.2 mV

Question 60

Different leads and their corresponding electrode
placement

Answer 60

● Bipolar limb leads
○ Lead I - left arm positive (+) terminal and right arm negative (-) terminal
○ Lead II - left leg positive (+) and right arm negative (-)
○ Lead III - left leg positive (+) and left arm negative (-)

● Unipolar limb leads
○ aVR - right arm (RA) electrode (+)
○ aVL - left arm (LA) electrode (+)
○ aVF - left leg (LL) electrode (+)

● Chest leads (Precordial leads)
○ V1 - 4th intercostal space, right sternal border
○ V2 - 4th intercostal space, left sternal border
○ V3 - midway between V2 and V4
○ V4 - 5th ICS, left midclavicular line
○ V5 - left anterior axillary line at the same horizontal level as V4
○ V6 - 5th ICS, left mid axillary line at the same horizontal level as V4 and V5

Question 61

COMPONENTS OF THE NORMAL ELECTROCARDIOGRAM AND ITS ELECTRO-PHYSIOLOGIC BASIS

P wave

Answer 61

● represents depolarization of atrial muscle.
● Does not include atrial repolarization, which is “buried in the QRS complex.”
● Location: precedes the QRS complex
● Amplitude: 2 - 3 mm High
● Duration: 0.06 - 0.12 second
● Configuration: usually rounded and upright
● Deflection: positive or upright in leads I, lI, aVf, and V2 to V6; usually positive but may vary in leads IlI and aVL; negative or inverted in lead aVr: biphasic or variable in lead V1.

Question 62

COMPONENTS OF THE NORMAL ELECTROCARDIOGRAM AND ITS ELECTRO-PHYSIOLOGIC BASIS

PR interval

Answer 62

● Is the interval from the first atrial depolarization to the beginning of the Q wave (initial depolarization of the ventricle)
● increases if conduction velocity through the AV node is slowed (as in heart block)
● Location: from the beginning of the P wave to the beginning of the QRS complex
● Duration: 0.12 - 0.20 second

Question 63

COMPONENTS OF THE NORMAL ELECTROCARDIOGRAM AND ITS ELECTRO-PHYSIOLOGIC BASIS

QRS complex

Answer 63

● represents depolarization of the ventricle.
● Location: follows the PR interval
● Amplitude: 5 - 30 mm High, but differs for each lead used
● Duration: 0.06 - 0.10 second or half of the PR interval
● Configuration: consists of the Q wave (the first negative deflection, or deflection below the baseline, after the P wave), the R wave (the first positive deflection after the Q wave) and the S wave (the first negative deflection after the R wave). All 3 waves may not be seen always in the
ECG.

● Deflection: positive (with most of the complex above the baseline) in leads I, II, Ill, aVL, AvF, and V4 to V6, negative in leads aVR and V1 to V2, and biphasic in lead V3.

Question 64

COMPONENTS OF THE NORMAL ELECTROCARDIOGRAM AND ITS ELECTRO-PHYSIOLOGIC BASIS

QT interval

Answer 64

QT interval

● measures the time needed for ventricular depolarization and repolarization
● Its length varies according to heart rate
● Location: extends from the beginning of the Q wave to the end of the T wave
● Duration: varies according to age, gender, and heart rate; usually lasts from 0.36 - 0.44 second; shouldn’t be greater than half the distance between the two consecutive R wave (called the R -R interval) when the rhythm is regular

Question 65

COMPONENTS OF THE NORMAL ELECTROCARDIOGRAM AND ITS ELECTRO-PHYSIOLOGIC BASIS

ST segment
● represents the end of ventricular conduction or depolarization and the beginning of ventricular recovery or repolarization

● Location: extends from the end of the S wave to the beginning of the T wave

● Deflection: usually isoelectric or on the baseline (neither positive nor negative); may vary from -0.5 to 1 mm in some precordial leads

Answer 65

T wave

● represents the relative refractory period of repolarization or ventricular recovery (ventricular repolarization)
● Location: follows the ST segment
● Amplitude: 0.5 mm in leads I, ll, and III and up to 10 mm in the precordial leads
● Configuration: typically rounded and smooth
● Deflection: usually positive or upright in leads I, II, and V2 to V6; inverted in lead aVr; variable in leads III and V1

Question 66

DETERMINATION OR CALCULATING THE HEART RATE IN ECG: (3)

Answer 66

1500 method
R-R method
6-second method

Question 67

What is the most precise way to determine heart rate, can be used only if the rhythm is regular, no irregular beats seen?

Answer 67

1500 method

● Count the number of small squares between 2
consecutive QRS complexes. Since there are 1500 small squares/minute (0.04 sec. per square), divide 1500 by the number of small squares.
● Example: If there are 25 small squares between 2 consecutive QS complexes, the heart rate is 60/min (1,500 ÷ 25 = 60).

Question 68

A variation of the 1500 method and requires minimal calculation. To be accurate the heart rate must be regular.

Answer 68

R-R method

● Find the QRS where the peak of the R wave falls on a heavy line. Use this QRS as a reference. If the next QRS falls on the very next dark line, the rate is 300 beats/min.
● The distance between 2 QRS complexes is five small boxes. The heart rate is 1500 divided by 5 small boxes equals 30 beats/min.
● The heart rate can be calculated rapidly by remembering the heart rate of each heavy line. Those important numbers are: 300, 150, 100, 75, 60, and 50.

Question 69

The easiest but least accurate approach for calculating the heart rate. It provides an estimate and is useful when the rhythm is irregular.

Answer 69

6-second mtd

● Note the short vertical lines or dots at the top of the ECG graph paper. This usually represents 1, 2, 3 second intervals.
● Simply count the number of QRS complexes occurring in seconds and multiply the result by 10. The product equals the heart rate/min.

Question 70

Amplitude and duration of ECG deflection:

Answer 70

● The sequence in which the parts of the heart are depolarized and the position of the heart relative to the electrodes are the important considerations in interpreting the configuration of the waves in each lead.

● The atria are located posteriorly in the chest. The
ventricles form the base and anterior surface of the heart, and the right ventricles are antero-lateral to the left.

● Thus, aVR “looks at” the cavities of the ventricles, atrial depolarization, ventricular in depolarization, and ventricular repolarization move away from the exploring electrode, and the P wave, QRS Complex, and T wave are therefore all negative (downward) deflections; aVL and aVF look at the ventricles, and the deflections are therefore predominantly positive and biphasic.

● There is no Q wave in V, and v2, and the initial portion of the QRS complex is a small upward deflection because ventricular depolarization first moves across the midportion of the septum from the left to right toward the exploring electrode.

● The wave of excitation then moves down the septum and into the left ventricle away from the electrode producing a large S wave.

● Finally, it moves back along the ventricular wall toward the electrode, producing the return to the isoelectric line.

● Conversely, there is an initial small Q wave (left to right septal depolarization), and there is a large R wave (septal and left ventricular depolarization) followed in V4 and Vs by a moderate S wave (late depolarization of the ventricular walls moving back toward the AV junction)

Question 71

Determine the AV conduction time in ECG:

Answer 71

● His bundle electrogram (HBE) records the electrical activity in the AV node, bundle of His, and Purkinje system by inserting a catheter containing an electrode at its top through a vein to the right side of the heart and manipulated into a position close to the tricuspid valve.

● It normally shows an A deflection when the AV node is activated, and H spike during transmission through the His bundle and a V deflection during ventricular depolarization.

● With the HBE and the standard electrocardiographic leads, it is possible to accurately time 3 intervals:
○ PA interval
■ the time from the first appearance of atrial depolarization to the A wave in the HBE, which represents conduction time from the SA node to the AV node. Normal value: 27ms

○ AH interval
■ from the A wave to the start of the H spike, which represents the AV nodal conduction time. Normal value: 92 ms

○ HV interval
■ the time from the start of the H spike to the start of the QRS deflection in the ECG, which represents conduction in the bundle of His and the bundle branches. Normal Value: 43 ms.

Question 72

Determine the electrical axis in ECG:

Answer 72

● The standard limb leads are records of the potential differences between 2 points, the deflection in each lead at any instant indicates the magnitude and direction in the axis of the lead of the electromotive force generated in the heart (cardiac vector or axis).

● The vector at any given moment in two dimensions of the frontal plane can be calculated from any two standard limb leads if it is assumed that the three electrode locations are from the points of an equilateral triangle (Eithoven’s triangle) and that the heart lies in the center of the
triangle.

● An approximate mean QRS vector (“electrical axis of the heart”) is often plotted using the average QRS deflection in each lead.

● This is a mean vector as opposed to an instantaneous vector, and the average QRS deflection should be measured by integrating the QRS complexes.

● However, they can be approximated by measuring the net differences between the positive and negative peaks of the QRS.

● The normal direction of the mean QRS vector is generally said to be (-) 30 to (+) 110 degrees on the coordinate system. Left or right axis deviation is said to be present if the calculated axis falls to the left of (-) 30 degrees or to the right of (+) 110 degrees, respectively.

● Right axis deviation suggests right ventricular
hypertrophy, and left axis deviation may be due to left ventricular hypertrophy.

Question 73

Figure 28-8. Cardiac vector: Left: Einthovens triangle.

Perpendiculars dropped from the midpoints of the sides of the equilateral triangle intersect at the center of electrical activity.

RA, right arm: LA, left arm: LL. left leg. Center: Calculation of mean QRS vector. In each lead, distances equal to the height of the h wave minus
the height of the largest negative deflection in the QRS complex are measured off from the midpoint of the side of the triangle representing that lead. An arrow drawn from the center of electrical activity to the point of intersection of perpendiculars extended from the distances measured on the sides represents the magnitude and direction of the mean QRS vector. Right:

Reference axes for determining the direction of
the vector.

Question 74

What refers to the lack of oxygen due to inadequate perfusion, which results from an imbalance between myocardial oxygen supply and demand?

Answer 74

Myocardial Ischemia

Question 75

This episodic clinical syndrome is due to transient
myocardial ischemia.

Answer 75

Angina Pectoris

Question 76

● Episodes of chest discomfort, usually described as heaviness, pressure, squeezing, smothering or choking and only rarely as frank pain.

● The typical patient is a man >50 years or a woman >60 years of age and when asked to localize the sensation, typically places a hand over the sternum, sometimes with a clenched fist, to indicate a squeezing, central, substernal discomfort (LEVINE’S SIGN).

● Usually crescendo - decrescendo in nature, typically lasts 2 - 5 minutes, and can radiate to either shoulder and to both arms (especially the ulnar surface of the forearm and hand). Also can arise in or radiate to the back, interscapular region, root of the neck, jaw, teeth and epigastrium.

● Rarely localized below the umbilicus or above the mandible.

● A useful finding in assessing a patient with chest discomfort is the fact that myocardial ischemic discomfort does not radiate to the trapezius muscles; that radiation pattern is more typical of pericarditis.

● Episodes of angina typically are caused by exertion (e.g. exercise, hurrying, or sexual activity) or emotions (e.g. anger, fright, or frustration) and are relieved by rest, they also may occur at rest.

Answer 76

Angina Pectoris

Question 77

What is an angina that occurs at night while the patient is recumbent?

Answer 77

Angina Decubitus

Question 78

● The patient may be awakened at night distressed by typical chest discomfort and dyspnea.

● Nocturnal angina may be due to episodic tachycardia, diminished oxygenation as the respiratory pattern changes during sleep, or expansion of the intrathoracic blood volume that occurs with recumbency; the latter causes an increase in cardiac size (end - diastolic volume), wall tension, and myocardial oxygen demand that can lead to ischemia and transient left ventricular failure.

Answer 78

Angina Decubitus

Question 79

What is a syndrome of severe ischemic pain that occurs at rest but not usually with exertion and is also associated with transient ST - segment elevation?

Answer 79

Prinzmetal’s Variant Angina

Question 80

This syndrome is due to focal spasm of an epicardial coronary artery, leading to severe myocardial ischemia.

Answer 80

Prinzmetal’s Variant Angina

● The cause of the spasm is not well defined, but it may be related to hypercontractility of vascular smooth muscle due to vasoconstrictor mitogens, leukotrienes, or serotonin.

● Patients are generally younger and have fewer coronary risk factors (exception is cigarette smoking).

● Cardiac examination is usually unremarkable in the absence of ischemia.

● Clinical diagnosis is made with the detection of transient ST = segment elevation with rest pain

● Nitrates and calcium channel blockers are the main agents used to treat acute episodes and to abolish recurrent episodes.

Question 81

Characterized by having either of the following clinical features:

predictable pattern of chest discomfort, begins gradually lasting over a period of 10 to 15 minutes, precipitated by effort and relieved by rest or nitrates.

Answer 81

Chronic Stable Angina

Question 82

Physical findings to look for in patients suspected of having angina pectoris:

Answer 82

● The physical examination is often normal in the patient with stable angina.
○ Examination during an anginal attack is useful, since ischemia can cause transient left ventricular failure with the appearance of a third and/or fourth heart sound, a dyskinetic cardiac apex, mitral regurgitation and even pulmonary edema.

● General examination: signs of risk factors for atherosclerosis, xanthelasma, xanthomas, diabetic skin lesions, signs of anemia, thyroid disease and nicotine stains on the fingertips.

● Palpation: thickened or absent peripheral arteries, signs of cardiac enlargement and abnormal contraction of the cardiac impulse (left ventricular akinesia or dyskinesia).

● Fundic examination: increased light reflexes and arteriovenous nicking.

● Auscultation: arterial bruits, a third and/or fourth heart sound and an apical systolic murmur due to mitral regurgitation (if acute ischemia or a previous infarction has impaired papillary muscle function).
○ The auscultatory signs are best appreciated with the patient in the left lateral decubitus position.

Question 83

What is the most common cause of myocardial ischemia?

Answer 83

Atherosclerotic disease epicardial coronary arteries

Specific causes include:
○ Conditions which reduce the lumen of the coronary artery resulting in (1) reduced myocardial perfusion in the basal state or appropriate increase in perfusion when the demand for f augmented (e.g., exertion, excitement), and (2) limited co blood flow:
■ Atherosclerosis
■ Spasm
■ Arterial thrombi
■ Coronary emboli
■ Ostial narrowing due to luetic aortitis

Question 84

What are common causes in infancy but rare causes in adults?

Answer 84

Congenital Abnormalities

e.g., anomalous origin of the left descending coronary artery from the pulmonary artery.

Question 85

Markedly increased myocardial oxygen demand seen in

Answer 85

Severe ventricular hypertrophy due to aortic stenosis

Question 86

Conditions which reduce the O2-carrying capacity of the blood:

Answer 86

○ Extremely severe anemia
○ Carboxyhemoglobinemia

Question 87

What are the risk factors for atherosclerosis?

Answer 87

● High plasma low-density lipoprotein (LDL)
● Low plasma high-density lipoprotein (HDL)
● Cigarette smoking
● Hypertension
● Diabetes mellitus

Question 88

PATHOPHYSIOLOGY OF ISCHEMIC HEART DISEASE

Answer 88

● Segmental atherosclerotic narrowing of epicardial coronary artery most commonly by the formation of a plaque, which is subject to hemorrhage and thrombosis.
○ Any of these events can temporarily obstruct, reduce coronary blood flow, and cause clinical manifestations of myocardial ischemia.
● The location of the obstruction will influence the quantity of myocardium rendered ischemic and thus determine the severity of the clinical manifestations.

● Severe coronary narrowing and myocardial ischemia are frequently accompanied by the development of collateral vessels, especially when the narrowing develops gradually.

● When well developed, such vessels can, by themselves, provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased
demand.

● Once stenosis of a proximal epicardial artery has reduced the cross-sectional area by more than approximately 70%, the distal resistance vessels dilate to reduce vascular resistance and maintain coronary blood flow.
○ A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls.

● When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction.
○ In these circumstances, ischemia in the region perfused by the stenotic artery can be precipitated by increases in myocardial oxygen demands caused by physical activity, emotional stress and/or tachycardia.
○ Changes in the caliber of the stenosed coronary artery due to physiologic vasomotion, loss of endothelial control of dilation, pathologic spasm, or small platelet plugs can all upset the critical balance between oxygen supply and demand and thus precipitate myocardial ischemia.

Question 89

PATHOGENESIS OF ATHEROSCLEROSIS

Answer 89

The pathogenesis of atherosclerosis consists of several processes characterized by specific morphologic lesions.

Figure 241-1. A. The normal artery. The normal artery consists of three layers. The intima, lined by a monolayer of endothelial cells in contact with the blood, contains resident smooth-muscle cells embedded in extracellular matrix.

● The internal elastic lamina forms the border of the intima with the underlying tunica media. The media contains layers of smooth-muscle cells invested with a collagenand elastin-rich extracellular matrix.

● Elastic arteries such as the aorta contain concentric lamellae of smooth-muscle cells sandwiched between dense bands of elastin.
○ Muscular arteries have a looser organization of smooth-muscle cells dispersed within the matrix.
○ The external elastic lamina forms the border of the media with the adventitia containing nerves and some mast cells and is the origin of the vasa vasorum, which supplies blood to the outer two-thirds of the tunica media.

● Accumulation of lipoprotein particles. Lipoprotein particles can accumulate in the intima of arteries, particularly when the ambient concentration is increased by hypercholesterolemic states. The lipoprotein particles often associate with constituents of the extracellular matrix, notably proteoglycans. Sequestration within the
intima separates lipoproteins from some plasma antioxidants and can favor oxidative modification. Such modified lipoprotein particles may trigger a local inflammatory response responsible for signaling subsequent steps in lesion formation.

● Adhesion of leukocytes. In hypercholesterolemic, adhesion of mononuclear leukocytes to the luminal
endothelial occurs early. The augmented expression of various adhesion molecules of leukocytes probably triggers this first step in the recruitment of white blood cells to the site of a nascent arterial lesion.

● Penetration of leukocytes. Once adherent, some white blood cells will migrate into the intima. The directed migration of leukocytes probably depends on chemoattractant factors including modified lipoprotein particles themselves and chemoattractant cytokines such as the chemokine macrophage chemoattractant protein 1 produced by vascular wall cells in response to modified lipoproteins.

● Accumulation of leukocytes. Leukocytes resident in the evolving fatty streak can divide and exhibit augmented expression of receptors for modified lipoproteins (scavenger receptors). These mononuclear phagocytes imbibe lipids and transform into foam cells whose cytoplasm is filled with lipid droplets.

● Formation of the fibrous cap and lipid core. As the fatty streak evolves into a more complicated atherosclerotic lesion, smooth-muscle cells accumulate within the expanding intima and the amount of extracellular matrix increases. The fibrous cap, formed of extracellular matrix elaborated by the smooth-muscle cells in the intima, characteristically overlies a lipid core filled with macrophages. In addition to dividing, these cells in the lipid core can die, releasing their lipid contents into the extracellular space.

Question 90

What represents the initial lesion of
atherosclerosis?

Answer 90

Fatty streak

Its formation most often seems to arise
from focal increases in the content of lipoproteins within the region of the intima (Fig. 241-1B).

○ This accumulation of lipoprotein particles may not result simply from an increased permeability, or “leakiness” of the overlying endothelium.

○ Rather, these lipoproteins may collect in the intima of arteries because they bind to constituents of the extracellular matrix, increasing the residence time of the lipid-rich particles within the arterial wall.

Question 91

What often associate with proteoglycan molecules of the arterial extracellular matrix? At sites of lesion formation, the balance of different matrix constituents may vary in important ways.

Answer 91

Lipoproteins that accumulate in the extracellular space of the intima of the arteries

Question 92

Of the three major classes of proteoglycans, a relative excess of _____________ molecules in relation to keratin sulfate or chondroitin sulfate may promote the retention of lipoprotein particles by binding them and slowing their egress from nascent lesions.

Answer 92

heparan sulfate

Question 93

Lipoprotein particles in the extracellular space of the intima, particularly those bound to matrix macromolecules, may undergo

Answer 93

two types of chemical modifications

Question 94

Lipoprotein Oxidation

Answer 94

● Lipoproteins sequestered from plasma antioxidants in the extracellular space of the intima may be particularly susceptible to oxidative modification. Oxidatively modified LDL comprises a variable and incompletely defined mixture.

● Modifications of the lipids may include formation of hydro-peroxides, lysophospholipids, oxysterols and
aldehydic breakdown products of fatty acids.

● Modifications of the apo-protein moieties may include breaks in the peptide backbone as well as derivatization of certain amino acid residues.

● A more recently recognized modification may result from local hypochlorous acid production by inflammatory cells within the plaque, giving rise to chlorinated species such as chlorotyrosyl residues.

Question 95

Nonenzymatic Glycation

Answer 95

In diabetic patients with sustained hyperglycemia, nonenzymatic glycation of apolipoproteins and other arterial proteins likely occurs that may alter their function and propensity to accelerate atherogenesis.

Question 96

What is the second step in the formation of the fatty streak?

Answer 96

Leukocyte Recruitment

Question 97

The white blood cell types typically found in the evolving atheroma include primarily cells of the mononuclear lineage:

Answer 97

monocytes and lymphocytes

○ A number of adhesion molecules or receptors for leukocytes expressed on the surface of the arterial endothelial cell likely participate in the recruitment of leukocytes to the nascent fatty streaks.

Question 98

What can also suppress the expression of leukocyte adhesion molecules?

Answer 98

Laminar shear forces, such as those encountered in most regions of normal arteries

○ Sites of predilection for forming atherosclerotic lesions (e.g., branch points) often have disturbed laminar flow.

Question 99

Ordered laminar shear of normal blood flow augments the production of:

Answer 99

Nitric oxide by endothelial cells

Question 100

This molecule, in addition to its vasodilator properties, can act at the low levels constitutively produced by arterial endothelium as a local anti-inflammatory autocoid.

Answer 100

NO

Question 101

True or False.

Not all fatty streaks progress to yield atheroma.

Answer 101

True. While accumulation of lipid-laden macrophages is the hallmark of the fatty streaks, accumulation of fibrous tissue typifies the more advanced atherosclerotic lesion.

Question 102

● Arterial remodeling during atherogenesis. During the initial part of the life history of an atheroma, growth is often outward, preserving the caliber of lumen. This phenomenon of “compensatory enlargement” accounts in part for the tendency of coronary arteriography to underestimate the degree of atherosclerosis.

● Focal inflammation characterizes unstable atherosclerotic plaques. Foci of inflammation often occur in atheroma. Analysis of lesions that have ruptured and caused fatal myocardial infarction characteristically show a prominent infiltration of macrophages and T lymphocytes. Both the leukocytes and the intrinsic vascular cells around points of plaque rupture show markers of inflammatory activation.

● Rupture of the plaque’s fibrous cap causes thrombosis. Physical disruption of the atherosclerotic plaque commonly causes arterial thrombosis by allowing blood coagulant factors to contact thrombogenic collagen found in the arterial extracellular matrix and tissue factor produced by macrophage-derived arterial foam cells in the lipid core of lesions.
○ In this manner, sites of plaque rupture form the nidus for thrombi. The normal, artery wall possesses several fibrinolytic or antithrombotic mechanisms that tend to resist thrombosis and lyse clots that begin to form in situ.
○ Such antithrombotic or thrombolytic molecules include thrombomodulin, tissue and urokinase-type plasminogen activators, heparin sulfate proteoglycans, prostacyclin, and nitric oxide.

● When the clot overwhelms the endogenous fibrinolytic mechanism, it may propagate and lead to arterial occlusion (E). In some cases, the thrombus may lyse or organize into a mural thrombus without occluding the vessel.
○ Such instances may be clinically silent. The subsequent thrombin-induced fibrosis and healing causes a fibroproliferative response that can lead to a more fibrous lesion, one that can produce an eccentric plaque that causes a hemodynamically significant stenosis (D).

● Healing of a mural thrombus leads to lesions fibrosis and progression and luminal narrowing. Local thrombin activation can stimulate smooth-muscle proliferation. Proteins released from platelets including platelet-derived growth factors and transforming growth factor B also augment collagen production by smooth-muscle cells and modulate their growth.
○ In this way, a nonocclusive mural thrombus, even if clinically silent or causing unstable angina, rather than infarction, can provoke a healing response that can promote lesion fibrosis and luminal encroachment.
○ Such a sequence of events may convert a “vulnerable” atheroma with a thin fibrous cap prone to rupture into a more “stable” fibrous plaque with a reinforced cap.
○ Angioplasty of unstable coronary lesions may “stabilize” the lesions by a similar mechanism, producing a wound followed by healing.

● Plaque rupture with a propagated, occlusive thrombus can cause acute myocardial infarction.
○ When a stable, occlusive thrombus forms in a coronary artery, the consequences depend on the degree of existing collateral vessels.
○ In a patient with chronic multivessel, occlusive coronary artery disease, collateral channels have usually formed.
○ In such circumstances, even a total arterial occlusion may not lead to myocardial infarction, or may produce an unexpectedly modest or a non-Q-wave infarct because of collateral flow.
○ In the patient with less advanced disease and without substantial stenotic lesions to provide a stimulus to collateral vessel formation, sudden plaque rupture and arterial occlusion commonly with myocardial infarction or sudden death as a first manifestation of coronary atherosclerosis.

● Atherosclerosis literally means hardening of the arteries; more accurately, however, it is a generic term for three patterns of vascular disease that have in common, thickening and loss of elasticity of arterial walls:
○ The dominant pattern is atherosclerosis, characterized by the formation of intimal fibrous plaques that often have a central grumous core rich in lipid.
○ Of much less clinical importance is the second morphologic form, the Mönckeberg medial calcific sclerosis, characterized by calcific deposits in medium-sized muscular arteries in persons older than 50 years.
■ The calcifications, which occasionally undergo ossification, take the form of irregular medial plates or discrete transverse rings; they create a nodularity on palpation and are readily visualized radiographically.
■ Although these medial lesions do not encroach on the vessel lumen, arteries so affected may also develop atherosclerosis.
○ Disease of small arteries and arterioles (arteriosclerosis) is the third pattern.
■ The two anatomic variants, hyaline and hyperplastic, cause thickening of vessel walls
with luminal narrowing that may induce downstream ischemic injury. Arteriosclerosis is most often associated with hypertension and diabetes mellitus.

Question 103

What are the key processes in atherosclerosis?

Answer 103

intimal thickening and lipid accumulation, producing the characteristic atheromatous plaques.

Question 104

● The basic lesion consists of a raised focal plaque within the intima, having a core of lipid (mainly cholesterol and cholesterol esters) and a covering fibrous cap.

● Also called fibrous, fibrofatty, lipid or fibrolipid plaques, atheromatous plaques appear white to whitish yellow and impinge on the lumen of the artery.

● They vary in size from approximately 0.3 to 1.5 cm in diameter but sometimes coalesce to form larger masses.

● On section, the superficial portion at the luminal surface tends to be firm and white (the fibrous cap) and the deep portions yellow or whitish yellow and soft. The centers of larger plaques may contain a yellow, grumous debris, hence the term, atheroma.

● Atherosclerotic plaques have three principal components:
○ Cells, including smooth muscle cells, macrophages and other leukocytes;
○ Connective tissue extracellular matrix, including collagen, elastic fibers and proteoglycans;
○ Intracellular and extracellular lipid deposits.
○ These three components occur in varying proportions in different plaques, giving rise to a spectrum of lesions.

● Typically, the superficial fibrous cap is composed of smooth muscle cells with a few leukocytes and relatively dense connective tissue; a cellular area beneath and to the side of the cap (the shoulder), consisting of a mixture of macrophages, smooth muscle cells and T lymphocytes; and a deeper necrotic core, in which there is a disorganized mass of lipid material, cholesterol clefts, cellular debris, lipid-laden foam cells, fibrin, thrombus in various stages of organization and other plasma proteins.

Answer 104

Atheromatous Plaque

Question 105

● Fatty streaks are not significantly raised and thus do not cause any disturbance in blood flow. They may be precursors, however, of the more ominous atheromatous plaques.

● The streaks begin as multiple yellow, flat spots (fatty dots) less than 1 mm in diameter that coalesce into elongated streaks, 1 cm long or longer.

● They are composed of lipid-filled tam cells with T lymphocytes and extracellular lipid present in smaller amounts than in plaques.

Answer 105

Fatty streak

Question 106

What are the causes transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium?

Answer 106

Myocardial Ischemia

Question 107

Myocardial Ischemia, Mechanical effects:

Answer 107

● The abrupt development of severe ischemia is associated with almost instantaneous failure of the normal muscle contraction and relaxation.

● Ischemia of large portions of the ventricle will cause transient left ventricular failure and if the papillary muscles are involved, mitral regurgitation can complicate this
event.

● Prolonged transient ischemia associated with angina pectoris can lead to myocardial necrosis and scarring with or without the clinical picture of acute myocardial infarction.

● Coronary atherosclerosis is a focal process that causes nonuniform ischemia which may lead to regional disturbances of ventricular contractility resulting in bulging (dyskinesia) that can greatly reduce myocardial pump
function.

Question 108

Myocardial Ischemia, Biochemical effects:

Answer 108

● When oxygenated, the normal myocardium metabolizes fatty acids and glucose to carbon dioxide and water.
○ With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is broken down to lactate; intracellular pH is reduced, as are the myocardial stores of high-energy phosphates, ATP, and creatine phosphate.
○ Impaired cell membrane function leads to potassium leakage and the uptake of sodium by myocytes.

● The severity and duration of the imbalance between myocardial oxygen supply and demand will determine whether the damage is reversible (0 to 20 minutes for total occlusion) or whether it is permanent, with
subsequent myocardial necrosis (>20 minutes)

Question 109

Myocardial Ischemia, Electrical effects:

Answer 109

● Ischemia causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion of the T wave and, when more severe, by displacement of the
ST segment.

● Transient ST-segment depression often reflects subendocardial ischemia.

● Transient ST-segment elevation is thought to be caused by more severe transmural ischemia.

● Ischemia can also cause electrical instability which may lead to ventricular tachycardia or ventricular fibrillation.

● Most patients who die suddenly from IHD do so as a result of ischemia-induced malignant ventricular tachyarrhythmias

Question 110

DIFFERENTIAL DIAGNOSIS FOR ANGINA PECTORIS

Answer 110

• aortic stenosis
• aortic regurgitation
• pulmonary hypertension
• hypertrophic cardiomyopathy

● These disorders may cause angina in the absence of coronary atherosclerosis.

Question 111

Differential Diagnosis of Chest Pain Syndromes

Answer 111

1. Cardiovascular
   - Aortic dissection
2. Gastrointestional
   - Esophageal disorders (esophageal spasm, hiatal hernia)
   - Peptic ulcer dse
   - Gastritis
   - Cholecystitis
3. Neuromusculoskeletal
   - Costochondritis (Tietze’s syndrome)
   - Chest wall pain
   - Cervical or thoracic radiculopathy
   - Shoulder arthropathies
4. Pulmonary
   - Pneumothorax
   - Mediastinitis
   - Pleuritis
   - Intrathoracic malignancy
5. Psycologic

Question 112

What are the Ancillary Procedures important to confirm the diagnosis of Angina Pectoris?

Answer 112

● Although the diagnosis of ID can be made with confidence from the clinical examination, a number of simple laboratory tests can be helpful.

● Urinalysis - examine for evidence of diabetes mellitus and renal disease

● Examination of the blood - lipids (cholesterol - total, LDL, HDL, and triglyceride), glucose (hemoglobin Ac), creatinine, hematocrit, thyroid function (if indicated based on the physical examination), and C - reactive protein (CRP).
○ Elevated level of high - sensitivity C-reactive protein (specifically between 0 - 3 mg/dL) may be useful in therapeutic decision making about the initiation of hypolipidemic treatment.

● Chest x-ray - check for the consequences of IHD: cardiac
enlargement, ventricular aneurysm or signs of heart failure

● 12-lead ECG
○ May be normal in about half of patients with typical anginal pain when taken at rest or may show signs of an old myocardial infarction
○ Nonspecific findings that may suggest IHD include T-wave and ST-segment changes, left ventricular hypertrophy and disturbance of cardiac rhythm or interventricular conduction.
○ Typical ST-segment and T-wave changes that accompany episodes of angina pectoris and disappear
thereafter are more specific. The displacement of the ST-segment that is similar in every way to that induced during a stress test is the most characteristic.

● Stress Testing
○ Most widely used test both for the diagnosis of IHD and establishing the prognosis.
○ Involves recording the 12-lead ECG before, during and after exercise on a treadmill or using a bicycle ergometer.
○ Seeks to discover any limitation in exercise
performance and establish the relationship between chest discomfort and the typical EGG signs of myocardial ischemia.
○ Performance is usually symptom-limited and the test is discontinued upon evidence of chest discomfort, severe shortness of breath, dizziness, fatigue, ST-segment depression of >0.2 mV (2 mm), a fall in systolic BP exceeding 10 mm Hg, or the development of a ventricular tachyarrhythmia
○ A positive result on exercise indicates that the likelihood of CAD is 98% in males over 50 years of age with a history of typical angina pectoris who develop chest discomfort during the test.
○ The overall sensitivity of exercise stress ECG is only about 75% so that a negative result does not exclude CAD, although it makes the likelihood of three-vessel
or left main CAD extremely unlikely.

● Coronary arteriography
○ Outlines the coronary anatomy and can be used to detect important evidence of coronary atherosclerosis or to exclude this condition.
○ Assessment of the severity of obstructive lesions. In combination with left ventricular angiocardiography, it can evaluate both global and regional function of the
left ventricle.
○ Indications:
■ Patients with chronic stable angina pectoris who are severely symptomatic despite medical therapy and who are being considered for revascularization procedures.
■ Patients with troublesome symptoms that present diagnostic difficulties in whom there is a need to confirm or rule out the diagnosis of IHD.
■ Parents with known or possible angina pectoris who have survived sudden cardiac death.
■ Patients judged to be at high risk of sustaining coronary events based on signs of severe ischemia on noninvasive testing, regardless of the presence or severity of symptoms.
■ Patients with angina or evidence of ischemia on noninvasive testing with clinical or laboratory evidence of ventricular dysfunction.

Question 113

What are the prognostic indicators in patients with ischemic heart disease?

Answer 113

● The principal prognostic indicators in patients with ID are age, the functional state of the left ventricle, the location and severity of coronary artery narrowing and the severity or activity of myocardial ischemia.

The following signs during noninvasive testing indicate a high risk for coronary events:
○ A strongly positive exercise test showing onset of myocardial ischemia at low workloads [≥0.1 mV ST-segment depression before completion of stage II (Bruce protocol) of the exercise test.
○ A ≥0.2 mV ST depression in any stage.
○ ST depression for >5 minutes following the cessation of exercise.
○ A decline in systolic BP >10 mmHg during the exercise.
○ The development of ventricular tachyarrhythmias during exercise.
○ The development of large or multiple perfusion defects or increased lung uptake during stress radioisotope perfusion imaging.
○ A decrease in left ventricular ejection fraction during exercise on radionuclide ventriculography or during
stress echocardiography.
○ Inability to exercise for 6 minutes, i.e., stage lI (Bruce protocol) of the exercise test.

● The following are the most important signs of left ventricular dysfunction during cardiac catheterization and are associated with a poor prognosis:
○ Elevations in left ventricular end-diastolic pressure and volume
○ Reduced ejection fraction

Question 114

ANGINA PECTORIS MANAGEMENT
● The degree of disability as well as the physical and emotional stress that precipitate angina must be carefully recorded in order to set treatment goals. The management plan should consist of the following:

Answer 114

Explanation and reassurance
● Patients need to understand their condition and realize that a long and useful life is possible.
● A planned program of rehabilitation can encourage patients to lose weight, improve exercise tolerance and control risk factors with more confidence.

Identification and treatment aggravating conditions
● Aortic valve disease and hypertrophic cardiomyopathy may cause angina and should be excluded or treated.
● Obesity, hypertension and hyperthyroidism must be managed successfully in order to reduce the frequency of anginal attacks.
● Decreased myocardial oxygen supply may be due to reduced oxygenation of the blood (e.g., pulmonary disease or, when carboxyhemoglobin is present due to
cigarette or cigar smoking) or decreased oxygen-carrying capacity (e.g., in anemia). Correction of these abnormalities may reduce or even eliminate angina
pectoris.

Adaptation of activity
● Patients must understand the fundamental concept of eliminating the discrepancy between the demand of the heart muscle for oxygen and the ability of the coronary
circulation to meet this demand.
● Patients must appreciate the diurnal variation in their tolerance for certain activities and should reduce their energy requirements in the morning and immediately after meals.
● It may be necessary to recommend a change in employment residence to avoid physical stress; however, with the exception of manual laborers, most patients with IHD can continue to function merely by allowing more time to complete a task.
● Training in stress management may be useful to avoid anger frustration which may precipitate myocardial ischemia.
● Physical conditioning usually improves the exercise tolerance of patients and exerts substantial psychological benefits.
● An exercise program within the limits of each patient’s threshold the development of angina pectoris should beencouraged.

Treatment of risk factors
● Treatment of dyslipidemia is central when aiming for long-term relief from angina, reduced need for revascularization reduction in myocardial infarction and death.

Question 115

Treatment Goals of Dyslipidemia

Answer 115

Patient: Men, age >45 years; Women, age >55 years; Diabetic patient, any age

Clinical/Risk factors:
Evidence of atherosclerotic disease or any 2 of the ff:
- Family history of premature IHD
- Cigarette smoking
- Hypertension
- Diabetes mellitus

Goals of Treatment:
Total cholesterol = ≤ 200 mg/dL
LDL = ≤ 100 mg/dL
HDL = ≥ 40 mg/dL

Question 116

The control of lipids can be achieved by the combination of:

Answer 116

• a diet low in saturated fatty acids
• exercise
• weight loss

Question 117

What are required and can lower LDL cholesterol by 25%-50%, raise HDL cholesterol by 5%-9% and lower triglycerides by 5%-30%?

Answer 117

HMG CoA reductase inhibitors (statins)

Question 118

What can be used to raise HDL cholesterol
and lower triglycerides?

Answer 118

Niacin and Fibrates

Question 119

Risk reduction on women with IHD

Answer 119

○ The incidence of clinical IHD in premenopausal women is very low. Following menopause, the atherogenic risk factors increase (e.g., increased LDL, reduced HDL) and the rate of coronary events accelerates to the levels observed in men.

○ Women have not given up cigarette smoking as effectively as have men.

○ Diabetes mellitus, which is more common in women, greatly increases the occurrence of clinical IHD and amplifies the deleterious effects of hypertension, hyperlipidemia and smoking.

Question 120

GUIDELINES IN CHOOSING MEDICAL THERAPY, PTCA, or CABG:
Parameters

Answer 120

• History
• Exercise ECG Test or Stress Thallium 2-D Echocardiography
• Cardiac catheterization
• Cardiac catheterization treatment
• Treatment
• Cost

Question 121

Better with Medical Treatment

Answer 121

History: No angina or angina class I

Exercise ECG Test or Stress Thallium 2-D Echocardiography: No or mild ischemia by non-invasive testing Good LV function or very poor LV function (EF <20%)

Cardiac catheterization: Only 1-vessel
disease; mild stenosis (50%-70%)

Cardiac catheterization treatment: Any lesion

Treatment: Good medical response

Cost: Cheap

Question 122

Better with PTCA

Answer 122

History: Angina class III IV

Exercise ECG Test or Stress Thallium 2-D Echocardiography: Severe ischemia by non-invasive testing Good LV function

Cardiac catheterization: Only 1-vessel
disease

Cardiac catheterization treatment: Type A lesion (easy to balloon)

Treatment: Medical treatment failure

Cost: Expensive

Question 123

Better with CABG

Answer 123

History: Angina class III-IV

Exercise ECG Test or Stress Thallium 2-D Echocardiography: Severe ischemia by non-invasive testing Poor LV function (EF 20%-40%)

Cardiac catheterization: Left main or proximal LAD lesions; 3-vessel disease

Cardiac catheterization treatment: Type C lesion (difficult to balloon)

Treatment: Medical treatment failure or PTCA failure

Cost: Expensive

Question 124

Medical treatment
● Drug therapy for CAD or chronic stable angina aims to increase blood supply or decrease the demand:

Answer 124

○ ↑ supply:
■ Vasodilation of coronary arteries: Nitrates
■ Bypass or relieve obstruction: PTCA, CABG
■ Correct anemia

○ ↓ demand:
■ ↓ Heart rate:
● Beta-blockers
● Calcium channel blockers (Diltiazem
Verapamil)
● Sedation for anxious individuals
■ ↓ Contractility: B-blockers
■ ↓After load: Vasodilators - calcium channel blockers
■ ↓ Preload: Nitrates

Question 125

Page 15 Tables (3)

• Nitroglycerin and Nitrates for Px with IHD
• Properties of BB in Clinical Use for IHD
• CCB in Clinical Use for IHD

Question 126

Pharmacological Properties of Selected Drugs

Answer 126

● Hypolipidemic Agents (Please refer to page 121)
● Nitrates
● Nitrites, organic nitrates, nitroso compounds and a variety of other nitrogen oxide-containing substances lead to the formation of the reactive free radical nitric oxide (NO) which can activate guanylyl cyclase and increase the synthesis of cyclic GMP in smooth muscle and other tissues.

● The pharmacological and biochemical effects of the nitrovasodilators appear to be identical to those of an endothelium-derived relaxing factor which has been shown to be NO.

● Biotransformation of organic nitrates is the result of reductive hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase.

● Cardiovascular Effects:
○ Hemodynamic effects:
■ Relaxation of smooth muscle, including that in arteries and veins
■ Venodilation results in decreased left and right ventricular chamber size and end-diastolic pressures but little change in systemic vascular resistance
■ Systemic arterial pressure may fall slightly and heart rate is unchanged or slightly increased reflexly
■ Pulmonary vascular resistance and cardiac output both are slightly reduced
■ Effects on myocardial oxygen requirements
■ Reduced myocardial oxygen demand
■ Do not directly alter the inotropic and chronotropic state of the heart
■ Reduced preload )and afterload as a result of respective dilation of venous capacitance and arteriolar resistance vessels

● B-blockers
○ Can be distinguished by the following properties: relative affinity of B1 and B2 receptors, intrinsic sympathomimetic activity, blockade of receptors, differences in lipid solubility, capacity to induce vasodilation, and pharmacokinetic parameters.
○ Are classified as:
■ Non subtype
- selective (FIRST GENERATION)
■ B1 - selective (SECOND GENERATION)
■ Non - subtype or subtype - selective with
additional cardiovascular actions (THIRD
GENERATION)

● The major therapeutic effects are on the cardiovascular system:
○ Slow heart rate
○ Decrease myocardial contractility

● Effective in reducing the severity and frequency of attacks of exertional angina and improve survival in patients who have had a myocardial infarction.

● Not useful for spastic angina and, if used in isolation, may worsen the condition.

● Most agents appear to be equally effective in the treatment of exertional angina. The effectiveness is attributable primarily to a fall in myocardial oxygen consumption at rest and during exertion, although there is also some tendency for increased flow toward ischemic regions.

● The decrease in myocardial oxygen consumption is due to a negative chronotropic effect (particularly during exercise), a negative inotropic effect and a reduction in arterial blood pressure (particularly systolic pressure)
during exercise.

Table page 16

Question 127

MOA of CCB:

Answer 127

○ Increased concentration of cytosolic Ca2+ causes increased contraction in both cardiac and vascular smooth muscle cells.

○ The entry of extracellular Ca2+ is more important in initiating the contraction of cardiac myocytes (Ca2+-induced Ca2+ release).

○ The release of Ca2 + from intracellular storage sites also contributes to contraction of vascular smooth muscle, particularly in some vascular beds, Cytosolic Ca2+ concentrations can be increased by diverse
contractile stimuli on vascular smooth muscle cells.

○ Many hormones and autocoids increase Ca2+ influx through so-called receptor-operated channels, whereas increases in external concentrations of K+
and depolarizing electrical stimuli increase Ca2+ influx through voltage-sensitive or “potential operated” channels,

○ The calcium channel antagonists produce their effects by binding to the alpha 1 subunit of the L - type Ca2+ channels and reducing Ca2+ influx through the
channel.

Question 128

Cardiovascular effects of CCB:

Answer 128

○ Relax arterial smooth muscle but have a less pronounced effect on most venous beds and hence do not affect cardiac preload significantly.

○ Negative inotropic effects

○ Hemodynamic effects
■ Decreased coronary vascular resistance and increased coronary blood flow.
■ Effects vary depending on the route of administration and then extent of left ventricular dysfunction

Table on page 16

Question 129

What are the different antiplatelet drugs?

Answer 129

• aspirin
• dipyridamole
• ticlopidine
• clopidogrel
• prasugrel
• glycoprotein IIb/IIIa inhibitors
• abciximab
• eptifibatide
• tirofiban
• cangelor
• ticagrelor

Question 130

Aspirin - Case # 3 Page 167

Question 131

What interferes with platelet function by increasing the cellular concentration of cyclic AMP?

This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and/or by blockade of uptake of adenosine, which acts at adenosine A2 receptors to stimulate platelet adenylyl cyclase and cellular cyclic AMP.

Answer 131

Dipyridamole

Question 132

What is a vasodilator that in combination with WARFARIN, inhibits embolization from prosthetic heart valves, and has little or no benefit as an antithrombotic agent?

Answer 132

Dipyridamole

Question 133

What is a thienopyridine prodrug that inhibits P2Y2 receptor?

Answer 133

Ticlopidine

Question 134

○ Platelets contain two purinergic receptors, P2Y1, and P2Y12. Both receptors must be stimulated to result in platelet activation.

○ Permanently inhibits P2Y12 receptor by forming a disulfide bridge between the thiol on the drug and a free cysteine residue in the extracellular region of the receptor

○ Like ASPIRIN, it has a short t ½ but a long duration of action

○ Maximal inhibition of platelet aggregation is not seen until 8 - 11 days after starting therapy

○ Usual dose is 250 mg twice daily

○ Loading of 500 mg sometimes are given to achieve a more rapid onset of action

○ Adverse effects:
■ Most common - nausea, vomiting, diarrhea
■ Most serious - severe neutropenia
■ Fat agranulocytosis with thrombopenia
■ Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)

○ Therapeutic use - to prevent cardiovascular events in secondary prevention of stroke

Answer 134

Ticlopidine

Question 135

What is an irreversible inhibitor of platelet P212 receptors but is more potent and has a more favorable toxicity profile than TICLOPIDINE, with thrombocytopenia and
leukopenia and occurring only rarely?

Answer 135

Clopidogrel

Question 136

○ A prodrug with a slow onset of action

○ Usual dose is 75 mg/day with or without an initial loading dose of 300 or 600 mg.

○ Combination of CLOPIDOGREL and ASPIRIN is superior to ASPIRIN alone for prevention of recurrent ischemia in patients with unstable angina. This combination is used after angioplasty and coronary stent implantation, and should be continued for at least 4 - 6 weeks in patients with a bare metal stent and for at least 1 year in those with a drug - eluting stent.

○ FDA - approved indications (U-S) - to reduce the rate of stroke, myocardial infarction, and death in patients with recent myocardial infarction or stroke, established peripheral arterial disease, or acute coronary syndrome.

Answer 136

Clopidogrel

Question 137

What is the newest member of the thienopyridine class?

Answer 137

Prasugrel

Question 138

○ Produces greater and more predictable inhibition of ADP - induced platelet inhibition

○ A prodrug that requires metabolic activation

○ Onset of action is more rapid than that of
TICLODIPINE or CLOPIDOGREL

○ Rapid and complete absorption from the gut

○ The active metabolites of this drug and the other thienopyridines bind irreversibly to the P2Y12 receptor; so these drugs have a prolonged effect after discontinuation. This can be problematic if patients require urgent surgery. There is increased risk for bleeding unless the administration of these drugs (#c,
d, e) is stopped at least 5 days prior to the procedure

○ Has higher rates of fatal and life - threatening bleeding

○ Contraindicated in patients with a history of cerebrovascular disease

○ Dosage - 10 mg once daily
■ Loading dose is 60 mg
■ For patients > 75 years of age or weighing < 60 ma - 5 mg daily

Answer 138

Prasugrel

Question 139

What is a platelet - surface integrin?

Answer 139

Glycoprotein lIb/IlIa

surface integrin, which is designated aIIbß1 by the integrin nomenclature. It is inactive on resting platelets but undergoes a conformational transformation when
platelets are activated by platelet agonists such as thrombin, collagen, or thromboxane A2. This transformation endows glycoprotein lib/lla with the capacity to serve as a receptor for fibrinogen and von Willebrand factor, which anchor platelets to foreign surfaces and to each other, thereby mediating aggregation. Inhibition of binding to this receptor blocks platelet aggregation induced by any agonist.

Glycoprotein lIb/IIla INHIBITORS

Question 140

○ A Fab fragment of a humanized monoclonal antibody directed against the alpha IIb ß1 receptor.

○ Also binds to vitronectin receptors on platelets, vascular endothelial cells, and smooth muscle cells.

○ Administered to patients undergoing percutaneous angioplasty for coronary thrombosis, and when used in conjunction with ASPIRIN and HEPARIN, has been shown to prevent restenosis, recurrent myocardial
infarction, and death.

○ Given as a 0.25 mg/kg bolus followed by
0.125 ug/kg/minute for 12 hours or longer

○ Major side - effect is bleeding

○ Contraindication- similar to those for the fibrinolytic agents

Answer 140

Abciximab

Question 141

Absolute Contraindications to Fibrinolytic Therapy

Answer 141

• prior intracranial hemorrhage
• known structural cerebral vascular lesion
• known malignant intracranial neoplasm
• ischemic stroke within 3 months
• suspected aortic dissection
• active bleeding or bleeding diathesis (excluding menses)
• significant closed-head trauma within 3 months

Question 142

Relative Contraindications to Fibrinolytic Therapy

Answer 142

• Uncontrolled hypertension (sys BP >180; dias BP >110)
• Traumatic or prolonged CPR or major surgery within 3 wks
• Recent (within 2-4 wks) internal bleeding
• Noncompressible vascular punctures
• For streptokinase: prior exposure (more than 5 days ago) or prior allergic reaction to SK
• Pregnancy
• Active peptic ulcer
• Current use of warfarin and INR >1.7

Question 143

What is a cyclic peptide inhibitor of the fibrinogen binding site on alpha IIb ß3?

Answer 143

Eptifibatide

Question 144

○ Administered intravenously and blocks platelet aggregation

○ Given as a bolus of 180 ug/kg followed by
2ug/kg/minute for up tp 96 hours

○ Used to treat acute coronary syndrome and for angioplastic coronary intervention

○ Duration of action is relatively short, and platelet aggregation is restored within 6 - 12 hours after cessation of infusion

○ Administered in conjunction with ASPIRIN and HEPARIN

○ Major side effect is bleeding

Answer 144

Eptibafide

Question 145

What is a nonpeptide, small - molecule inhibitor alpha IIb ß3 that appears to have a mechanism of action similar to EPTIFIBATIDE?

Answer 145

Tirofiban

Question 146

○ Has a short duration of action and has efficacy in non - Q- wave myocardial infarction and unstable angina

○ Specific to alpha IIb ß3 and does not react with the vitronectin receptor same as EPTIFIBATIDE

○ Side effects are similar to those of EPTIFIBATIDE

Answer 146

Tirofiban

Question 147

What is an adenosine analog that binds reversibly to P2Y12 and inhibits its activity?

Answer 147

Cangrelor

Question 148

What has a t½ of 3 - 6 minutes and is given intravenously as a bolus followed by an infusion?

Answer 148

Cangrelor

Question 149

○ Given twice daily

○ An orally active, reversible inhibitor of P2Y12.

○ Has a more rapid onset and offset of action than CLOPIDOGREL and produces greater and more predictable inhibition of ADP - induced platelet aggregation.

Answer 149

Ticagrelor

Question 150

While the basic management of patients with CAD is medical, many patients are improved by coronary revascularization procedures. These interventions are employed in conjunction with but do not replace the continuing need to modify risk factors.

Answer 150

Surgical tx

Question 151

What is a widely used method to achieve revascularization of the myocardium in patients with symptomatic IHD and suitable stenoses of the epicardial coronary arteries?

● Widely employed in patients with symptoms and evidence of ischemia due to stenoses of one or two vessels

Answer 151

PTCA (Percutaneous Transluminal Coronary Angioplasty)

● Most commonly used percutaneous coronary intervention (PCI)
● Also known as stenting

Question 152

Indications and Patient Selection: (PTCA)

Answer 152

○ The most common clinical indication is angina pectoris, stable or unstable, accompanied by evidence of ischemia in an exercise test.

○ Not generally indicated in asymptomatic or mildly symptomatic patients.

○ Treatment of stenoses in native coronary arteries as well as in bypass grafts in patients who have recurrent angina following coronary artery surgery.

Question 153

What are the risks of PTCA?

Answer 153

○ Absolute contraindication: left main coronary artery stenosis

○ The following conditions increase the likelihood of complications but are not absolute contraindications:
■ Advanced age
■ Stenosis with thrombus
■ Left ventricular dysfunction
■ Stenosis of an artery perfusing a large segment of myocardium without collaterals
■ Long eccentric or irregular stenosis
■ Calcified plaques

○ Major complications
■ Dissection or thrombus with vessel occlusion
■ Uncontrolled ischemia
■ Ventricular failure

Question 154

What is the efficacy of PTCA?

Answer 154

○ Primary success, which is adequate dilation (an increase in luminal diameter to a residual diameter obstruction <50%) with relief of angina, is achieved in approximately 95% of cases.

○ Recurrent stenosis of the dilated vessels occurs in 20% of cases within 6 months of
the procedure.

○ Angina will recur in 10% of patients within 6 to 12 months of the procedure.

○ Recurrence of symptoms is more common in patients with diabetes mellitus, unstable angina, incomplete dilation of the stenosis, dilation of the left anterior descending coronary artery and stenoses containing thrombi.

○ Successful deployment of a metal stent lowers the restenosis rate to 10% to 30% at 6 months but initially requires vigorous antiplatelet surgery.

○ Successful PCI produces effective relief of angina in over 95% of cases and is more effective than medical therapy for up to 2 years

○ Successful PCI requires only 1 to 2 days in the hospital and permits considerable savings in the initial cost of care. It allows earlier return to work and resumption of an active life. However, this economic benefit is reduced over time because of the greater need for follow-up and for repeat procedures.

Question 155

Prognosis of PTCA

Answer 155

○ If patients do not develop restenosis or angina within the first year of the procedure, the prognosis for maintaining improvement over the subsequent 4 years is excellent

○ If restenosis occurs, PTCA can be repeated with the same success and risk, but the likelihood of restenosis increases with the third or subsequent attempt.

Question 156

A section of a vein (usually the saphenous) is used to form a connection between the aorta and the coronary artery distal to the obstructive lesion.

Answer 156

CABG (Coronary Artery Bypass Grafting)

Question 157

● Alternatively, anastomosis of one or both of the internal mammary arteries or radial artery to the coronary artery distal to the obstructive lesion may be employed and is now preferable whenever possible.

● Mortality rate is less than 1% in patients without serious comorbid disease and normal left ventricular function, when the procedure is performed by an experienced surgical team.

● Indications are usually based on the severity of symptoms, coronary anatomy and ventricular function.

● Intraoperative and postoperative mortality increase with the degree of ventricular dysfunction, comorbidities, age above 80 years and surgical inexperience. The following conditions are associated with a higher perioperative morality:
○ Congestive heart failure and/or left ventricular dysfunction (ejection fraction <40%)
○ Advanced age (≥80 years)
○ Reoperation
○ Urgent need for surgery
○ Diabetes mellitus

● Occlusion of the vein grafts is observed in 10% to 20% during the first postoperative year and in approximately 2% per year during the 5 to 7 year follow-up and 4% per year thereafter.

● Long-term patency rates are considerably higher for internal mammary and radial artery implantations.

● Angina is abolished or greatly reduced in approximately 90% of patients following complete revascularization. Within 3 years, angina recurs in about one-fourth of patients but is rarely severe.

● The procedure does not appear to reduce the incidence of myocardial infarction in patients with chronic IHD.

● The procedure reduces mortality in patients with stenosis of the left main coronary artery as well as in patients with three-or two-vessel disease with significant obstruction of the proximal left anterior descending coronary artery. The survival benefit is greater in patients with abnormal left ventricular function (ejection fraction <50%).

Answer 157

CABG

Question 158

Comparison of Revascularization Procedures in Multivessel Disease:

Answer 158

Next

Question 159

Percutaneous coronary intervention (PCI)
Advantage

Answer 159

Less invasive

Shorter hospital stay

Lower initial cost

Easily repeated

Effective in relieving symptoms

Question 160

Coronary artery bypass grafting (CABG)
Advantage

Answer 160

Effective in relieving symptoms

Improved survival in certain subsets

Ability to achieve complete revascularization

Question 161

Percutaneous coronary intervention (PCI)
Disadvantage

Answer 161

Restenosis

Higher incidence of incomplete revascularization

Unknown effect on outcomes in patients with severe LV dysfunction

Limited to specific anatomic subsets

Poor outcome in diabetics with 2 or 3 vessel coronary disease

Question 162

Coronary artery bypass grafting (CABG)
Disadvantage

Answer 162

Cost

Increased risk of a repeat procedure due to late graft closure

Morbidity and mortality of major surgery

Question 163

DRUG THERAPY FOR HYPERCHOLESTEROLEMIA & DYSLIPIDEMIA

RATIONALE FOR TREATMENT OF HYPERCHOLESTEROLEMIA/DYSLIPIDEMIA

Answer 163

● Cardiovascular diseases are the principal causes of death in industrialized countries.

● Most deaths secondary to cardiovascular diseases are related to atherosclerosis.

● Atherosclerosis is a slow progressive generalized disease of the arterial tree involving deposition of plaques containing cholesterol & lipid material in the intima of arteries.

● The development of atherosclerosis is associated with high levels of plasma lipoproteins involved in cholesterol
transport.

Question 164

CHOLESTEROL-DIET-CHD HYPOTHESIS

Answer 164

● Elevated plasma cholesterol levels cause Coronary Heart Disease (CHD).

● Diets rich in saturated fat (animal fat) and cholesterol raise cholesterol levels.

● The lowering of cholesterol levels reduces CHD risk.

Question 165

NATIONAL CHOLESTEROL EDUCATION PROGRAM GUIDELINES FOR TREATMENT (NCEP GUIDELINES)

Answer 165

● Population-based approach
○ Intended to lower blood cholesterol by dietary recommendations
■ Reduce total calories from fat to <30% & from saturated fat to <10%
■ Consume <300 mg of cholesterol/day
■ Maintain desirable body weight

● Patient-based approach
○ 2001 Adult Treatment Panel III Guidelines

table on page 20

Question 166

DRUG THERAPY
● Targets specific steps, enzymes or substrates in:

Answer 166

○ Cholesterol biosynthesis
○ Lipoprotein metabolism

table onn page 20

Question 167

● Spherical particles made up of hundreds of lipid & protein molecules
● Smaller than RBCs; visible only by EM

Answer 167

Lipoproteins

● Major lipids:
○ Cholesterol - nonpolar lipids, insoluble in aqueous environments (hydrophobic)
○ Triglycerides - nonpolar lipids, insoluble in aqueous environments (hydrophobic)
○ Phospholipids - soluble in both lipid & aqueous environments (amphipathic); cover the surface of the particles & act as the interface between the plasma & the core components

Question 168

Classification oÿ Lipoproteins

Answer 168

● Chylomicrons
● Very low density lipoproteins (VLDL)
● Intermediate-density lipoproteins (IDL)
● Low-density lipoproteins (LDL)
● High-density lipoproteins (HDL)

table on page 21

Question 169

● Also referred to as apos
● A family of proteins that also occupies the surface of the lipoproteins
● Functions:
○ Regulation of lipid transport & lipoprotein metabolism
○ Provide structural stability to the lipoproteins & determine the metabolic fate of the particles upon which they reside

Answer 169

Apolipoproteins

Question 170

○ Major lipoprotein of VLDL, IDL & LDL
○ Synthesized in the liver

Answer 170

Apo B100

Question 171

○ Encoded by the same gene & mRNA as Apo B100

○ A cytidine deaminase in the intestine changes a cytidine to a uridine in base 6666 of the Apo B100 mRNA to produce a stop codon so that Apo B48 contains only the N-terminal 48% of the full-length of Apo B100

○ Role in the metabolism of chylomicrons in plasma is
unclear

Answer 171

Apo B48

Question 172

● Synthesized in the liver
● Present in all lipoproteins
● Individual Apo Cs have different metabolic roles but all inhibit the removal of plasma chylomicrons & VLDL remnants by the liver

Answer 172

Characteristics of the Apo C Series

Question 173

● Synthesized mainly by hepatocytes but also made in other cells (macrophages, neurons, glial cells)

● E2, E3 & E4

● Complete absence increases plasma levels of chylomicron & VLDL remnants & causes early atherosclerosis

Answer 173

Characteristics of the Apo E Series

Question 174

Synthesized in the SI & liver & found primarily on HDL

Answer 174

Characteristics of the Apo A Series

Question 175

○ Activates the enzyme lecithin: cholesterol
acyltransferase (LCAT) which esterifies free
cholesterol in plasma
○ Plasma levels of HDL cholesterol & Apo Al are inversely related to risk for CHD

Answer 175

Apo Al

Question 176

What is the 2nd most abundant apoprotein in HDL but the function has not been determined?

Answer 176

Apo All

Question 177

A minor component of HDL & chylomicrons; may play a role in the activation of LCAT

Answer 177

Apo AIV

Question 178

What mediates the hydrolysis of the TGs of chylomicrons & VLDL to gen rate FFA & glycerol?

Answer 178

Lipoprotein lipase (LPL)

Question 179

Removes TGs from VLDL remnants (IDL) thus promoting th onversio of VLDL to LDL

Answer 179

Hepatic triglyceride lipase (HTGL)

Question 180

What mediates the transfer of linoleate from lecithin to free cholesterol on the surface of HDL to form cholesteryl esters that are then transferred to VLDL & eventually to LDL?

Answer 180

Lecithin:cho esterol acyltransÿ ase (LCAT)

Question 181

What mediates the exchange of cholesteryl esters from HDL with TG from chylomicrons of VLDL?

Answer 181

Cholesteryl est transÿer protein (CETP)

Question 182

What provides PLs to the mature, enlarging HDL particles?

Answer 182

Phospholipid transÿer protein (PLTP)

table on page 21

Question 183

Factors Influencing Lipoprotein Metabolism

Answer 183

● Obesity - increased VLDL levels (some LDL), decreased HDL levels

● Diet
○ Diet high in saturated fat increased VLDL & LDL levels
○ Alcohol increased VLDL levels

● Exercise - increased HDL levels

● Hormone
○ Thyroxine increased LDL receptor level activity –> decreased LDL levels
○ Androgens decreased HDL levels –> puberty HDL levels in boys fall from prepubertal levels
○ Estrogens increased LDL receptor function –> decreased LDL levels

● Age - changes reflect the hormonal effects of puberty & menopause and the gains in body weight common in middle age

Question 184

What are the drugs used in the treatment of hypercholesterolemia/Dyslipidemia?

Answer 184

• Bile acid-binding resins
• Cholesterol synthesis inhibitors (e.g., HMG-CoA reductase inhibitors)
• VLDL secretion inhibitors (e.g., Niacin)
• Lipoprotein lipase stimulants (e.g., fibric acid derivatives)
• Lipophilic antioxidants (e.g., Probucol)

Question 185

What has the action to reduce fat absorption from intestines by sequestering bile acids?

Answer 185

Bile acid-binding resins

Question 186

What has the action to modify synthesis of cholesterol in the liver?

Answer 186

Cholesterol synthesis inhibitors (e.g., HMG-CoA reductase inhibitors)

Question 187

What has the action to modify release of lipoproteins?

Answer 187

VLDL secretion inhibitors (e.g., Niacin)

Question 188

What has the action to increase peripheral clearance of lioproteins?

Answer 188

Lipoprotein lipase stimulants (e.g., fibric acid derivatives)

Question 189

What has the action that has uncertain mechanism, possible inhibition of oxidation of LDL & decrease in LDL uptake by macrophages?

Answer 189

Lipophilic antioxidants (e.g., Probucol)

Question 190

What is most effective and best tolerated?

Answer 190

Statins

Question 191

Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate-limitng step cholesterol biosynthesis.

Answer 191

Statin

Question 192

Possess a side group that is structurally similar to HMG-CoA

Answer 192

Statin

Question 193

Statin agents:

Answer 193

Lovastatin, Pravastatin, Simvastatin
Atorvastatin, Fluvastatin, Cerivastatin (synthetic)

Question 194

Mechanism of Action of Statin

Answer 194

Mevalonic acid moiety competitively inhibits HMG-CoA reductase –> Reduction cholesterogenesis in the liver –> Increased expression of the LDL receptor gene –> Reduction in LDL-C levels

Question 195

Effects:

Triglyceride reduction

Answer 195

TG > 250 mg/dl are substantially reduced (% reduction similar to that of LDL)

Question 196

HDL-C levels

Answer 196

● In patients with elevated LDL-C levels & gender-appropriate HDL-C levels (40-50 mg/dl for men & 50-60 mg/dl for women), an increase in HDL-C of 5% to 1 % was observed

● In patients with reduced HDL-C levels (<35 mg/dl), preliminary studies suggest that statins have different effects: simvastatin (80 mg) increases HDL-C & apoA-I levels more than a comparable dose of atorvastatin

Question 197

LDL-C levels

Answer 197

Statins lower LDL-C by 20% to 55% depending on the dose & statin used

table on page 22

Question 198

What are administered as the active B-hydroxy acid form except lovastatin & simvastatin which are administered in the lactone form & must be hydrolyzed in vivo to the corresponding B-hydroxy acid form?

Answer 198

Statins

Question 199

All statins a e subject to extensive first-pass metabolism by the liver:

Answer 199

○ < 5%-20% of a dose reaches the general circulation

○ > 95% of most of these drugs & their active metabolite, the B hydrox acids, are bound to plasma proteins

• Biotransformation results in low systemic availability
• 70% of metabolites are excreted by liver
• Peak plasma concentrations develop in 1-4 hours

Question 200

Adverse Effects of Statins

Answer 200

Hepatotoxicity - dose-related elevations in hepatic transaminases

Myopathy
- the only major adverse effect of clinical significance

• associated with ALL statins, together with rhabdomyolysis
• <1% in patients without concomitant administration of drugs that enhance the risk of myopathy
  > statin + fibrates or niacin - myopathy is probably caused by enhanced inhibition of skeletal muscle sterol synthesis
  > Drug metabolized by cytochrome P450: macrolide antibiotics (e.g., erythromycin), apple antifungals (e.g, itraconazole), cyclosporine, phenylpiperazine antidepressant, nerazodome & protease inhibitors.
• intense myalgia (arms -> thighs -> entire body)
• symptoms progress as long as patients continue to take drugs
• serum creatinine kinase (CK) levels typically 10-fold higher than the upper limit
  > routine monitoring is not recommeded unless the statins are used with other drugs that predispose to myopathy.

Question 201

Pregnancy

Answer 201

safety during pregnancy has not been established

Question 202

• Cholestyramine & Colestipol
• Among the oldest of the hypolipidemic drugs
• Probably the safest since hey are not absorbed by the intestine
• The only hypocholeserolemic drugs currently recommended for children 11-20y.o.
• Most often used as second agents if statin therapy does not lower LDl-C levels sufficiently
• When used with a statin, they are usually prescribed at submaximal doses
• Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable GIT side effects (bloating & con pation) that limit compliance
• Colesevelam is new agent prepared as an anhydrous gel & taken as a tablet that lowers LDL-C by 18% at its maximum dose
  ○ Safety & efficacy have not been studied in children & pregnant women

Answer 202

BILE ACID-SEQUESTRANTS OR RESINS

Question 203

Chemistry of Bile Acid-Sequestrants or Resin

Answer 203

• Both agents are anion-exchange resins
• Cholestyramine is a polymer of styrene & divinylbenzene and is a quaternary amine
• Coletipol is a copolymer of diethelenetriamine & 1-chloro-2,3-epoxypropsne and is a mixture of tertiary & quaternary diamines
• Both agents are hygroscopic powders administered as chloride salt & are insoluble in water

Question 204

MOA of BILE ACID-SEQUESTRANTS OR RESINS

Answer 204

Agents are highly positively charged & bind negatively charged bile acids –> Because of their large sizes, they are not absorbed & the bound bile acids are excreted in the stools –> Increase in hepatic bile acid synthesis –> Decreased hepatic cholesterol content –> Production of LDL receptors –> increased LDL clearance & decreased LDL-C levels

Question 205

What are the Adverse Effects of Bile Acid-Sequestrants or Resins?

Answer 205

Hyperchloremic acidosis

Gritty sensation
- both agen are available as a powder that must be mixed with water & drank as a slurry

Bloating & Dyspepsia
- main adverse effects
- can be reduced if the drugs are completely suspended in liquid several hours before ingestion

Constipation
- prevented by adequate daily water intake & psyllium

Question 206

Drug interactions of Bile Acid-Sequestrants or Resins

Answer 206

• Cholestyramine & Colestipol bind many drugs & interfere with their absorption
• Administer the following drugs either 1 hour before or 3-4 hours after a dose of Cholestyramine or Colestipol
  ○ Thiazides
  ○ Furosemide
  ○ Propanolol
  ○ Thyroxine
  ○ Cardiac glycosides
  ○ Coumarin
  ○ Statins (some)

Question 207

What is a Pyridine-3-carboxylic acid?

Answer 207

Niacin or Nicotinic Acid

Question 208

What is most versatile because it favorably affects virtually all lipid parameters?

Answer 208

Niacin or Nicotinic Acid

Question 209

Water-soluble B-complex vitamin that functions as a vitamin only after its conversion to nicotinamide adenine dinucleotide -> nicotinamide does no affect lipid levels.

Answer 209

NIACIN OR NICOTINIC ACID

Question 210

Hypolipidemic effects require larger doses than that needed for

Answer 210

vitamin effects

Question 211

• Best agent fo increasing HDL-C levels (increments of 30% to 40%)
• Lowers TG by 35% to 40% (as effectively as fibrates & the more potent statins) & reduces LDL-C level by 20% to 30%
• The only lipid-lowering drug that reduces Lp(a) levels significantly (about 40%)

Answer 211

NIACIN OR NICOTINIC ACID

Question 212

Mechanism of Action of Niacin or Nicotinic Acid

Answer 212

• Niacin has multiple effects on lipoprotein metabolism
• Adipose tissue
  inhibits lipolysis of TG by hormone-sensitive lipase -> reduces transport of FFA to liver - decrease hepatic TG synthesis
• Liver
  reduces both the synthesis & esterification of FA -> increases apo B degradation -> reduces TG synthesis -> reduces hepatic VLDL production -> reduced LDL levels
• Enhanced LPL activity
  promotes clearance of chylomicrons & VLDL TG
• Decreased fractional clearance of apoA-I HDL
  increased HDL-C levels

Question 213

Pharmacokinetic Properties of Niacin/Nicotinic Acid

Answer 213

• Pharmacological doses (>1 gm/day) are almost completely absorbed
• Peak plasma concentrations (up to 0.24 mM) is achieved in 30-60 minutes
• Half-life: 60 minutes
  necessity of twice or thrice daily dosing
• At lower doses, most niacin is taken up by the liver, only the major metabolite, nicotinuric acid, is found in the urine
• At higher doses, a greater proportion is excreted in the urine as unchanged nicotinic acid

Question 214

Adverse Effects of Niacin/Nicotinid Acid

Answer 214

● Flushing & dyspepsia
○ limit patient compliance

● Cutaneous effects
○ flushing, pruritus of the face & upper trunk, skin rashes & acanthosis nigricans

● Hepatotoxicity
○ Elevate serum transaminases
○ > 2 gm of sustained-release, OTC preparations
○ Flu-like fatigue & weakness

● Hyperglycemia
○ niacin-induced insulin resistance

● Elevation of uric acid evels & reactivation of gout

Question 215

What are the Fibric Acid Derivatives?

Answer 215

• Clofibrate
• Gemfibrozil
• Fibric acid analogs

Question 216

• Prototype
• Ethyl ester of p-chlorophenoxyisobutyrate

Answer 216

Clofibrate

Question 217

What is a nonhalogenated phenoxypentanoic acid?

Answer 217

Gemfibrozil

Question 218

What are examples of Fibric acid analogs?

Answer 218

Fenofibrat , Bezafibrate, Ciprofibrate

Question 219

What is the MOA of Fibric Acid Derivatives?

Answer 219

• Remains unclear despite extensive studies
• Many of the effects are madiated by interaction with peroxisome proliferator-activated receptors (PPARs, isotypes a, b and y) which regulate gene transcription
• PPARa is expressed primarily in the liver & brown adipose tissue & to a lesser extent, in the kidney, heart & skeletal muscle

table on page 24

Question 220

Pharmacokinetic Properties

Answer 220

● Absorbed rapidly & efficiently (>90%) when given with a meal

● Peak plasma concentrations achieved within 1-4 hour

● >95% of the drugs plasma are protein bound; nearly exclusively to albumin

● Half -life differ significantly:
- Gemfibrozil: 1.1 hours
- Fenofibrate: 20 hours

● Widely distributed throughout the body & concentrations in the liver, kidney & intestine exceed the plasma level

● Excreted predominantly as glucoronide conjugates: 60% to 90% of an oral dose is excreted the urine with smaller amounts appearing in th feces

● Excretion is impaired in renal failure

● Use of fibrates is contraindicated in patients with renal failure

Question 221

Adverse Effects of Fibric Acid Derivatives

Answer 221

● Side effects occur in 5% to 10% of patients ○ most often not sufficient to cause discontinuation of the drug

● GIT side effects
○ 5%

● Cutaneous effects:
○ rash, urticaria, hair loss

● Others:
○ myalgia, fatigue, headache, impotence, anemia

● Minor increases in liver transaminases & decreases in alkaline phosphatase

● Myositis flu-like syndrome

● Increased lithogenicity of bile
○ increased gallstone formation