CV Guiding Questions

Question 1

Elastic artery

Answer 1

The alternating layers of elastic lamellae and smooth muscle cells in the thick wall are characteristic. In this schematic diagram, the two brown “spaces” are not histological features; they are artificial separations to emphasize the differences between layers. Same is true in figures 2, 3, and 4.

Question 2

Vein (small to medium).

Answer 2

The presence of a few bundles of longitudinal smooth muscle cells in a thick adventitia indicate that this is a vein. The relatively thin tunica media is also characteristic, but this may be readily apparent only when compared with a companion muscular artery.

Question 3

Muscular artery

Answer 3

Compare with the elastic artery (#1). There are internal and external elastic lamellae bounding the smooth muscle tuncia media.

Question 4

Large vein

Answer 4

The main difference from the medium-sized vein (#2) is the presence of more bundles of smooth muscle in the adventitia.

Question 5

Venule

Answer 5

Note the single layer of smooth muscle external to the endothelial cells.

Question 6

Arteriole

Answer 6

There are two layers of smooth muscle surrounding the endothelium, whose cells have elongated nuclei that are cut in cross section and bulge into lumen because of the contracted state of the arteriole. The side-by-side comparison of the venule and arteriole emphasizes the differences between arteries and veins in general. The venule is larger, but has a thinner wall. And the lumen of the venule has a smoother contour than the endothelium of the arteriorle (slightly scalloped).

Question 7

1. Which of the following blood vessels has the highest oxygenation levels?

A. Embryologic umbilical arteries
B. Adult pulmonary arteries
C. Ductus arteriosus
D. Embryonic inferior vena cava
E. Fetal pulmonary arteries

Answer 7

. The umbilical vein from the placenta has the highest level of oxygen and continues into the inferior vena cava. The umbilical arteries (A) carry deoxygenated (venous) blood to the placenta. Adult pulmonary arteries (B) carry deoxygenated blood to the lungs (the only arteries with “venous” blood). The ductus arteriosus (C) is a continuation of the pulmonary trunk from the right ventricle. Much of the blood in the right ventricle comes from the superior vena cava (with some mixing from the IVC), which has venous blood from the upper embryo. Fetal pulmonary arteries (E) would have the same blood as the fetal right ventricle.

Question 8

2. Soon after birth, blood flow increases significantly in which of the following?

A. Umbilical vein
B. Left atrium
C. Ductus arteriosus
D. Right atrium
E. Ductus venosus

Answer 8

2-B. With the first breaths after birth, amniotic fluid is cleared from the airway, and the vascular beds in the lungs open from reduced intrapulmonary pressure. As a result, blood starts rushing into the lungs and from there into the left atrium (B). The umbilical vein (A) collapses for lack of blood. The ductus arteriosus (C) has greatly reduced blood flow as the pressure in the lungs becomes rapidly lower than in the aortic arch. There is little change in flow in the right atrium (D), and ductus venosus (E) blood flow decreases as liver blood flow and function increases.

Question 9

3. Faulty development of the supracardinal vein system results in impaired venous flow from which of the following?

A. Thoracic wall
B. Upper extremity
C. Kidneys
D. Heart muscle
E. Lungs

Answer 9

3-A. The supracardinal veins become the azygos system of veins draining blood from the thoracic wall into the superior vena cava.

Question 10

4. A large, septum primum type of interatrial septal defect occurs when the septum primum does not properly fuse to which of the following?

A. Septum secundum
B. Spiral septum
C. Endocardial cushions
D. Interventriuclar septum
E. Crista terminalis

Answer 10

4. A large, septum primum type of interatrial septal defect occurs when the septum primum does not properly fuse to which of the following?

A. Septum secundum
B. Spiral septum
C. Endocardial cushions
D. Interventriuclar septum
E. Crista terminalis

Question 11

5. The semilunar valves develop just above which of the following?

A. Ductus arteriosus
B. Endocardial cushions
C. Truncus arteriosus
D. Sinus venosus
E. Bulbus cordis

Answer 11

5-E. The bulbus cordis gives rise to the smooth outflow parts of both ventricles under the semilunar valves, the aortic vestibule in the left ventricle and the conus arteriosus in the right ventricle.

Question 12

6. The sinus venosus contributes to which of the following adult structures?

A. Auricle of the right atrium
B. Coronary sinus
C. Inferior vena cava
D. Posterior wall of the left atrium
E. Conus arteriosus

Answer 12

6-B. The left horn of the sinus venosus gives rise to the coronary sinus (B); the right horn gives rise to the smooth, posterior wall of the right atrium. The auricle of the right atrium (A) comes from the primitive atrium. The fetal inferior vena cava (C) drains into the sinus venosus; it does not develop from it. “B” is a much better answer. The posterior wall of the left atrium (D) comes from the pulmonary veins. The conus arteriosus (E) develops from the bulbus cordis.

Question 13

S1

Answer 13

closure of the mitral and tricuspid valves.

Question 14

S2

Answer 14

closure of the mitral and tricuspid valves.

Question 15

S3

Answer 15

sloshing in” of blood flow into a dilated ventricle from the atria in early diastole after opening of the mitral valve (you can also have a right sided S3, but this is less common). Therefore, this is an early diastolic sound, percieved as a sound soon after S2.

Question 16

S4

Answer 16

atrial kick (atrial systole) during late ventricular diastole forcing blood into a stiff heart. This is tricky: atrial systole corresponds to late ventricular diastole. Therefore this is a late diastolic sound, perceived as happening just before S1 (which corresponds to the onset of physiological systole).

Question 17

a wave

Answer 17

right atrial systole

Question 18

descent

Answer 18

reflecting atrial relaxationThe initiation of ventricular systole with closure of the tricuspid valve perturbs the x descent

Question 19

The v wave

Answer 19

reflects atrial filling during ventricular systole while the tricuspid valve is closed

Question 20

y descent

Answer 20

is inscribed when the tricuspid valve opens, and terminates when atrial pressures begin to rise as atrial filling from venous return exceeds runoff into the right ventricle.

Question 21

• How does electrical current spread throughout the myocardium?

Answer 21

Broadly, from the SA node through the atria to the AV node, then down the His-Purkinje system then the bundle branches. The depolarization at the level of the individual myocyte spreads down the sarcolemma, and down the T-tubules where calcium-induced calcium release is effected.

Question 22

• Describe the process of calcium-induced calcium release

Answer 22

From the learning guide: We will now follow calcium and its important role in stimulating contraction of the cardiomyocyte. As a result of membrane depolarization, extracellular calcium enters the cell through L-type calcium channels (these can also be called dihydropyridine receptors because they are the target of the dihydropyridine class of calcium channel blockers). This trigger calcium is sensed by ryanodine receptors (RyR) in the terminal cisternae of the sarcoplasmic reticulum. This then stimulates further release of calcium from the sarcoplasmic reticulum through a process termed calcium-induced calcium release.

Question 23

• Describe the role of the ryanodine receptor in excitation-contraction coupling.

Answer 23

Sits on the sarcoplasmic reticulum, senses the trigger calcium, and leads to calcium-induced calcium release.

Question 24

• Describe the function of troponin T, troponin I, and troponin C

Answer 24

troponin T binds tropomyosin, Troponin C binds calcium, and troponin I inhibits contraction when bound to actin.

Question 25

. Attached State

Answer 25

This shows the attached myosin head to the thin filament after a power stroke has been completed.

Question 26

Cocked State

Answer 26

ATP hydrolysis to ADP and Pi occurs. The products of hydrolysis remain on the myosin head, causing the myosin head to unhinge by 11 nm, lining up with an actin monomer 2 positions over from the previous binding site.

Question 27

Cross-bridge State

Answer 27

The myosin head binds to actin.

Question 28

Power-stroke State

Answer 28

Pi dissociates from the myosin, triggering the power stroke.

Question 29

SERCA (most important). Also: a sarcolemmal calcium pump and a Na+/Ca2+ exchanger.

Answer 29

• What are the major steps of second messenger signalling after the 1-adrenergic receptor is bound by ligand (ending with activation of Protein Kinase A)?

Question 30

• What are the major steps of second messenger signalling after the 1-adrenergic receptor is bound by ligand (ending with activation of Protein Kinase A)?

Answer 30

When the β_1 receptor is bound, the α subunit of Gs (stimulatory G protein) binds adenylyl cyclase, stimulating production of the second messenger cyclic AMP (cAMP). Through protein kinase A (PKA), phosphorylation of multiple sites is effected

Question 31

• Describe the role of phospholamban in modulating myocardial performance

Answer 31

Phosphorylation of phospholamban results in dissociation of phospholamban from the SERCA pump, disinhibiting Ca2+reuptake. This in turn results in increased Ca2+ available for release through the ryanodine receptors, improving contractility. Importantly, the faster reuptake of Ca2+ through SERCA enhances myocardial relaxation, or improves lusitropy. Positive lusitropy is a critical mechanism to improve cardiac output as this allows improved myocardial filling.

Question 32

• How does digoxin enhance contractility?

Answer 32

Digoxin blocks the membrane Na+/K+ ATPase. Consequently intracellular Na+ levels climb, increasing the driving force for the Na+/Ca2+ exchanger, thereby increasing intracellular calcium levels and increasing inotropy.

Question 33

• Define contractility.

Answer 33

Contractility is the strength of contraction of the myocyte for a given preload and a given afterload. A myocyte that contracts more strongly than another in the setting of the same preload and afterload is said to exhibit greater contractility. Of note, if a myocyte increases the force of contraction because of increased preload,

Question 34

• How does an increased heart rate increase contractility?

Answer 34

More calcium left in the myocardium for the next contraction (ascending staircase effect).

Question 35

• Define preload.

Answer 35

Preload is the stretch on muscle prior to contraction.

Question 36

• If myocardial stretch increases, what happens to active tension? What happens to passive tension?

Answer 36

Active tension increases until the stretch becomes past optimal, at which point it decreases (see point D as compared to point C in figure 11 of the learning guide). Passive tension continues to increase with length at all physiologic amounts of stretch. If the muscle actually physically ruptures, then the tension would abruptly drop.

Question 37

• Define afterload.

Answer 37

Afterload is the amount of load against which a muscle must contract.

Question 38

• If the systolic blood pressure increases, what do you predict happens to the volume of blood ejected from the heart?

Answer 38

Decreases, because the velocity of contraction is less, so the total change in volume of the heart during ejection is shorter. Furthermore, the increased systolic blood pressure will tend to close the aortic valve sooner.

Question 39

• What happens to the cardiac function curve with increased inotropy?

Answer 39

Moves up

Question 40

• What happens to the cardiac function curve Decreased inotropy

Answer 40

Moves down

Question 41

• What happens to the vascular function curve with increased plasma volume?

Answer 41

Moves up and to the right.

Question 42

Decreased plasma volume?

Answer 42

Moves down and to the left.

Question 43

• What happens to the vascular function curve with increased venous tone?

Answer 43

Moves up and to the right.

Question 44

Decreased venous tone?

Answer 44

Moves down and to the left. (an increase in venous tone has the same functional effect as an increase in plasma volume, and vice versa).

Question 45

• Describe the changes that happen with increased SVR on both the cardiac and vascular function curves.

Answer 45

The cardiac function curve moves downward. The vascular function curve rotates counterclockwise, with the x-intercept fixed.

Question 46

• Why does the x-intercept not change on the vascular function curve with decreased SVR?

Answer 46

Because changes in SVR happen because of arteriolar resistance, which has a negligible effect the total volume of circulation. Therefore, the stressed volume of circulation does not appreciably change. Therefore, at a CO of 0, the right atrial pressure does not change.

Question 47

2. What are the major events and biological mediators of each step of platelet activation?

Answer 47

When a blood vessel injury occurs, a series of events facilitate platelet adhesion and activation. This includes exposure of collagen and von Willebrand factors that bind platelet receptors, causing platelets to become tethered to the site of injury and they become activated. Changes in the endothelium also facilitate platelet activation including thrombin generation and decreased production of factors that normally quiet platelets. Activated platelets change shape and secrete factors that recruit additional platelets including ADP and thromboxane A2. Cellular signaling events within the platelets lead to the presentation of active GPIIbIIIa (fibrinogen) receptors and presentation of anionic phospholipids on the outer leaflet of the platelet plasma membrane which promote assembly of coagulation factor tenase and prothrombinase complexes on their surfaces. These processes lead to platelet aggregation through fibrinogen binding as well as assembly of active coagulation complexes and the formation of a fibrin-platelet plug. Platelets contract and pull against each other through adhesions between GPIIbIIIa and fibrin; important processes for formation of the mature platelet-fibrin thrombus.

Question 48

3. What are the major platelet membrane glycoprotein defects that cause hereditary bleeding disorders?

Answer 48

Platelets have several important glycoprotein receptor complexes on their surface, including GP Ib/V/IX (vWF receptor); GPIIbIIIa (otherwise known as IIb3 or fibrinogen receptor) and collagen receptors GPIaIIa (21) and GP VI. A defective GP Ib/V/IX (vWF Receptor) does not bind effectively to von Willebrand factor in the subendothelial extracellular matrix in the autosomal recessive Bernard-Soulier Syndrome. Affected patients have a variable, but often severe bleeding tendency. A GPIIbIIIa receptor defect that does not bind fibrinogen effectively in autosomal recessive Glanzmann’s Thrombasthenia. Patients with this disorder often present in childhood with a severe bleeding disorder. Persons with a rare autosomal recessive glycoprotein VI (collagen signaling receptor) deficiency may experience epistaxis, surgical bleeding or menorrhagia. Very rarely, patients with deficient expression collagen binding receptor GPIaIIa may be encountered with a mild bleeding disorder.

Question 49

4. What is the role of platelet granule release and TxA2 synthesis on platelet activation?

Answer 49

Activated platelets change shape and secrete factors including adenosine diphosphate (ADP) and thromboxane A2 (TxA2) that recruit additional platelets. When platelets become activated, they secrete alpha and dense granules, the latter of which contain ADP, ATP, serotonin, Ca2+ and pyrophosphate. In the presence of healthy endothelium expressing CD39 ecto-ADPase, ADP is hydrolyzed and removed from the system. ADP has the effect to activate platelets through purinergic receptors including P2Y1 and P2Y12 and P2X1 ATP-gated Ca2+ channel. Of these receptors, the P2Y12 receptor has become the most targetable for antiplatelet therapy with thienopyridine drugs like clopidigrel. Thromboxane A2 is produced from arachidonic acid liberated from the platelet membrane by phospholipase A2 in the activated platelet. Arachidonic acid is converted through the cyclooxygenase pathway to the short-lived TxA2 which has autocrine and paracrine effects to amplify the initial stimulus for platelet activation as well as to recruit additional platelets in the vicinity through the thromboxane receptors, TP and TP. Thromboxane A2 and ADP, as well as thrombin (FIIa) have an amplifying effect on platelet activation.

Question 50

5. What mediators do platelets provide that contribute to chronic inflammation and atherothrombosis development?

Answer 50

Platelets provide several factors including platelet factor-4 (CXCL4), RANTES, CXCL12, CXCL7, PDGF, CD40L, P-selectin, TxA2, Tissue Factor and IL-1 to the microenvironment. Platelets may also produce superoxide and reactive oxygen species that contribute to platelet activation and inflammation. Collectively, these factors increase endothelial cell adhesion, cytokine expression and reactive oxygen production which promote inflammation. These effects cause leukocyte recruitment, attachment, activation and differentiation into foam cells. Platelets bring into the microenvironment factors that promote inflammation and atheroma formation.

Question 51

6. How do aspirin, clopidigrel and abciximab affect platelet function?

Answer 51

Aspirin acetylates platelet cyclooxygenase and irreversibly inhibits its activity upon exposure in the venous portal circulation. The effect of aspirin lasts for the life of the platelet (~9-10 days) and the effect is lost as platelets are gradually replaced by new synthesis. Thus, aspirin blocks TxA2 secretion and its amplifying and recruitment effects on platelet activation. Clopidogrel inhibits platelet activation by blocking ADP activation of the purinergic P2Y12 receptor. Clopidogrel is a pro-drug which must be metabolized to the active form by the cytochrome P450 system. Some individuals have genetic polymorphisms which cause them to metabolize clopidogrel poorly, causing drug resistance. Alternative antiplatelet drugs or increased clopidogrel doses may be needed to obtain a therapeutic effect for these individuals. Abciximab is a humanized murine monoclonal Fab antibody that binds to and inhibits GPIIb/IIIa fibrinogen receptor function. It has a very potent effect to inhibit platelet function and is used under specific conditions, such as acute coronary syndrome during or in preparation for cardiac catheterization.