Cardiovascular Microanatomy

Microanatomy of heart

• Three layers of ventricular wall:
- Epicardium: consisting of the outer mesothelium (visceral pericardium) and epicardial connective tissue with collagen (pink), fat (beneath the collagen), sympathetic nerves (dark fibers of axon), blood vessels and lymphatics.
- Myocardium: cardiac muscles with blood vessels and fine connective tissues
- Endocardium: lined with endothelium facing the blood, and beneath is endocardial connective tissue consisting of elastin, collagen and smooth muscles fibers. Conducting system of the heart exists in this layer
• Mitral valve:
- Made from dense irregular connective tissue and is covered by flattened endothelium on its atrial and ventricular surfaces
- Leaflet itself is avascular and receives oxygen through diffusion. Benefit in heart valves transplantation is that it is less rejected due to immune response.
• Fibrous annulus: dense irregular connective tissues forming a ring around the margin of the valve. It separates the cardiac muscles of the atrium from the ventricle.
• Chordae tendineae: collagen fibers that are continue with the endomysium of the papillary muscles.
• Sino-atrial node: located in the RA wall at the junction of SVC with RA.
- Located within the myocardium just below the transition of tunica media of SVC
- Distinguishing feature is the tangle of brown muscular fibers within a dense network of collagen and elastin. Clear black nucleus can also be seen.
- Nodal artery supplies this
• Purkinje fibres:
- 4 to 5 times the width of normal myocytes with empty nucleus. Myofibrils are scattered along the outside
- These are located in the subendocardial layer
- The papillary muscles are first supplied by these fibres to contract and tighten the tendinous cords before systole.
• Aortic valve:
- Layer of elastin exist on the ventricular side to store elastic tension during ejection and shut rapidly with backflow.
- Valve is avascular

Cardiac Muscles

• Structures of heart:
- Fibroblasts
- Nerve
- Smooth muscles around coronary vessels
- Myocytes: accounts for largest volume of heart muscles around 20 µm thick and 100 µm long. Striated in appearance and connected via gap junctions.
• Important cellular structure:
- Sarcolemma: a permeable cell membrane that contains ion channels, pumps, and transporters vital to cardiac function. Outer surface of SL contains a layer of acidic mucopolysaccharides called glycocalyx (divided into surface coat and external lamina) which is rich in sialic acid residues.
- T-tubules: invaginations of sarcolemma rich in Ca2+ channels (making up 21-33% of SL).
- Contractile protein: makes up 50% of myocytes and locater close to T-tubules for rapid response to calcium release. Nebulin, located in I band, binds to actin and regulate thin filament length during sarcomere assembly and growth.
- Caveolae: small invaginations of SL that holds scaffolding proteins caveolin-3 and signalling molecules such as nitric oxide synthase and protein kinase C.
- Intercalated discs: regions of cellular connection through gap junctions, intermediate junction and desmosomes
- Sarcoplasmic reticulum: intracellular membrane-bounded compartment for Ca2+. It is coupled to the T-tubules (region contains abundant RyR or Ca2+ release channels) and external SL. SR Ca2+-ATPase (SERCA) is responsible for re-uptake of Ca2+ into the SR (regulated by phospholamdan).
- Mitochondria: aerobic respiration organelles to fulfil the energy demand of the working heart. Scattered ubiquitously.
- Nucleus: mononucleated for cardiomyocyte with some binucleated.
- Other: golgi apparatus, lysosomes, lipid droplets, beta-glycogen granules, well developed cytoskeleton with micro-tubule/filaments.
• Phospholamban: protein that when dephosphorylated, interacts with SERCA and decreases its activity thus less Ca2+ uptake into SR. Main function is to increase heart rate by pumping Ca2+ out (repolarizing)
- Phospholamban is phosphorylated by protein kinase A. During beta-adrenergic stimulation, there is an increased level of PKA, thus causing increase Ca2+ uptake in SR and thus more Ca2+ is available for release to increase contractility of the heart
• Calciquestrin: molecules in the SR that buffer Ca2+ (30-40 ions per molecule)
• Structural differences to skeletal muscles:
- Longer T-tubules
- More SR
- Mainly oxidative
- Smaller cells and electrically connected
• Important extracellular component:
- Around 60% vascular and 23% ground substance similar to glycocalyx (the rest are connective tissue)
• Cardiac action potential: the changing membrane potential in which electrical stimulation is transmitted to cause contraction of muscles.
- The properties of action potentials are different depending on the cardiac tissue, i.e. nature and number of ion channels and transporters, cell characteristics and electrical connection.
- SA node and AV nodes: action potential is slow in depolarization and repolarization
- Atrial, purkinje fibres, ventricular muscles: rapid depolarization and slow repolarisation (plateau periodically)
• Determinant of membrane potential:
where g represents conductance and E is equilibrium potential
At rest: is much greater than so Vm is close to that of which is -90mV
At threshold: is much greater than so Vm is close to that of which is +40mV
• SA node action potential: the fastest rate of depolarization hence becomes the pacemaker of the heart. Rate of depolarization is slow but constant and controlled by the Ca2+ channel of the cells (Na+ inactivated)
- Sympathetic effect: noradrenaline increases the slope of pacemaker potential (i.e. faster depolarization to threshold)
- Parasympathetic effect: acetylcholine decreases the slope of pacemaker potential (by increase of potassium conductance) and hyperpolarisation of resting membrane potential (more negative).
• AV node action potential: similar to that of SA AP and propagation is slowed down
• Atrial ventricular action potential: depolarize from -80mV to 35-50mV as a result of Na+ current. Repolarization of atrial cells is faster than other cardiomyocytes to prepare for next AP.
- Ventricular feature: action potentials have a long plateau (i.e. remain depolarized) which prevents electric re-excitation and allows contraction to relax before next beat (no tetany unlike skeletal muscles). Its duration is 200ms.
• Ion fluxes at each phase:
- Phase 0: depolarization with Na+ ion influx (iNa)
- Phase 1: early repolarization with K+ efflux (ito)
- Phase 2: plateau with Ca2+ ion influx (iCa) through DHPR to balance K+ efflux
- Phase 3: final repolarization with efflux of K+ from three currents, ito, iK¬, iK1
- Phase 4: efflux of K+ (iki) to maintain hyperpolarized membrane potential (Na/K ATPase stabilize) but slow depolarization occurs with if Na+ influx.
• Delayed rectifier: the ik potassium channels which delay their opening upon stimulation during depolarization phase. Factors that can affect the time-course of delay include catecholamine, noradrenaline and adrenaline that collectively reduce the delay (i.e. faster heart rate require faster repolarization)
• Excitation-contraction coupling: calcium induced calcium release plays a major role in contraction. DHPR are functional voltage gated Ca2+ channels and depolarization causes the channels to open and influx of Ca2+ (ICa triggers Ca2+ release from the SR when bound to RyR). Bigger trigger leads to bigger response
- Calcium sparks: spontaneous local increase in calcium levels. Amplitude and number of calcium spark determines the calcium transient.
- Repolarization: during repolarization, Ca2+ is extruded with most taken up by the SR. RyR are closed and Ca2+ unbinds from troponin and cystolic Ca2+ goes to normal
- Membrane potential maintained with Na/K ATPase
• Role of DHPR: these are stimulated by catecholamine and inhibited by dihydropyridine (also Mg2+)
- Contribute to AP plateau
- Triggers E-C coupling
- Inhibited by SR release
• Sources of calcium:
- Extracellular: voltage-dependent L-type Ca+ channels and passive leakage channels in the sarcolemma
- Intracellular: SR release through CICR and mitochondria (dominant source)
• Mechanism of calcium removal: multiple independent methods to allow controlled regulation.
- Stores of calcium: Ca2+is either extruded across the sarcolemma or uptake into the SR
- Calcium pumps in the sarcolemma that pumps out 1 Ca2+ for 1 ATP. It is activated by cGMP which is derived from guanylate cylase under cholinergic stimulation.
- Na+/Ca+ exchanger that exchange 3Na+ for 1 Ca2+. The exchange is ATP-independent and is driven by the low intracellular Na+ concentration, and negative membrane potential (during relaxation-forward mode). This exchanger however can work in both directions depending on membrane potential. After depolarization (-40mV), Ca2+ enters but in later AP phases, Na+ enters to promote Ca2+ exit
- SL Ca2+-ATPase extrudes Ca2+ out of cell
- Mitochondrial uniporter transports Ca2+ into mitochondria
• Balance of extrusion and entrance: in steady state, Ca2+ extrusion is equal to influx. When imbalance occurs Ca2+ will accumulate inside cell leading to:
- Higher SR Ca2+ content
- Increased Ca2+ extrusion to balance
• Contraction of heart:
- Isometric contraction: isovolumic ventricular contraction (build up pressure)
- Isotonic contraction: ventricular ejection (volume reduce)
- All muscle fibres are activated so can’t recruit fibres to regulate force
• Starling’s Law of the Heart: an increase in end-diastolic volume will cause an increased stroke volume via stretch-induced calcium contractility.
- However when a certain diastolic volume is reached that beyond the heart’s capacity to eject, stroke volume decreases.
- Stretch channels increase calcium transient from Ca2+ influx and overload
• Force-frequency relationship: increase in frequency of heart beat will mean faster depolarization. As an result there is less time for Ca2+extrusion and Ca2+ levels accumulates in the myoplasms causing stronger contraction force.
- Failing heart muscles: the relationship changes in failing myocytes. Contractility decreases with increased heart beat.
• Force-length relationship: active tension relationship is steeper in cardiac muscles compared to skeletal muscles and passive tension starts at shorter sarcomere lengths. Optimum range is between 2 -2.2 µm.
• Modulators of heart pump:
- Inotropic: strength of contraction, altering amplitude and duration of Ca2+ or myofilament Ca2+ sensitivity
- Lusitropic: relaxation
- Chonotropic: rate of beating
- The above properties are all under the control by sympathetic stimulation via beta-adrenergic receptors activation.
- Alter dimensions of the heart
• Myofilament Ca2+ sensitivity:
- Acidosis (decrease)
- Sarcomere length
- Catecholamines
- ATP (decrease)
- Caffeine (increase)
- Inorganic phosphate (decrease)
• Effect of Beta-Adrenergic stimulation: agonists bind to receptors and stimulate adenylyl cyclase and increase cAMP level which will activate cAMP-dependent protein kinase. These proceed to phosphorylate key proteins and confer an effect:
- Decrease myofilament Ca2+ sensitivity due to troponin I phosphorylation (calcium transient compensate)
- Increase ICa
- Enhance SR Ca2+ ATPase rate by phosphorylation of phospholamban
- Increased SA node discharge rate
- SR Ca2+ release channels (modifying RyR gating)
• Modulation of force by drugs:
- Digoxin, a cardiotonic steroids, works by inhibiting Na+/K+ pump and so calcium extrusion (increase Na+ inside).
- Sympathomimetics act via beta-1 receptors
- Bypyridine act via phosphodiesterase and increase cAMP
• Cardiac failure: increased ventricular dimensions which decrease efficiency. Increased radius of heart increases the tension to generate same force. Vicious cycle, increased wall tension requires increased pressure to overcome the afterload.
- Therapies are aimed to decrease cardiac dimensions by decrease filling pressure. Examples include: NO to relax vasculature, diuretics to decrease blood volume, ACE inhibitor to depress angiotensin axis

Structure of Blood Vessels I

• Components of the cardiovascular system:
- Left ventricle: pump (95mmHg) with thick muscular walls, inlet and outlet valves
- Large arteries: elastic to conduct blood away from pump
- Medium sized arteries: muscular to distribute blood (95-85mmHg) with the ability to control lumen diameter and connective for strength
- Arterioles: control distribution of blood for capillaries (85-35mmHg) with smooth muscle to control diameter and little connective tissue. Here the blood pressure drop the greatest
- Capillaries: exchange nutrient and gas (35-15 mmHg) with endothelium and no muscle and CT
- Venules: collection of blood (15-0mmHg) with thin walls but large diameter
- Veins: conducting of blood and large reservoir (low) with thin walled, variable structure, and valves to assist return
- Right atrium: reservoir and pre-pump (0-2mmHg) with thin muscular wall
• Elastic arteries: conducting arteries such as the aorta and pulmonary arteries just downstream of the ventricles. The function is storing blood during systole and then recoil during diastole to propel blood forward into the arterial tree.
- Intima: thicker than muscular arteries and contains longitudinal elastin fibres in subendothelial connective tissue. IEL is present by indistinguishable.
- Media: comprised of many layers of fenestrated elastic lamellar units (50-60 in aorta). Each unit is made up of elastic lamina, smooth muscle and collagens fibres running in circular around the vessel.
- Adventitia: collagen and elastic fibers with small blood vessels called vasa vasorum (supply¬ O2 and glucose to 2/3 of outer wall) and autonomic nerves.
• Muscular arteries:
- Intima: innermost coat consisting of a single layer of endothelium, basement membrane, subendothelial CT and smooth distinctive IEL (wrinkled after death).
- Media: the middle thickest coat with smooth muscles to control the diameters and elastin fibers to give resiliency and collagen fibers to limit expansion and prevent rupture. The outer margin includes EEL which is not as prominent as IEL.
- Adventitia: outermost coat with collagen and elastin fibers and vasa vasorum. Sympathetic nerve also present to cause tonic contraction by rapid and slow discharges (no parasympathetic)
• Arterial disease:
- Atherosclerosis: macrophages become foam cells and smooth muscle cell transform into synthetic fibres and produce fibrous cap to stop blood from contacting the lipid. The wall also becomes weak and may rupture under high pressure leading to haemorrhage
- Berry aneurysm: localized weakness of the wall allowing ballooning. Occurs at branch points and asymptomatic
- Dissecting aneurysm: blood cut through different layers of the arterial wall as it is the lowest resistance.
- Hypertension: increase in blood pressure causes splitting of internal lamina and thickening of the media and intima. This is a disease of small muscular arteries and arterioles.
• Arterioles: smallest muscular arteries. IEL is present in larger arterioles but not small ones.
- Overall diameter of 100 µms or less
- Three or fewer layers of smooth muscle in the media
- Wall thickness about equal to diameter of lumen
- No subendothelial layer and spiral arrangement of the muscle fibres
• Vessel resistance against atherosclerosis: lumen size is maintained as vessel enlarges to compensate hence there is no immediate effect of obstruction. As a result 40% of coronary artery lumen lost will still not cause symptoms.

Structure of Blood Vessels II

• Microcirculation: labyrinth of small arterioles, capillary beds and post capillary venule that supply the tissues
- Capillaries are unable to adjust their diameter; distribution of blood is controlled upstream by arterioles, terminal arterioles, metarterioles, sphincter.
- Terminal arterioles: the ending part of the arterioles with a single layer of smooth muscle and gives off metarterioles
- Metarterioles: vessels with an incomplete layer smooth muscle running from terminal arteriole to post-capillary venule. This is the arteriole that directly feeds into the capillary and contains a precapillary sphincter just at the branching points for final control of blood flow.
• Thoroughfare channel: terminal parts of metarteriole in which blood bypass the capillary bed directly to the venules when the precapillary sphincters is close or capillary is blocked (e.g. cold temperature cause constriction of skin capillaries)
• Arterovenous anastomoses: when arterioles directly lead to venules without any capillaries branches. When their smooth muscle is contracted, blood is forced into metarterioles nearby and supply he capillary beds.
• Capillaries: small vessel with internal diameter of 8-10 µm and a wall comprised of endothelium with basal lamina and no CT or muscle.
- Continuous capillaries with closed intercellular cleft: located in CNS forming the blood brain barrier. Tight junction is a complete seal where cells meet each other. Feet of astrocytes contact the basement membrane for support (damage to astrocytes will cause blood leakage)
- Continuous capillaries with open intercellular cleft: found in muscles, CT and lung. Clefts are 6nm and allow passage of water, ion and other small molecules but not plasma proteins.
- Fenestrated capillaries with closed perforations: 60nm fenestrae closed by a thin non-membranous diaphragm and have fine fibrous basement membrane. These are located in the intestines and allow water and small molecules but not plasma protein to pass through.
- Fenestrated capillaries with open perforations: no diaphragm and found in endocrine glands and kidney glomeuli with open fenestrae. Main function is fluid exchange.
- Sinusoids: wide bore capillaries with 100-1000nm gaps between endothelial cells for passage of large molecules and whole cells. This occur in bone marrow, spleen (red blood cells leave the bloodstream), liver (endothelial cells are interspersed with phagocytic Kupffer cells). Wide lumen of sinusoids causes blood to flow very slowly.
• Venules: run parallel to arterioles
- Postcapillary venules: vessels 10-25 µm in diameter and lack smooth muscles. These drain capillary beds and during inflammation and allergy, venules increase leakage of blood plasma causing oedema and migration of neutrophils, monocytes and lymphocytes through vessel wall.
- Muscular venule: larger venules with up to two layers of smooth muscle in the media. Characterized by thin walls in relation to diameter and endothelial nuclei that bulge into the lumen.
• Veins: vein conduct blood at low pressure so thin-walled and large diameter. Differences to arteries:
- All three layers are reduced in thickness especially media
- Absence of a well-developed IEL
- After death and loss of BP, veins collapse
- Bicuspid valves present made from folds of the intima to prevent backflow of blood
• Pressure variation:
- Standing adults: blood in leg veins leaks slowly through closed venous valves and form long columns of increasing pressure downwards. Venous pressure at feet is around 100mmHg hence leg veins have muscular walls
- Walking adults: venous valves break the column into segments and each segment experience only the gravitation pressure of its height. Skeletal muscle compresses the veins so pumps the blood to the right heart.
• Disease of the veins:
- Venous thrombosis: formation of blood clot in the deep veins of lower leg usually. Causes include slow blood flow (economy class syndrome), increase coagulability, or damage endothelium can lead to thrombosis. 1/3 of patient above 40 that have undergone surgery or suffered MI develop thrombosis. Emboli can pass through right heart and lodge in pulmonary arterial tree and can be fatal.
- Varicose vein: superficial vein of the legs becomes dilated sufficiently that the venous valve cusps do not meet. The valves become incompetent and veins become swollen and tortuous.
• Lymphatic capillaries: blind-ending endothelial tubes that drains the interstitial fluid. Difference to blood capillaries:
- Endothelial cells are tethered by surrounded CT by anchoring filament. Anchoring filament pulls on the endothelial cells to open the lumen of lymphatic capillary when swollen to increase effective drainage
- Lymphatic endothelial lack basement membrane so increased permeability
- Incomplete right junctions (large intercellular cleft) so proteins and whole cells can enter the vessels.
• Larger lymphatic vessel: collecting vessels that resembled vein but with thinner walls and great number of valves. Valves prevent backflow and lymph is propelled by any mechanism that compress the lymph:
- Contraction of smooth muscles around the vessel in response to stretching
- Compression of muscles (movement and breathing etc)
• Importance of lymph vessel: present in all tissues except, bone, nervous system, thymus, cornea and teeth. The lymphatic vessels enter lymph nodes in which metastatic cancer commonly lodges and establish.

Microanatomy of Blood Vessels

• Features of vein:
- Distinct layering in the media of veins, brown, pink (collagen) and black (elastin).

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