B4M1C2: Cardiovascular System Flashcards

Question

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

Answer 1

Circumflex artery

Answer 2

Left marginal artery

Answer 3

Anterior ventricular and posterior ventricular branches

Answer 4

Atrial branches

Answer 5

See page 2

Answer 6

**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

Answer 7

Coronary Sinus

Answer 8

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

Answer 9

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)***

Answer 10

Great cardiac vein

Answer 11

Small cardiac vein

Answer 12

Middle cardiac vein

Answer 13

Posterior vein of the left ventricle

Answer 14

Oblique vein of the left atrium

Answer 15

Anterior cardiac vein

Answer 16

Venae Cordis Minimae (Thebesius' veins)

Answer 17

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

Answer 18

Less than 0.5% of total body weight

Answer 19

**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.***

Answer 20

Myocardium

Answer 21

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

Answer 22

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**).

Answer 23

root of the aorta behind the cusps of the aortic valves

Answer 24

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

Answer 25

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.

Answer 26

Epicardial veins

Answer 27

Epicardial veins

Answer 28

● 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.

Answer 29

● 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.

Answer 30

● **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.

Answer 31

● 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.

Answer 32

● 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.

Answer 33

Einthoven's triangle

Answer 34

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

Answer 35

● **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

Answer 36

● 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.***

Answer 37

● 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***

Answer 38

● 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.**

Answer 39

**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

Answer 40

**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**

Answer 41

1500 method R-R method 6-second method

Answer 42

**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).

Answer 43

**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.

Answer 44

**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.

Answer 45

● 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)

Answer 46

● **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.***

Answer 47

● 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.**

Answer 48

Myocardial Ischemia

Answer 49

Angina Pectoris

Answer 50

Angina Pectoris

Answer 51

Angina Decubitus

Answer 52

Angina Decubitus

Answer 53

Prinzmetal's Variant Angina

Answer 54

**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.

Answer 55

Chronic Stable Angina

Answer 56

● 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.***

Answer 57

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

Answer 58

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

Answer 59

Severe ventricular hypertrophy due to aortic stenosis

Answer 60

○ Extremely severe anemia ○ Carboxyhemoglobinemia

Answer 61

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

Answer 62

● **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.

Answer 63

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.

Answer 64

**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.

Answer 65

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

Answer 66

heparan sulfate

Answer 67

two types of chemical modifications

Answer 68

● 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.

Answer 69

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.

Answer 70

Leukocyte Recruitment

Answer 71

**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.

Answer 72

**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.

Answer 73

**Nitric oxide** by endothelial cells

Answer 74

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

Answer 75

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

Answer 76

Atheromatous Plaque

Answer 77

Fatty streak

Answer 78

Myocardial Ischemia

Answer 79

● 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.

Answer 80

● 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**)

Answer 81

● 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

Answer 82

- aortic stenosis - aortic regurgitation - pulmonary hypertension - hypertrophic cardiomyopathy ● These disorders may cause angina in the absence of coronary atherosclerosis.

Answer 83

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**

Answer 84

● 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.

Answer 85

● 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***

Answer 86

**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.

Answer 87

**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

Answer 88

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

Answer 89

HMG CoA reductase inhibitors (statins)

Answer 90

Niacin and Fibrates

Answer 91

○ 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.

Answer 92

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

Answer 93

**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

Answer 94

**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

Answer 95

**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

Answer 96

○ ↑ 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

Answer 97

● 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

Answer 98

○ 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.

Answer 99

○ 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

Answer 100

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

Answer 101

Dipyridamole

Answer 102

Dipyridamole

Answer 103

Ticlopidine

Answer 104

Ticlopidine

Answer 105

Clopidogrel

Answer 106

Clopidogrel

Answer 107

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

Answer 108

- 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

Answer 109

- 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

Answer 110

Eptifibatide

Answer 111

Eptibafide

Answer 112

Ticagrelor

Answer 113

Surgical tx

Answer 114

**PTCA (Percutaneous Transluminal Coronary Angioplasty)** ● Most commonly used percutaneous coronary intervention (PCI) ● Also known as stenting

Answer 115

○ 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.

Answer 116

○ 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

Answer 117

○ 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.

Answer 118

○ 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.

Answer 119

CABG (Coronary Artery Bypass Grafting)

Answer 120

Less invasive Shorter hospital stay Lower initial cost Easily repeated Effective in relieving symptoms

Answer 121

Effective in relieving symptoms Improved survival in certain subsets Ability to achieve complete revascularization

Answer 122

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

Answer 123

Cost Increased risk of a repeat procedure due to late graft closure Morbidity and mortality of major surgery

Answer 124

● **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.

Answer 125

● 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.

Answer 126

● 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

Answer 127

○ Cholesterol biosynthesis ○ Lipoprotein metabolism table onn page 20

Answer 128

**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

Answer 129

● Chylomicrons ● Very low density lipoproteins (VLDL) ● Intermediate-density lipoproteins (IDL) ● Low-density lipoproteins (LDL) ● High-density lipoproteins (HDL) table on page 21

Answer 130

Apolipoproteins

Answer 131

Characteristics of the Apo C Series

Answer 132

Characteristics of the Apo E Series

Answer 133

Characteristics of the Apo A Series

Answer 134

Lipoprotein lipase (LPL)

Answer 135

Hepatic triglyceride lipase (HTGL)

Answer 136

Lecithin:cho esterol acyltransÿ ase (LCAT)

Answer 137

Cholesteryl est transÿer protein (CETP)

Answer 138

Phospholipid transÿer protein (PLTP) table on page 21

Answer 139

● **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

Answer 140

- 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)

Answer 141

Bile acid-binding resins

Answer 142

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

Answer 143

VLDL secretion inhibitors (e.g., Niacin)

Answer 144

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

Answer 145

Lipophilic antioxidants (e.g., Probucol)

Answer 146

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

Answer 147

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

Answer 148

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

Answer 149

● 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

Answer 150

Statins lower LDL-C by 20% to 55% depending on the dose & statin used table on page 22

Answer 151

○ < 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

Answer 152

**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.

Answer 153

safety during pregnancy has not been established

Answer 154

BILE ACID-SEQUESTRANTS OR RESINS

Answer 155

- 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***

Answer 156

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

Answer 157

**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

Answer 158

- **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)

Answer 159

Niacin or Nicotinic Acid

Answer 160

Niacin or Nicotinic Acid

Answer 161

NIACIN OR NICOTINIC ACID

Answer 162

vitamin effects

Answer 163

NIACIN OR NICOTINIC ACID

Answer 164

- 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

Answer 165

- 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

Answer 166

● 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

Answer 167

- Clofibrate - Gemfibrozil - Fibric acid analogs

Answer 168

Clofibrate

Answer 169

Gemfibrozil

Answer 170

Fenofibrat , Bezafibrate, Ciprofibrate

Answer 171

- 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

Answer 172

● 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

Answer 173

● 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