Lecture Notes #1: Cardiovascular System

What is 'intimal thickening'?

'Intimal thickening' with lipid-laden 'foam' macrophages, T-lymphocytes, and smooth muscle cells in 'plaques' characterizes atherosclerosis and reflects endothelial damage.

*Vasa vasorum*:

('vessels of the vessels') in larger vessels and heart, also may extend into outer part of the media

b. *Reticular fibers, elastic fibers and lamellae*:

(perforated/fenestrated 'sheets'), and proteoglycans, produced by and interspersed b/w smooth muscle cell layers.

*Vasoconstriction*

(small 'terminal'/'feed' artery & arteriolar constriction = tunica media) increases arterial & arteriolar pressure but reduces 'downstream' capillary and venous pressures

a. *Atrioventricular* valves

(tricuspid (right AV) & bicuspid mitral (left AV)) limit back-flow from ventricles back into atria. Cusps of valves attached to *chordae tendinae* connected to *papillary muscles* extending from ventricular wall.

PRESSURE TABLE

*Pressure (mm Hg) - ventricle - arteries - arterioles - capillaries - venules - veins* *systemic (left)* 130/10 - 120/80 - 80/60 - 15-35 - 5-15 - <5 *pulmonary (right)* 30/5 - 15/5 - 10/5 - <10 - <5 - <5

B. Components of cardiovascular system

*TABLES TO KNOW* 1. Heart 2. Elastic Arteries ('large', 'conducting') 3. Medium arteries ('muscular', 'distributing') 4. Small arteries & arterioles ('resistance' vessels) 5. Capillaries ('exchange vessels') 6. Venules 7. Small-to-medium-sized veins 8. Large veins

Order of three subendothelial layers for *Semilunar: aortic & pulmonary*

*arterial or atrial side endothelium* - *F*ibrosum, *S*pongiosum, *V*entricularis - *ventricular side endothelium*

Order of three subendothelial layers for *AtrioVentricular: mitral & tricuspid*

*arterial or atrial side endothelium* - *S*pongiosum, *F*ibrosum, *V*entricularis --> chordae tendinae --> papillary muscles - *ventricular side endothelium*

a. *Systole*

*ventricles contract* ejecting blood (systemic arterial pressure @ ~120 mm Hg; pulmonary arterial pressure @ ~30mm Hg) over ~300 msec (@75 bpm)

b. *Diastole*

*ventricles relax* (systemic arterial pressure ~80 mm Hg; pulmonary arterial pressure @~10mm; essentially no pressure vena cava entering right atrium) over ~ 500 msec

C. Impulse-generating and conducting system continued:

- Autonomic *nerves do not initiate contraction but do modulate impulse rate* from SA node. Axons from cranial and splanchnic nerves synapse with post-synaptic ganglionic neurons which terminate amongst the conducting myocytes within the SA and AV nodes. Release of their neurotransmitters thus modulates the intrinsic conduction rate - paracrine not synaptic mechanism. Sympathetic (adrenergic) fibers increase rate (-->'fight/flight') whereas parasympathetic (cholinergic) fibers decrease it (-->'R&R').

1. Fibrous skeleton

- Base of dense (collagenous & elastic), irregular CT structurally supporting the heart and forming fibrous rings for the valve leaflets; includes annuli fibrosi at atrioventricular (AV) orifices and at the arterial foramina, the trigonal fibrosa, and the septum membranaceum.

A. Function

- Collect excess extracellular 'interstitial' fluid (= *lymph*) from tissue spaces not reentering capillaries, then *return lymph to vascular system via lymph nodes*; transport leukocytes from lymphoid tissues to the blood vascular system then to all organs; absorption of nutrients from gut. Incomplete lymphatic drainage causes edema.

A. Histological structure

- Endocardium (~ tunica intima) - Myocardium (~ tunica media) - Epicardium (~ tunica adventitia; mostly serosal ~ *'visceral serous pericardium'*)

2. Valves (total of four)

- Extensions ('flaps') of endocardium prevent back-flow of blood during & after contraction. Essentially, avascular CT covered by endothelium; small vessel and scattered smooth muscle bundles at valve base extending into endocardial layer. a. *Atrioventricular* valves b. *Semilunar* valves

*Lymphatic vessels/ducts*

- Formed by convergence of lymphatic capillaries. Thin, vein-like walls; no clear, layered tunic structure, but smooth muscle aids lymph flow toward heart. *Valves are more numerous than in veins*.

*Myocardium (~ tunica media)*:

- Functional syncytium of cardiac muscle bundles of variable thickness, with strands of vascular CT intermingled. (Cardiac myocytes extend into the base of muscularis of large veins (vena cava, pulmonary) supplying atria.) Capillaries run in endomysium ECM. Branches of *Purkinje (myocyte) fibers* run within the subendothelial layer of the myocardium.

II. *Heart*

- Heart has 4 chambers forming coordinated, paired pumps: 2 thin-walled *atria* which collect returning blood and 2 thick-walled *ventricles* which pump out blood. Systemic venous blood enters the right atrium via the vena cava which pumps blood to the right ventricle which delivers it to the lung via the pulmonary artery. Oxygenated blood returns to the left atrium via the pulmonary vein then is pumped by the left ventricle through the *aorta* to all other organs. Valves within the heart force uni-directional flow (~5 L/min). A. Histological structure B. Anatomical structure C. Impulse-generating and conducting system

*Lymphatic capillaries*

- Single layer of endothelium forming blind-ended vessels. Very *permeable* = no fenestrae, no zonula occludens junctions, little/no basal lamina.

*Endocardium (~tunica intima)*:

- Underlying the simple squamous *endothelium* is subendothelial CT layer (collagen and elastic fibers plus some smooth muscle cells & adipocytes) of variable thickness (thicker in atria then ventricles).

1) *Continuous ('tight') capillaries*:

- endothelium with *occluding 'tight' junctions* - continuous basal lamina - pinocytotic calveolae and calveolin-coated vesicles mediate bidirectional transcytosis - many tissues: CNS (BBB), lung, muscle, thymic cortex

2) *Fenestrated ('visceral', 'windows') capillaries*:

- fenestrated (50-100 nm) endothelium with (w/out diaphragms in renal glomerulus) - continuous basal lamina - tissues rapidly exchanging molecules with blood: kidney, endocrine tissues, intestinal villi, choroid plexus, ciliary processes

3) *Discontinuous ('sinusoidal') capillaries*:

- much larger diameter (up to 30 um) than other capillaries - numerous, large fenestrae, no diaphragms - inter-endothelial 'gaps' (100-1000 nm ' discontinuities' b/w cells) - discontinuous/absent basal laminae; reticular fibers - blood-tissue exchange of molecules and phagocytosis: liver, bone marrow, spleen

Common characteristics of an *artery*:

- thicker, 'muscular' wall - smaller, rounder lumen - prominent internal elastic lamella - tunica media >> tunica adventitia - No valves

Common characteristics of a *vein*:

- thinner wall - larger, irregular lumen - none/indistinct IEL - tunica media << tunica adventitia - Valves

*Pericytes*:

- undifferentiated mesenchymal *'stem' cells* enclosed within endothelial basal lamina of capillaries and venules - presumably differentiate to endothelial and/or smooth muscle cells.

A. General structure of blood vessels

-*three 'tunics'* (L. coat, layers) 1. Tunica intima 2. Tunica media 3. Tunica adventitia

C. Impulse-generating and conducting system

-Network of *specialized 'conducting' myocytes intrinsically initiate and propagate* (gap junctions) the contraction wave, first forcing blood from the atria into the ventricles then into the aorta and pulmonary arteries. a. Sinoatrial (SA) node b. Atrioventricular (AV) node c. AV bundle of His d. Subendocardial Purkinje fibers (myocytes)

3 important endothelial secretions to know:

1) endothelins 2) prostacyclin (PGI2) 3) nitric oxide (NO)

B. Anatomical Structure

1. Fibrous skeleton 2. Valves (total of four)

B. Structure and location

1. Lymphatic vessels *resemble venules and veins*, with no arterial equivalent; large ducts have some longitudinal and circular smooth muscle bundles in media. *Valves* produce uni-directional flow of lymph, entering vena cava via thoracic duct and right lymphatic duct. 2. Look for vessels with eosinophilic ('proteinaceous' lymph) contents with some leukocytes, but no erythrocytes near lymph-generating organs: intestinal villi ('lacteals'), tonsils, lymph nodes.

III. Lymphatic vascular system

A. Function B. Structure and Location

I. Blood vascular (cardiovascular) system

A. General structure of blood vessels B. Components of cardiovascular system C. Comparison of veins and arteries

C. *Comparison of veins and arteries*:

Arteries and veins are generally paired yet differ in their relative wall thickness, lumen shape, internal elastic lamina prominence, and the presence of valves.

*'Microcirculatory control'*

Arterioles regulate blood flow to capillary beds by *vasoconstriction and vasodilation* - under neuroendocrine control. Major site of *resistance* within vascular system: partially increase arteriolar contraction (*tone*) important mechanism of BP (and hypertension); decreased arteriolar tone important mechanism in shock. *Precapillary sphincters* (thickened tunica media) in *metarterioles* (10-15 um) regulate blood flow into capillary beds. In skin and erectile organs, blood flow can bypass the capillary beds via an anastomosis (*'arteriovenous shunt'*).

What are atheromas and how do they affect the arterial lumen?

Atheromas involve thickening of the tunica intima due to infiltration of macrophages and smooth muscle cells leading to formation of a lipo-fibrous plaque which progressively reduces the diameter of the arterial lumen.

In addition to O2 delivery and CO2 removal, what other function does blood have?

Blood carries drugs and toxins.

c. *AV bundle of His*:

Branches from apex of muscular interventricular septum to conduct contraction impulse *across the fibrous skeleton* to the right and left ventricles. Bundle of His gives rise to right and left anterior and posterior bundle branches, which extend inferiorly in right and left regions of the interventricular septum and then extend in the ventricular subendocardium.

What does the cardiovascular system consist of?

CV system consists of *heart and blood vessels* (including arteries, arterioles, capillaries, venules, and veins). These structures have a *similar overall organization* consisting of an inner (endothelium lining plus minimal CT), medial (muscle plus fibers), and outer layer (CT, vessels, nerves). The relative thickness and composition of these layers varies between individual structures.

*Epicardium* (~ tunica adventitia; mostly serosal ~ *'visceral serous pericardium'*):

Composed of fibrous and adipose CT with autonomic nerves and vasa vasorum but mostly covered by mesothelium (= serosa). The *visceral 'serous'* and *parietal 'fibrous'* pericardium refer to mesothelium-lined regions of the fluid-filled *pericardial sac* surrounding the heart. Coronary arteries branching from the proximal aorta enter ('outside in') to supply oxygenated blood to the heart wall. [Their blockage yields myocardial ischemia - 'heart attack'].

*Special note about valves*

Each valve contains *three* subendothelial CT sublayers (lamina) yet their order differs b/w the AV and semilunar valves: fibrosa, spongiosa, ventricularis

Where does excess interstitial fluid go?

Excess interstitial fluid that does not re-enter the blood capillaries, enters lymphatic capillaries which return *lymph* back to venous circulation via the lymphatic vessels, passing the lymph through lymph nodes (for immune surveillance) along the way.

What is edema?

Fluid accumulation in ECM.

Calcification, fibrosis, and/or inflammation of valves yields?

Heart dysfunction

Three units to be covered in this lecture:

I. Blood vascular (cardiovascular) system II. Heart III. Lymphatic vascular system

*Special note about endothelium in the tunica intima*:

It is *not an inert lining* but is sensitive and *responsive* to changes in blood flow, pressure, oxygen tension, and nutrients via exocrine and endocrine mechanisms, often contributing to pathogenesis.

Is the cardiovascular system an open or closed system?

It is a closed system circulating blood through the *pulmonary circuit* to oxygenate blood, and through the systemic circuit to *deliver oxygenated blood, nutrients & hormones ('communication') plus remove carbon dioxide, metabolic 'waste' products, & heat* from tissues.

What critical role does the tunica intima play?

It plays a critical role in many diseases, particularly in atherosclerosis leading to myocardial ('heart-attack') and cerebral ('stroke') ischemia (no blood flow).

Activation of endothelial cells (damage, cytokines) can induce what?

Localized clotting (thrombus formation), increased permeability, or adhesion and diapedesis of neutrophils leading to edema (excessive interstitial fluid volume) and acute inflammation.

a. *Sinoatrial (SA) node*:

Located in superior right atrium just inferior to superior vena cava. Fastest contracting *'pacemaker'* myocytes which *set 'heart rate' by initiating contractions*.

*Lymph nodes*

Permanent, encapsulated organs to expose antigens in lymph to macrophages (APCs) and lymphocytes of immune system.

b. *Atrioventricular (AV) node*:

Point of origin of AV bundle of His; located in inferior right atrium adjacent to coronary sinus. Delays contractions impulse to ventricles.

Refresh: *Define diapedesis.*

Transendothelial movement of *leukocytes* from intravascular lumen to extravascular matrix compartment - during *inflammatory and immune responses*.

Regional ischemia due to blocked coronary arteries triggers...

a myocardial infarction (plus secondary stroke) which can trigger necrosis of the myocytes. With very minimal potential for myocyte repair or regeneration, the affected region of the myocardium becomes *replaced by connective 'scar' tissue which not only does not contribute to contraction but impairs normal heart function*; this yields *lower 'ejection volumes'* requiring the heart to work harder and less efficiently. Myocardial necrosis can be semiquantitatively assessed by measuring the appearance of myocyte-specific cytoplasmic protein/enzyme levels in the blood.

7. *Small-to-medium-sized veins*

a. Diameter 0.2-10 mm (small); 1-9 mm (medium). b. One-way *valves* (folds in intima, lined by endothelium) to force uni-directional flow in veins >2mm diameter. c. Media consists of layers of smooth muscle cells intermixed with collagen and elastic fibers. Vasa vasorum penetrate deeply into media of veins. d. Adventitia well developed, thicker than media; some longitudinal smooth muscle cells.

4. *Small arteries & arterioles ('resistance' vessels)*:

a. Diameter <0.5 mm (includes all three layers). b. Internal elastic lamina present in small arteries >40um diameter but not arterioles. c. Media has 1-2 concentric smooth muscle layers. d. Thin tunica adventitia.

3. *Medium arteries ('muscular', 'distributing')*:

a. Diameter ~ 0.3 mm - 1.0 cm b. Distribute blood to body, with flow adjusted by smooth muscle layers of tunica media in response to sympathetic nerve stimulation (radial, tibial, popliteal, axillary, splenic, mesenteric, intercostal, femoral, hepatic, and coronary arteries). c. *Prominent internal elastic lamina* in tunica intima is a hallmark for these vessels; 3-40 concentric smooth muscle layers in media with progressive decrease in elastic lamellae as artery size decreases; neuromotor terminations; *external elastic lamina* at junction of tunica media and tunica adventitia usually visible in bigger vessels but not smaller ones.

6. *Venules*

a. Diameter: 10-50 um. Wall as thin as capillary, but lumen is 5-10 times larger. b. Tunica media consists of pericytes in post-capillary venules; several indistinct layers of smooth muscle cells; longitudinal collagen fibers present. c. Low-to-high permeability for fluid and cell exchange with surrounding tissue; vasoactive amines (i.e. serotonin, histamine) increase permeability (important in inflammation). d. *Post-capillary venules* are primary site of *diapedesis*; specialized post-capillary 'high endothelial' venules in lymph node parenchyma characterized by a cuboidal endothelium.

5. *Capillaries ('exchange vessels')*:

a. Diameter: 5-10um wall can be as thin as 0.2-1um. Length: ~0.25-1 mm; ~100,000 km combined length; ~6,000 m2 in body! System pressure drops from ~35 mm Hg at arteriolar end to ~10 mm Hg at venule; pulmonary pressure from ~10 mm Hg. Erythrocytes must be very flexible and pliable to squeeze through narrow bore of capillaries.

8. *Large veins*:

a. Diameter: >9 mm b. *Valves* in intima. c. Media relatively thin, as in small-to-medium sized veins. d. Adventitia is the thickest layer; may be 4x thickness of media. Large veins have longitudinal bundles of smooth muscle in adventitia, in addition to collagen and elastic fibers, nerves and vasa vasorum. e. Examples: venae cavae, innominates, internal jugulars, portal, splenic, azygous, superior mesenteric, renal, adrenal, external iliac, and femoral veins.

2. *Elastic arteries ('large', 'conducting')*:

a. Larger arteries conducting blood from heart (*aorta and pulmonary arteries* plus branches); aorta diameter ~2.5 cm in adult. b. Relatively thick tunica intima; multi-layered internal elastic lamina; elongate endothelial cells contain von Willebrand factor in secretory vesicles ('Weibel-Palade bodies')

*Purkinje myocytes*

appear *pale and large* by LM when compared to 'working' contractile myocytes; EM shows pale cytoplasm due to *fewer myofibrils* and *abundant glycogen granules* (nuclear 'halo'); contain acetylcholinesterase.

5. *Capillaries ('exchange vessels')* continued:

b. *Permeability* depends on structural characteristics of endothelial cells and basal lamina. 1) Continuous ('tight') 2) Fenestrated ('visceral'; 'windows') 3) Discontinuous ('sinusoidal')

1. Tunica intima (continued)

b. Basal lamina of endothelium

1. Tunica intima (cont.)

c. *Subendothelial layer*: loose CT with a few longitudinal layers of collagen; distinct fenestrated, *internal elastic lamella* in arteries.

2. *Elastic arteries ('large', 'conducting')* continued:

c. *many elastic laminae in tunica media* (clearly seen with elastic stains) which stretch to absorb the bolus of ventricular blood ejected during systole (*~120mm Hg*), then passively contract during diastole to maintain systemic arterial pressure (*~80 mm Hg) -->continuous, pulsitile blood flow* while heart output/flow is intermittent. d. Tunica adventitia with vasa vasorum, nervi vasorum, and lymphatics.

5. *Capillaries ('exchange vessels')* continued 2:

c. Capillary density dependent on metabolic activity of tissue; *high* density in myocardium and skeletal muscle, but *low* density around smooth muscle and dense CT. d. No tunica media of smooth muscle cells; thin tunica adventitia of a few collagen fibers: *Pericytes*

3. *Medium arteries ('muscular', 'distributing')* continued:

d. Adventitia less than/equal to thickness of media; many elastic fibers visible with elastic stain in larger arteries. e. Myo-endothelial gap junctions (endothelial cell - smooth muscle cell communication) may mediate angiotensin regulation of BP via tunica media contraction. f. Nerve endings in specialized sensory structures in the vascular system monitor BP (baroreceptors) and composition (chemoreceptors: O2, CO2, pH (H+ ions)): - Carotid bodies and sinuses (common carotid arteries) - Aortic bodies (aortic arch)

*Vasodilation*

decreases arterial & arteriolar pressure and raises 'downstream' capillary and venous pressure.

*Parasympathetic neurotransmitter* (acetylcholine) release...

decreases myocyte [Ca2+] thus decreasing contraction rate & force. This also constricts coronary arteries supplying the heart.

What is Marfan's syndrome?

defective fibrillin --> dissecting aneurysm

ventricularis

dense, fibro-elastic (ventricular side - contiguous with chordae tendinae)

fibrosa

dense, irregular fibrous (contiguous with valve rings of heart 'skeleton')

d. *Subendocardial Purkinje fibers (myocytes)*:

distribute the electrical impulse conduction throughout the ventricles where 'conducting' Purkinje cells communicate via gap junctions with 'contractile' *myocardial myocytes*.

1. *Heart*

double muscular pump, right side (right atrium and right ventricle) receives blood from the body and pumps it to the lungs; left side (left atrium and left ventricle) receives oxygenated blood from lungs and pumps it to the rest of the body. a. Systole b. Diastole

5. *Capillaries ('exchange vessels')* continued 3:

e. Function to deliver blood-borne materials (nutrients, gases, hormones, etc.) to tissues and removal of waste products. 1) Selective permeability barrier for large (polypeptides, lipids) and small (H2O, CO2, electrolytes) molecule transport. 2) Metabolic activity (converts angiotensin I to II; degradation of bradykinin, prostaglandins, norepinephrine, thrombin, lipoproteins, and cholesterol). 3. Tremendous surface area in plexuses just below epidermis for cooling of blood by 'radiator effect'.

a. *Longitudinal* collagen (type I) and...

elastic fibers; fibroblasts; some smooth muscle cells forming longitudinal bundles in large veins, such as the vena cava.

5. *Capillaries ('exchange vessels')* continued 4:

f. *Portal system* is *two separate capillary beds connected serially by an artery or vein* allowing transport of materials from the first to second bed before dilution of the materials into systemic circulation: intestine to hepatic (portal vein); hypothalamic-hypophyseal vein to pituitary; renal glomerulus (efferent arterioles) to renal cortex or medulla.

FUNCTION TABLE

heart - *adaptive flow* -->-->--> arteries - *adaptive distribution & pressure* -->--> capillaries - *diffusion - filtration - exchange* <--|--> veins (& lymphatics) - *collection* <--<--

*Sympathetic neurotransmitter* (norepinephrine) release...

increases myocyte [Ca2+] thus increasing contraction rate & force. Molecules (catecholamines, T3/T4, caffeine) that increase myocyte cytoplasmic 'free' [Ca2+] increase rate and force. These molecules also dilate the coronary arteries supplying the heart.

1. Tunica intima

innermost layer, next to lumen (~*endocardium* in heart) a. *Endothelium*: simple squamous lining cells joined by zonula occludens junctions in most cases; variably, *selective permeability* barrier, often fenestrated; flattened nucleus easily visible - longitudinally oriented.

Which side of the heart is the systemic circuit located?

left side of heart that goes throughout the body

c. External elastic lamina:

less distinct than internal elastic lamina

b. *Semilunar* valves

limit back-flow from pulmonary artery and aorta back into ventricles. *Thinner than AV valves*, lacking smooth muscle, blood vessels, and lymphatics.

spongiosa

loose CT

2. Tunica media:

middle layer, muscular layer (~*myocardium* of the heart) a. Smooth muscle cells b. Reticular fibers c. External elastic lamina

3. Tunica adventitia:

outermost layer (~*epicardium* in heart), blends into CT surrounding vessels a. *Longitudinal* collagen... b. Generally...

Which side of the heart is the pulmonary circuit located?

right side of heart that goes to the lungs

The CNS-mediated influence is in response to...

sensory feedback on BP (baroreceptors - carotid/aortic bodies), blood volume (atria myocytes), and oxygen concentration (pO2: chemoreceptors - carotid/aortic bodies).

*Atrial myocytes* are...

smaller, contain *atrial natriuretic factor* (peptide), have fewer T-tubules, have more gap junctions, and have a faster conduction rate than ventricular myocytes. Ventricular myocardium has less elastic tissue than atrial myocardium. When stretched, atrial myocytes secrete ANF (exocytosis) leading to *decrease blood volume and pressure by stimulating excretion of urine (diuresis) and sodium (natriuresis)* by inhibiting secretion of renin (kidney) and aldosterone (adrenal cortex).

a. *Smooth muscle cells* (cardiac myocytes in heart):

spirally arranged, perpendicular to long axis of vessel in concentric layers; *secrete ECM*; variable vasoconstriction (--> vascular resistance) & vasodilation control blood arterial flow - *gap junctions* b/w cells.

*Nervi vasorum/vascularis*:

sympathetic unmyelinated nerve fibers (neurotransmitter norepinephrine via diffusion) do 'not' extend into the tunica media; gap junctions.

b. Generally...

thickest layer of venules and veins. *Vasa vasorum* and *Nervi vasorum/vascularis*

Vascular and blood effects of: *endothelins*

vasoconstrictor; endothelial mitosis

Vascular and blood effects of: *prostacyclin (PGI2)*

vasodilator (EDRF); anti-thrombogenic

Vascular and blood effects of: *nitric oxide (NO)*

vasodilator (EDRF); inflammation