Heart Circulation

Coronary circulation is the circulation of blood in the blood vessels of the heart.

Coronary circulation is the circulation of blood in the blood vessels of the heart muscle. The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries. The vessels that remove the deoxygenated blood from the heart muscle are known as cardiac veins. The blood supply to the heart is greater than that of other body tissues since the heart has a constant metabolic demand that must be satisfied to keep the heart pumping at all times.

Coronary Artery Structure

The coronary arteries originate from the left side of the heart descending from the aorta. There are multiple coronary arteries derived from the larger right and left coronary arteries. For example, important coronary arteries that branch off from the larger arteries include the left anterior descending (LAD) coronary and the right posterior coronary.

Coronary arteries run both along the surface of the heart and deep within the myocardium, which has the greatest metabolic demands of all the heart tissues due to its muscle content. Epicardial coronary arteries, which run along on the surface of the heart, are capable of autoregulating vasodilation and vasoconstriction to maintain coronary blood flow at appropriate levels to fit the metabolic demands of the heart muscle. These vessels are relatively narrow and thus vulnerable to blockage, which may cause a myocardial infarction. Subendocardial coronary arteries run deep within the myocardium to provide oxygen throughout the muscle tissue of the cardiac wall.

Systole and Diastole

In systole, the ventricular myocardium contracts, generating high intraventricular pressure and compressing the subendocardial coronary vessels while allowing the epicardial coronary vessels to remain fully open. With the subendocardial coronary vessels compressed, blood flow essentially stops below the surface of the myocardium.

In diastole, the ventricular myocardium contracts, lowering the intraventricular pressure and allowing the subendocardial vessels to become open again. Due to the high pressures generated in the ventricular myocardium during systole, most myocardial tissue perfusion occurs during diastole. Additionally, catecholamines such as norepinephrine, which normally cause vasoconstriction will instead cause vasodilation within the coronary arteries. This mechanism is due to beta-adrenergic receptors in the coronary arteries and helps enable the increased cardiac output associated with fight-or-flight responses.

Myocardial Infarctions

A myocardial infarction (heart attack) may be caused by prolonged ischemia (oxygen deprivation) in the heart, which occurs due to blockage of any of the coronary arteries. Since there is very little unnecessary blood supply to the myocardium, blockage of these vessels can cause serious damage. When these vessels become blocked, the myocardium becomes oxygen-deprived, a condition called ischemia. Brief periods of ischemia in the heart are associated with intense chest pain called angina, which may either be transient if the clot breaks up on its own or stable if it does not. As the time period of ischemia increases, the hypoxic conditions cause muscle tissue to die, causing myocardial infarction (heart attack).

Myocardial infarction is one of the most common causes of death worldwide. The clots that cause the infarction are usually the result of ruptured atherosclerotic plaques that break off and occlude the coronary arteries, but arterial thrombosis from injury or pooled blood may also cause a heart attack. The tissues of the heart do not regenerate, so those that survive a myocardial infarction will generally have scar tissue in their myocardium and may be more susceptible to other heart problems in the future.

Operation of Atrioventricular Valves

The atrioventricular valves separate the atria from the ventricles and prevent backflow from the ventricles into the atria during systole.

A heart valve allows blood flow in only one direction through the heart, and the combination of the atrioventricular and semi-lunar heart valves determines the pathway of blood flow. Valves open or close based on pressure differences across the valve. The atrioventricular (AV) valves separate the atria from the ventricles on each side of the heart and prevent the backflow of blood from the ventricles into the atria during systole.

Subvalvular Apparatus

The subvalvular apparatus describes the structures beneath the AV valves that prevent the valves from prolapsing. Valve prolapse means that the valves do not close properly, which may cause regurgitation or backflow of blood from the ventricle back into the atria, which is inefficient. The subvalvular apparatus includes the chordae tendineae and the papillary muscles. The AV valves are anchored to the wall of the ventricle by chordae tendineae (heartstrings), small tendons that prevent backflow by stopping the valve leaflets from inverting. The chordae tendineae are inelastic and attached at one end to the papillary muscles and at the other end to the valve cusps.

Papillary muscles are finger-like projections from the wall of the ventricle that anchor the chordae tendineae. This connection provides tension to hold the valves in place and prevent them from prolapsing into the atria when they close, preventing the risk of regurgitation. The subvalvular apparatus has no effect on the opening and closing of the valves, which is caused entirely by the pressure gradient of blood across the valve as blood flows from high pressure to low pressure areas.

The Mitral Valve

The mitral valve is on the left side of the heart and allows the blood to flow from the left atrium into the left ventricle. It is also known as the bicuspid valve because it contains two leaflets (cusps). The relaxation of the ventricular myocardium and the contraction of the atrial myocardium causes a pressure gradient that allows for rapid blood flow from the left atrium into the left ventricle across the mitral valve. Atrial systole (contraction) increases the pressure in the atria, while ventricular diastole (relaxation) decreases the pressure in the ventricle, causing the pressure-induced flow of blood across the valve. The mitral annulus, a ring around the mitral valve, changes in shape and size during the cardiac cycle to prevent backflow. The ring contracts at the end of the atrial systole due to the contraction of the left atrium around it, which aids in bringing the leaflets together to provide firm closure during ventricular systole.

The Tricuspid Valve

The tricuspid valve is the three-leaflet valve on the right side of the heart between the right atrium and the right ventricle and stops the backflow of blood between the two. The tricuspid valve functions similarly to the bicuspid valve except that three chordae tendineae connect the cusps of the valve to three papillary muscles, rather than the pair that connects the bicuspid valve. Blood passes through the tricuspid valve the same as it does through the bicuspid valve, based on a pressure gradient from high pressure to low pressure during systole and diastole.

The reason that the valves have different numbers of leaflets is not fully understood but may arise from differences in tissue structure and pressure that occur during fetal development.

Operation of Semilunar Valves

The semilunar valves allow blood to be pumped into the major arteries while preventing the backflow of blood from the arteries into the ventricles.

The semilunar valves are located at the connections between the pulmonary artery and the right ventricle, and the aorta and the left ventricle. These valves allow blood to be pumped forward into the arteries but prevent the backflow of blood from the arteries into the ventricles. These valves do not have subvalvular apparatus and are more similar to the semilunar valves in veins and lymphatic vessels than to atrioventricular (AV) valves.

The semilunar valves act in concert with the AV valves to direct blood flow through the heart. When the atrioventricular valves are open, the semilunar valves are shut and blood is forced into the ventricles. When the AV valves shut, the semilunar valves open, forcing blood into the aorta and pulmonary artery. The mechanism for this process depends on blood pressure gradients in the heart, which provide the force that pushes blood through the semilunar valves.

The Aortic Valve

The aortic valve separates the left ventricle from the aorta and has three cusps. During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle exceeds the pressure in the aorta, the aortic valve opens and blood flows from the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle drops rapidly, and the valve closes due to a lack of pressure imposed on them from the left ventricle. Blood pressure within the aorta following systole also causes the closing of the valve. The closing of the aortic valve produces a sound that is a component of the second heart sound.

The Pulmonary Valve

The pulmonary valve (also called the pulmonic valve), which also has three cusps, separates the right ventricle from the pulmonary artery. Similar to the aortic valve, the pulmonary valve opens in ventricular systole when the pressure in the right ventricle exceeds the pressure in the pulmonary artery. When ventricular systole ends, pressure in the right ventricle drops rapidly, and the pressure in the pulmonary artery forces the pulmonary valve to close. The closure of the pulmonary valve also produces a sound, however, it is softer than the aortic sound because the blood pressure in the right side of the heart is lower compared to the left side, due to the differences between pulmonary and systemic circulation.

Valve Problems

Valves are vulnerable to several conditions that impair their normal functions. Two of the most common problems with the semilunar valves are stenosis and regurgitation.  Valve stenosis refers to a narrowing of the valves, which prevents the valve from opening fully, causing an obstruction of blood flow. Valve stenosis is often caused by calcium buildup and scarring from rheumatic fever and may cause cardiac hypertrophy and heart failure. Valve regurgitation is backflow through the valves that occurs when they cannot close completely. It is the cause of most heart murmurs and is generally a minor problem, but if severe enough, it can cause heart failure. Stenosis and regurgitation can occur in both the semilunar and atrioventricular valves.

Systemic and Pulmonary Circulation

The cardiovascular system has two distinct circulatory paths, pulmonary circulation and systemic circulation.

The cardiovascular system is composed of two circulatory paths: pulmonary circulation, the circuit through the lungs where blood is oxygenated; and systemic circulation, the circuit through the rest of the body to provide oxygenated blood. The two circuits are linked to each other through the heart, creating a continuous cycle of blood through the body.

Pulmonary Circulation

Pulmonary circulation is the movement of blood from the heart to the lungs for oxygenation, then back to the heart again. Oxygen-depleted blood from the body leaves the systemic circulation when it enters the right atrium through the superior and inferior venae cavae. The blood is then pumped through the tricuspid valve into the right ventricle. From the right ventricle, blood is pumped through the pulmonary valve and into the pulmonary artery. The pulmonary artery splits into the right and left pulmonary arteries and travel to each lung.

At the lungs, the blood travels through capillary beds on the alveoli where gas exchange occurs, removing carbon dioxide and adding oxygen to the blood. Gas exchange occurs due to gas partial pressure gradients across the alveoli of the lungs and the capillaries interwoven in the alveoli. The oxygenated blood then leaves the lungs through pulmonary veins, which return it to the left atrium, completing the pulmonary circuit. As the pulmonary circuit ends, the systemic circuit begins.

Systemic Circulation

Systemic circulation is the movement of blood from the heart through the body to provide oxygen and nutrients to the tissues of the body while bringing deoxygenated blood back to the heart. Oxygenated blood enters the left atrium from the pulmonary veins. The blood is then pumped through the mitral valve into the left ventricle. From the left ventricle, blood is pumped through the aortic valve and into the aorta, the body’s largest artery. The aorta arches and branches into major arteries to the upper body before passing through the diaphragm, where it branches further into the iliac, renal, and suprarenal arteries which supply the lower parts of the body.

The arteries branch into smaller arteries, arterioles, and finally capillaries. Gas and nutrient exchange with the tissues occurs within the capillaries that run through the tissues. Metabolic waste and carbon dioxide diffuse out of the cell into the blood, while oxygen and glucose in the blood diffuse out of the blood and into the cell. Systemic circulation keeps the metabolism of every organ and every tissue in the body alive, with the exception of the parenchyma of the lungs, which are supplied by pulmonary circulation.

The deoxygenated blood continues through the capillaries which merge into venules, then veins, and finally the venae cavae, which drain into the right atrium of the heart. From the right atrium, the blood will travel through the pulmonary circulation to be oxygenated before returning gain to the system circulation, completing the cycle of circulation through the body. The arterial component of systemic circulation the highest blood pressure in the body. The venous component of systemic circulation has considerably lower blood pressure in comparison, due to their distance from the heart, but contains semi-lunar valves to compensate. Systemic circulation as a whole is a higher pressure system than pulmonary circulation simply because systemic circulation must force greater volumes of blood farther through the body compared to pulmonary circulation.

The nervous system regulates the cardiovascular system with the help of baroreceptors and chemoreceptors. Both receptors are located in the carotids and aortic arch. Also, both have afferent signals through the vagus nerve from the aortic arch and afferent signals through the glossopharyngeal nerve from the carotids.

• Baroreceptors are more specifically located in the carotid sinus and aortic arch. They respond quickly to changes in blood pressure.
• A decrease in blood pressure or blood volume causes hypotension, which leads to a decrease in arterial pressure, which creates a decrease in the stretch of the baroreceptors and decreases afferent baroreceptor signaling. This decrease in afferent signaling from the baroreceptor causes an increase in efferent sympathetic activity and a reduction in parasympathetic activity, which leads to vasoconstriction, increase heart rate, increase contractility, and an increase in BP. The vasoconstriction increases TPR in the equation MAP=CO*TPR to bring pressure (MAP) back up.
• An increase in blood pressure or blood volume causes hypertension which increases the stretch of the baroreceptors
• Chemoreceptors come in 2 types: peripheral and central. Peripheral chemoreceptors are specifically located in the carotid body and aortic arch. They respond to oxygen levels, carbon dioxide levels, and pH of the blood. They become stimulated when oxygen decreases, carbon dioxide increases, and the pH decreases. Central chemoreceptors are located in the medulla oblongata and measure the pH and carbon dioxide changes of the cerebral spinal fluid.

Autoregulation

Autoregulation is the method by which an organ or tissue maintains blood flow despite a change in perfusion pressure. When blood flow becomes decreased to an organ, arterioles dilate to reduce resistance.

• Myogenic theory: Myogenic regulation is intrinsic to the vascular smooth muscle. When there is an increase in perfusion, the vascular smooth muscle stretches, causing it to constrict the artery. If there is a decrease in pressure to the arteriole, then there is decreased stretching of the smooth muscle, which would lead to the relaxation of the smooth muscles and dilation of the arteriole.
• Metabolic theory: Blood flow is closely related to metabolic activity. When there is an increase in metabolism to muscle or any tissue, there is an increase in blood flow to that location. Metabolic activity creates substances that are vasoactive and stimulate vasodilation. The increase or decrease in metabolism leads to an increase or decrease in metabolic byproducts that cause vasodilation. Increased adenosine, carbon dioxide, potassium, hydrogen ion, lactic acid levels, and decreased oxygen levels, and increased oxygen demand all lead to vasodilation. Adenosine is from AMP, which derives from the hydrolysis of ATP and increases during hypoxia or increased oxygen consumption. Potassium is increased extracellularly during metabolic activity (muscle contraction) and has a direct effect on relaxing smooth muscles. Carbon dioxide is produced as a byproduct of the oxidative pathway and increases with metabolic activity. Carbon dioxide diffuses to vascular smooth muscle and triggers an intracellular pathway to relax the vascular smooth muscle.
• Heart: Metabolites that cause coronary vasodilation include adenosine, NO, carbon dioxide, and low oxygen.
• Brain: The primary metabolite controlling cerebral blood flow is carbon dioxide. An increase in arterial carbon dioxide causes vasodilation of cerebral vasculature. A decrease in arterial carbon dioxide causes vasoconstriction of the cerebral vasculature. Hydrogen ions do not cross the blood-brain barrier and thus are not a factor in regulating cerebral blood flow. A decrease in oxygen pressure in arteries causes vasodilation of the cerebral arteries; however, an increase in oxygen pressure in arteries does not cause vasoconstriction.
• Kidneys: Autoregulation of the kidneys is myogenic and with tubuloglomerular feedback. In severe cases of hypotension, kidney arterioles constrict, and renal function is lost.
• Lungs: Hypoxia of the lungs causes vasoconstriction, creating a shunt away from poorly ventilated areas of the lung and redirects perfusion to ventilated portions of the lung.
• Skeletal muscle: Adenosine, potassium, hydrogen ion, lactate, and carbon dioxide all increase during exercise and cause vasodilation. When resting, the skeletal muscle is controlled extrinsically by sympathetic activity and not by metabolites.
• Skin: Regulation of the skin occurs through sympathetic stimulation. The purpose of regulating blood flow in the skin is to regulate body temperature. In a warm environment, skin vasculature dilates due to a decrease in sympathetic stimulation. In cold environments, skin vasculature constricts due to an increase in sympathetic activity. During fever, the regulation of the body temperature is at a higher setpoint.

The starling equation can explain the capillary fluid exchange. This equation describes the forces of oncotic and hydrostatic pressure on the movement of fluid across the capillary membrane. Edema can result from an increase in capillary pressure (heart failure), a decrease in plasma proteins (liver failure), an increase in the interstitial fluid due to lymphatic blockage, or an increase in capillary permeability due to infections or burns.

Microscopic Anatomy

Cardiac muscle appears striated due to the presence of sarcomeres, the highly organized basic functional unit of muscle tissue.

Cardiac muscle, like skeletal muscle, appears striated due to the organization of muscle tissue into sarcomeres. While similar to skeletal muscle, cardiac muscle is different in a few ways. Cardiac muscles are composed of tubular cardiomyocytes or cardiac muscle cells. The cardiomyocytes are composed of tubular myofibrils, which are repeating sections of sarcomeres. Intercalated disks transmit electrical action potentials between sarcomeres.

Cellular

The cellular physiology for the heart is complicated and will be broken down into two sections: the action potential, which is unique in the heart to other action potentials in the body, and electrophysiology.

Action Potential

Please see the image following this article for visual representation

Cardiac Myocyte

The action potential (AP) in the heart is unique to other action potentials in the body. It has five distinct phases numbered 0-4. The resting potential or baseline of the AP is rough – 90 mV and is considered phase 4. For understanding, depolarization is considered the voltage change from the resting potential of – 90 mV toward a positive value. Repolarization will be represented by the return of the voltage of the cell from a positive value down to its resting potential of – 90 mV. The ultimate conclusion of a completed AP is a contraction of the cardiac myocyte.[rx][rx]

There are multiple types of potassium channels involved in the cardiac myocyte AP. To begin, phase 4 is at resting potential and consists of the first set of potassium channels open, with positively-charged potassium flowing out of the cell and thus keeping the voltage low at approximately – 90 mV. This set of potassium channels is passively open and consistently outflows potassium during phase 4.

In the next phase, phase 0, sodium channels open at approximately – 70 mV. The initial depolarization from – 90 mV to – 70 mV is caused by positive sodium and calcium ions entering the cell through gap junctions from neighboring cells. These ions depolarize the voltage just enough to open these voltage-gated (VG) sodium channels which further depolarize the cell to approximately + 50 mV. These voltage-gated sodium channels close very quickly upon depolarizing the cell.

Upon reaching peak voltage, voltage-gated potassium channels open and move potassium out of the cell, decreasing voltage once again. This is known as phase 1.

In phase 2, the plateau phase, potassium channels are open out of the cell, and voltage-gated calcium channels begin to open into the cell. This creates a net balance of charge in the cell, creating a plateau.

With phase 3, the voltage-gated calcium channels close, leaving the outward-flowing potassium channels as the only open channels. This causes rapid repolarization, dropping the voltage of the cell to – 90 mV and closing the currently open potassium channel. At the resting potential, the cell has only the original potassium channel slowly leaking potassium out of the cell, and we are returned to phase 4 of the action potential.

In summary, the 5 phases of the cardiac myocyte are as follows:

• Phase 4: Resting Potential at – 90 mV with minor depolarization from – 90 mV to – 70 mV; the passive outflow of potassium
• Phase 0: Rapid depolarization from – 70 mV to + 50 mV; inward VG sodium channels
• Phase 1: Minor repolarization; outward VG potassium channels
• Phase 2: Plateau at + 50 mV; outward VG potassium channels and inward VG calcium channels
• Phase 3: Repolarization from + 50 mV to – 90 mV; outward voltage-gated potassium channels

Cardiac Pacemaker Cell

The action potential for cardiac pacemaker cells (SA node, AV node, and Bundle of His/Purkinje Fibers) is unique to the AP of the general cardiac myocyte. These cells undergo automaticity and are responsible for the heart rate. Therefore, each AP corresponds to one beat of the heart and the inherent frequency of these cells is essential for maintaining proper rate control.

Additionally, the electrophysiology and anatomy of these pacemaker cells are discussed in a later section. We will use phases in line with the previous discussion of the cardiac myocyte; to explain, there are 3 basic phases of the pacemaker AP, but they are named phases 0, 3, and 4 correspondings with the phases of the myocyte action potential. The biggest difference to note in this AP is that calcium is the driving factor for rapid depolarization.

To begin, phase 4 involves sodium influx into the cell. This phase initiates at – 60 mV and the main ion influx is sodium. As the cell gains a positive charge due to the influx of positive ions, it reaches – 40 mV which is defined as the threshold for the pacemaker AP. As the voltage hits – 40 mV, voltage-gated calcium channels open into the cell to influx more positive ions. This influx of calcium ions denotes the beginning of phase 0, which is the action potential. The voltage continues to rise until it hits + 10 mV, which will shut off the voltage-gated calcium channels and open up voltage-gated potassium channels, which are efflux from the cell. The opening of the potassium channels begins phase 3 and the downslope of our voltage, and the voltage will drop back to the start of Phase 4 at – 60 mV where the potassium channels will close.

In summary, the 3 phases of the pacemaker action potential are as follows:

• Phase 4: Minor depolarization from – 60 mV to – 40 mV; passive inflow of sodium
• Phase 0: Rapid depolarization from – 40 mV to + 10 mV; inflow of VG calcium channels
• Phase 3: Repolarization from + 10 mV to – 60 mV; outflow of VG potassium channels

Lastly, each pacemaker cell has a different inherent rate at which it can maintain the heart. The SA node is responsible for heart rate under normal conditions; this means that the inherent rate of the SA node is typically around 60 to 100 beats per minute (BPM). The AV node is the second pacemaker which takes over rate if the SA node begins to fail; the AV node keeps the rate at 40 to 60 BPM. There are other foci situated around the SA and AV nodes (e.g., atrial foci and ventricular foci) that can contribute to the rate. In pathology such as atrial fibrillation, these Foci can even create a disease state through rapid firing which increases heart rate, but this discussion is out of scope for this article.

Electrophysiology

The electrical circuit of the heart follows a distinct pathway from the right atrium down throughout the ventricles of the heart. The electrical circuit begins at the Sinoatrial node, or SA node, which is located in the right atrium. This node is a unique bundle of cells that undergoes automaticity; these cells have their inherent rate of depolarization that is independent of other cells in the heart. As the SA node depolarizes, an electrical signal is simultaneously transmitted across from the right atrium to the left atrium via a bundle of cells termed “Bachman’s Bundle.” Following the SA node conduction, the current travels down to the Atrioventricular node, or AV node. The AV node is located further inferior in the Right Atrium by the interatrial septum. An important distinction to make about the AV node is that it creates a small pause in the electrical circuit. This pause is important because it delays the ventricles from contracting, and thus establishes successive contraction of the ventricles following the atria. If this pause did not occur, the atria and ventricles would contract simultaneously, and blood would not flow appropriately through the heart. The current leaves the AV node down a bundle of cells named the “Bundle of His” located inferior to the AV node in the interventricular septum. The Bundle of His then transmits the conduction down two bundle branches that arc throughout the two ventricles; specifically, these are named the right and left bundle branches. The right and left bundle branches have many fascicles that divide off and supply much of the ventricles. The main continuation of the right and left bundle branch is the Purkinje Fiber system, which is a set of many small branches arcing throughout the remaining ventricular space and supplying it with the electrical output. [rx][rx]

In summary, the order of flow through the electrical system is as follows:

• SA node and Bachman’s Bundle
• AV node
• Bundle of His
• Right and left bundle branches
• Purkinje Fibers

Sarcomere Structure

A sarcomere is the basic unit of muscle tissue in both cardiac and skeletal muscle. Sarcomeres appear under the microscope as striations, with alternating dark and light bands. Sarcomeres are connected to a plasma membrane, called a sarcolemma, by T-tubules, which speed up the rate of depolarization within the sarcomere.

Individual sarcomeres are composed of long, fibrous proteins that slide past each other when the muscles contract and relax. The two most important proteins within sarcomeres are myosin, which forms a thick, flexible filament, and actin, which forms the thin, more rigid filament. Myosin has a long, fibrous tail and a globular head which binds to actin. The myosin head also binds to ATP, the source of energy for muscle movement. Actin molecules are bound to the Z-disc, which forms the borders of the sarcomere. Together, myosin and actin form myofibrils, the repeating molecular structure of sarcomeres.

Myofibril activity is required for muscle contraction on the molecular level. When ATP binds to myosin, it separates from the actin of the myofibril, which causes a contraction. Muscle contraction is a complex process regulated by calcium influx and the stimulus of electrical impulses.

Intercalated Discs

Intercalated discs are gap junctions that link cardiomyocytes so that electrical impulses (action potentials) can travel between cells. In a more general sense, an intercalated disk is any junction that links cells together between a gap in which no other cells exist, such as an extracellular matrix. In cardiac muscle tissue, they are also responsible for the transmission of action potentials and calcium during muscle contraction. In cardiac muscle, intercalated discs connecting cardiomyocytes to the syncytium, a multinucleated muscle cell, to support the rapid spread of action potentials and the synchronized contraction of the myocardium. Intercalated discs consist of three types of cell-cell junctions, most of which are found in other tissues besides cardiac muscle:

• Adherens junctions, which anchor actin filaments to the cytoplasm of cardiomyocytes.
• Desmosomes, which bind adhesion proteins to the cytoskeleton within cells, thus connecting the cells.
• Gap junctions, which connect proteins to the cytoplasm of different cells and transmit action potentials between both cells, required for cellular depolarization. It is found primarily in nervous and muscular tissue.

Under light microscopy, intercalated discs appear as thin lines dividing adjacent cardiac muscle cells and running perpendicular to the direction of muscle fibers.

Mechanism and Contraction Events of Cardiac Muscle Fibers

Cardiac muscle fibers undergo coordinated contraction via calcium-induced calcium release conducted through the intercalated discs.

Cardiomyocytes are capable of coordinated contraction, controlled through the gap junctions of intercalated discs. The gap junctions spread action potentials to support the synchronized contraction of the myocardium. In cardiac, skeletal, and some smooth muscle tissue, contraction occurs through a phenomenon known as excitation-contraction coupling (ECC). ECC describes the process of converting an electrical stimulus from the neurons into a mechanical response that facilitates muscle movement. Action potentials are the electrical stimulus that elicits the mechanical response in ECC.

Calcium-Induced Calcium Release

In cardiac muscle, ECC is dependent on a phenomenon called calcium-induced calcium release (CICR), which involves the influx of calcium ions into the cell, triggering the further release of ions into the cytoplasm. The mechanism for CIRC is receptors within the cardiomyocyte that bind to calcium ions when calcium ion channels open during depolarization, releasing more calcium ions into the cell.

Similarly to skeletal muscle, the influx of sodium ions causes an initial depolarization; however, in cardiac muscle, the influx of calcium ions sustains the depolarization so that it lasts longer. CICR creates a “plateau phase” in which the cell’s charge stays slightly positive (depolarized) briefly before it becomes more negative as it repolarizes due to potassium ion influx. Skeletal muscle, by contrast, repolarizes immediately.

Pathway of Cardiac Muscle Contraction

The actual mechanical contraction response in cardiac muscle occurs via the sliding filament model of contraction. In the sliding filament model, myosin filaments slide along actin filaments to shorten or lengthen the muscle fiber for contraction and relaxation. The pathway of contraction can be described in five steps:

• An action potential, induced by the pacemaker cells in the sinoatrial (SA) and atrioventricular (AV) nodes, is conducted to contractile cardiomyocytes through gap junctions.
• As the action potential travels between sarcomeres, it activates the calcium channels in the T-tubules, resulting in an influx of calcium ions into the cardiomyocyte.
• Calcium in the cytoplasm then binds to cardiac troponin-C, which moves the troponin complex away from the actin-binding site. This removal of the troponin complex frees the actin to be bound by myosin and initiates contraction.
• The myosin head binds to ATP and pulls the actin filaments toward the center of the sarcomere, contracting the muscle.
• Intracellular calcium is then removed by the sarcoplasmic reticulum, dropping intracellular calcium concentration, returning the troponin complex to its inhibiting position on the active site of actin, and effectively ending contraction as the actin filaments return to their initial position, relaxing the muscle.

Energy Requirements

Cardiac cells contain numerous mitochondria, which enable continuous aerobic respiration and the production of adenosine triphosphate (ATP) for cardiac function.

The heart muscle pumps continuously throughout life and is adapted to be highly resistant to fatigue. Cardiomyocytes contain large numbers of mitochondria, the powerhouse of the cell, enabling continuous aerobic respiration and ATP production required for mechanical muscle contraction. Cardiac muscle tissue has among the highest energy requirements in the human body (along with the brain) and has a high level of mitochondria and a constant, rich, blood supply to support its metabolic activity.

Aerobic Metabolism

Aerobic metabolism is a necessary component to support the metabolic function of the heart. Oxygen is necessary, and if even a small part of the heart is oxygen-deprived for too long, a myocardial infarction (heart attack) will occur. Coronary circulation branches from the aorta soon after it leaves the heart, and supplies the heart with the nutrients and oxygen needed to sustain aerobic metabolism. Cardiac muscle cells contain larger amounts of mitochondria than other cells in the body, enabling higher ATP production.

The heart derives energy from aerobic metabolism via many different types of nutrients. Sixty percent of the energy to power the heart is derived from fat (free fatty acids and triglycerides), 35% from carbohydrates, and 5% from amino acids and ketone bodies from proteins. These proportions vary widely with available dietary nutrients. Malnutrition will not result in the death of heart tissue in the way that oxygen deficiency will, because the body has glucose reserves that sustain the vital organs of the body and the ability to recycle and use lactate aerobically.

Myoglobin: The heme component of myoglobin, shown in orange, binds oxygen. Myoglobin provides a backup store of oxygen to muscle cells.

Anaerobic Metabolism

While aerobic respiration supports normal heart activity, anaerobic respiration may provide additional energy during brief periods of oxygen deprivation. Lactate, created from lactic acid fermentation, accounts for the anaerobic component of cardiac metabolism. At normal metabolic rates, about 1% of energy is derived from lactate, and about 10% under moderately hypoxic (low oxygen) conditions. Under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contraction, and heart failure will occur.

Lactate can be recycled by the heart and provides additional support during nutrient deprivation. Recycling lactate is very energy-efficient in the nutrient-deprived myocardium since one NAD+ is reduced to NADH and H+ (equal to 2.5 or 3 ATP) when lactate is oxidized to pyruvate. The produced pyruvate can then be burned aerobically in the citric acid cycle (also known as the tricarboxylic acid cycle or Krebs cycle), liberating a significant amount of energy.

References

Microscopic Anatomy

Cardiac muscle appears striated due to the presence of sarcomeres, the highly organized basic functional unit of muscle tissue.

Cardiac muscle, like skeletal muscle, appears striated due to the organization of muscle tissue into sarcomeres. While similar to skeletal muscle, cardiac muscle is different in a few ways. Cardiac muscles are composed of tubular cardiomyocytes or cardiac muscle cells. The cardiomyocytes are composed of tubular myofibrils, which are repeating sections of sarcomeres. Intercalated disks transmit electrical action potentials between sarcomeres.

Cellular

The cellular physiology for the heart is complicated and will be broken down into two sections: the action potential, which is unique in the heart to other action potentials in the body, and electrophysiology.

Action Potential

Please see the image following this article for visual representation

Cardiac Myocyte

The action potential (AP) in the heart is unique to other action potentials in the body. It has five distinct phases numbered 0-4. The resting potential or baseline of the AP is rough – 90 mV and is considered phase 4. For understanding, depolarization is considered the voltage change from the resting potential of – 90 mV toward a positive value. Repolarization will be represented by the return of the voltage of the cell from a positive value down to its resting potential of – 90 mV. The ultimate conclusion of a completed AP is a contraction of the cardiac myocyte.[rx][rx]

There are multiple types of potassium channels involved in the cardiac myocyte AP. To begin, phase 4 is at resting potential and consists of the first set of potassium channels open, with positively-charged potassium flowing out of the cell and thus keeping the voltage low at approximately – 90 mV. This set of potassium channels is passively open and consistently outflows potassium during phase 4.

In the next phase, phase 0, sodium channels open at approximately – 70 mV. The initial depolarization from – 90 mV to – 70 mV is caused by positive sodium and calcium ions entering the cell through gap junctions from neighboring cells. These ions depolarize the voltage just enough to open these voltage-gated (VG) sodium channels which further depolarize the cell to approximately + 50 mV. These voltage-gated sodium channels close very quickly upon depolarizing the cell.

Upon reaching peak voltage, voltage-gated potassium channels open and move potassium out of the cell, decreasing voltage once again. This is known as phase 1.

In phase 2, the plateau phase, potassium channels are open out of the cell, and voltage-gated calcium channels begin to open into the cell. This creates a net balance of charge in the cell, creating a plateau.

With phase 3, the voltage-gated calcium channels close, leaving the outward-flowing potassium channels as the only open channels. This causes rapid repolarization, dropping the voltage of the cell to – 90 mV and closing the currently open potassium channel. At the resting potential, the cell has only the original potassium channel slowly leaking potassium out of the cell, and we are returned to phase 4 of the action potential.

In summary, the 5 phases of the cardiac myocyte are as follows:

• Phase 4: Resting Potential at – 90 mV with minor depolarization from – 90 mV to – 70 mV; the passive outflow of potassium
• Phase 0: Rapid depolarization from – 70 mV to + 50 mV; inward VG sodium channels
• Phase 1: Minor repolarization; outward VG potassium channels
• Phase 2: Plateau at + 50 mV; outward VG potassium channels and inward VG calcium channels
• Phase 3: Repolarization from + 50 mV to – 90 mV; outward voltage-gated potassium channels

Cardiac Pacemaker Cell

The action potential for cardiac pacemaker cells (SA node, AV node, and Bundle of His/Purkinje Fibers) is unique to the AP of the general cardiac myocyte. These cells undergo automaticity and are responsible for the heart rate. Therefore, each AP corresponds to one beat of the heart and the inherent frequency of these cells is essential for maintaining proper rate control.

Additionally, the electrophysiology and anatomy of these pacemaker cells are discussed in a later section. We will use phases in line with the previous discussion of the cardiac myocyte; to explain, there are 3 basic phases of the pacemaker AP, but they are named phases 0, 3, and 4 correspondings with the phases of the myocyte action potential. The biggest difference to note in this AP is that calcium is the driving factor for rapid depolarization.

To begin, phase 4 involves sodium influx into the cell. This phase initiates at – 60 mV and the main ion influx is sodium. As the cell gains a positive charge due to the influx of positive ions, it reaches – 40 mV which is defined as the threshold for the pacemaker AP. As the voltage hits – 40 mV, voltage-gated calcium channels open into the cell to influx more positive ions. This influx of calcium ions denotes the beginning of phase 0, which is the action potential. The voltage continues to rise until it hits + 10 mV, which will shut off the voltage-gated calcium channels and open up voltage-gated potassium channels, which are efflux from the cell. The opening of the potassium channels begins phase 3 and the downslope of our voltage, and the voltage will drop back to the start of Phase 4 at – 60 mV where the potassium channels will close.

In summary, the 3 phases of the pacemaker action potential are as follows:

• Phase 4: Minor depolarization from – 60 mV to – 40 mV; passive inflow of sodium
• Phase 0: Rapid depolarization from – 40 mV to + 10 mV; inflow of VG calcium channels
• Phase 3: Repolarization from + 10 mV to – 60 mV; outflow of VG potassium channels

Lastly, each pacemaker cell has a different inherent rate at which it can maintain the heart. The SA node is responsible for heart rate under normal conditions; this means that the inherent rate of the SA node is typically around 60 to 100 beats per minute (BPM). The AV node is the second pacemaker which takes over rate if the SA node begins to fail; the AV node keeps the rate at 40 to 60 BPM. There are other foci situated around the SA and AV nodes (e.g., atrial foci and ventricular foci) that can contribute to the rate. In pathology such as atrial fibrillation, these Foci can even create a disease state through rapid firing which increases heart rate, but this discussion is out of scope for this article.

Electrophysiology

The electrical circuit of the heart follows a distinct pathway from the right atrium down throughout the ventricles of the heart. The electrical circuit begins at the Sinoatrial node, or SA node, which is located in the right atrium. This node is a unique bundle of cells that undergoes automaticity; these cells have their inherent rate of depolarization that is independent of other cells in the heart. As the SA node depolarizes, an electrical signal is simultaneously transmitted across from the right atrium to the left atrium via a bundle of cells termed “Bachman’s Bundle.” Following the SA node conduction, the current travels down to the Atrioventricular node, or AV node. The AV node is located further inferior in the Right Atrium by the interatrial septum. An important distinction to make about the AV node is that it creates a small pause in the electrical circuit. This pause is important because it delays the ventricles from contracting, and thus establishes successive contraction of the ventricles following the atria. If this pause did not occur, the atria and ventricles would contract simultaneously, and blood would not flow appropriately through the heart. The current leaves the AV node down a bundle of cells named the “Bundle of His” located inferior to the AV node in the interventricular septum. The Bundle of His then transmits the conduction down two bundle branches that arc throughout the two ventricles; specifically, these are named the right and left bundle branches. The right and left bundle branches have many fascicles that divide off and supply much of the ventricles. The main continuation of the right and left bundle branch is the Purkinje Fiber system, which is a set of many small branches arcing throughout the remaining ventricular space and supplying it with the electrical output. [rx][rx]

In summary, the order of flow through the electrical system is as follows:

• SA node and Bachman’s Bundle
• AV node
• Bundle of His
• Right and left bundle branches
• Purkinje Fibers

Sarcomere Structure

A sarcomere is the basic unit of muscle tissue in both cardiac and skeletal muscle. Sarcomeres appear under the microscope as striations, with alternating dark and light bands. Sarcomeres are connected to a plasma membrane, called a sarcolemma, by T-tubules, which speed up the rate of depolarization within the sarcomere.

Individual sarcomeres are composed of long, fibrous proteins that slide past each other when the muscles contract and relax. The two most important proteins within sarcomeres are myosin, which forms a thick, flexible filament, and actin, which forms the thin, more rigid filament. Myosin has a long, fibrous tail and a globular head which binds to actin. The myosin head also binds to ATP, the source of energy for muscle movement. Actin molecules are bound to the Z-disc, which forms the borders of the sarcomere. Together, myosin and actin form myofibrils, the repeating molecular structure of sarcomeres.

Myofibril activity is required for muscle contraction on the molecular level. When ATP binds to myosin, it separates from the actin of the myofibril, which causes a contraction. Muscle contraction is a complex process regulated by calcium influx and the stimulus of electrical impulses.

Intercalated Discs

Intercalated discs are gap junctions that link cardiomyocytes so that electrical impulses (action potentials) can travel between cells. In a more general sense, an intercalated disk is any junction that links cells together between a gap in which no other cells exist, such as an extracellular matrix. In cardiac muscle tissue, they are also responsible for the transmission of action potentials and calcium during muscle contraction. In cardiac muscle, intercalated discs connecting cardiomyocytes to the syncytium, a multinucleated muscle cell, to support the rapid spread of action potentials and the synchronized contraction of the myocardium. Intercalated discs consist of three types of cell-cell junctions, most of which are found in other tissues besides cardiac muscle:

• Adherens junctions, which anchor actin filaments to the cytoplasm of cardiomyocytes.
• Desmosomes, which bind adhesion proteins to the cytoskeleton within cells, thus connecting the cells.
• Gap junctions, which connect proteins to the cytoplasm of different cells and transmit action potentials between both cells, required for cellular depolarization. It is found primarily in nervous and muscular tissue.

Under light microscopy, intercalated discs appear as thin lines dividing adjacent cardiac muscle cells and running perpendicular to the direction of muscle fibers.

Mechanism and Contraction Events of Cardiac Muscle Fibers

Cardiac muscle fibers undergo coordinated contraction via calcium-induced calcium release conducted through the intercalated discs.

Cardiomyocytes are capable of coordinated contraction, controlled through the gap junctions of intercalated discs. The gap junctions spread action potentials to support the synchronized contraction of the myocardium. In cardiac, skeletal, and some smooth muscle tissue, contraction occurs through a phenomenon known as excitation-contraction coupling (ECC). ECC describes the process of converting an electrical stimulus from the neurons into a mechanical response that facilitates muscle movement. Action potentials are the electrical stimulus that elicits the mechanical response in ECC.

Calcium-Induced Calcium Release

In cardiac muscle, ECC is dependent on a phenomenon called calcium-induced calcium release (CICR), which involves the influx of calcium ions into the cell, triggering the further release of ions into the cytoplasm. The mechanism for CIRC is receptors within the cardiomyocyte that bind to calcium ions when calcium ion channels open during depolarization, releasing more calcium ions into the cell.

Similarly to skeletal muscle, the influx of sodium ions causes an initial depolarization; however, in cardiac muscle, the influx of calcium ions sustains the depolarization so that it lasts longer. CICR creates a “plateau phase” in which the cell’s charge stays slightly positive (depolarized) briefly before it becomes more negative as it repolarizes due to potassium ion influx. Skeletal muscle, by contrast, repolarizes immediately.

Pathway of Cardiac Muscle Contraction

The actual mechanical contraction response in cardiac muscle occurs via the sliding filament model of contraction. In the sliding filament model, myosin filaments slide along actin filaments to shorten or lengthen the muscle fiber for contraction and relaxation. The pathway of contraction can be described in five steps:

• An action potential, induced by the pacemaker cells in the sinoatrial (SA) and atrioventricular (AV) nodes, is conducted to contractile cardiomyocytes through gap junctions.
• As the action potential travels between sarcomeres, it activates the calcium channels in the T-tubules, resulting in an influx of calcium ions into the cardiomyocyte.
• Calcium in the cytoplasm then binds to cardiac troponin-C, which moves the troponin complex away from the actin-binding site. This removal of the troponin complex frees the actin to be bound by myosin and initiates contraction.
• The myosin head binds to ATP and pulls the actin filaments toward the center of the sarcomere, contracting the muscle.
• Intracellular calcium is then removed by the sarcoplasmic reticulum, dropping intracellular calcium concentration, returning the troponin complex to its inhibiting position on the active site of actin, and effectively ending contraction as the actin filaments return to their initial position, relaxing the muscle.

Energy Requirements

Cardiac cells contain numerous mitochondria, which enable continuous aerobic respiration and the production of adenosine triphosphate (ATP) for cardiac function.

The heart muscle pumps continuously throughout life and is adapted to be highly resistant to fatigue. Cardiomyocytes contain large numbers of mitochondria, the powerhouse of the cell, enabling continuous aerobic respiration and ATP production required for mechanical muscle contraction. Cardiac muscle tissue has among the highest energy requirements in the human body (along with the brain) and has a high level of mitochondria and a constant, rich, blood supply to support its metabolic activity.

Aerobic Metabolism

Aerobic metabolism is a necessary component to support the metabolic function of the heart. Oxygen is necessary, and if even a small part of the heart is oxygen-deprived for too long, a myocardial infarction (heart attack) will occur. Coronary circulation branches from the aorta soon after it leaves the heart, and supplies the heart with the nutrients and oxygen needed to sustain aerobic metabolism. Cardiac muscle cells contain larger amounts of mitochondria than other cells in the body, enabling higher ATP production.

The heart derives energy from aerobic metabolism via many different types of nutrients. Sixty percent of the energy to power the heart is derived from fat (free fatty acids and triglycerides), 35% from carbohydrates, and 5% from amino acids and ketone bodies from proteins. These proportions vary widely with available dietary nutrients. Malnutrition will not result in the death of heart tissue in the way that oxygen deficiency will, because the body has glucose reserves that sustain the vital organs of the body and the ability to recycle and use lactate aerobically.

Myoglobin: The heme component of myoglobin, shown in orange, binds oxygen. Myoglobin provides a backup store of oxygen to muscle cells.

Anaerobic Metabolism

While aerobic respiration supports normal heart activity, anaerobic respiration may provide additional energy during brief periods of oxygen deprivation. Lactate, created from lactic acid fermentation, accounts for the anaerobic component of cardiac metabolism. At normal metabolic rates, about 1% of energy is derived from lactate, and about 10% under moderately hypoxic (low oxygen) conditions. Under more severe hypoxic conditions, not enough energy can be liberated by lactate production to sustain ventricular contraction, and heart failure will occur.

Lactate can be recycled by the heart and provides additional support during nutrient deprivation. Recycling lactate is very energy-efficient in the nutrient-deprived myocardium since one NAD+ is reduced to NADH and H+ (equal to 2.5 or 3 ATP) when lactate is oxidized to pyruvate. The produced pyruvate can then be burned aerobically in the citric acid cycle (also known as the tricarboxylic acid cycle or Krebs cycle), liberating a significant amount of energy.

References

Heart Circulation

Coronary circulation is the circulation of blood in the blood vessels of the heart.

Coronary circulation is the circulation of blood in the blood vessels of the heart muscle. The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries. The vessels that remove the deoxygenated blood from the heart muscle are known as cardiac veins. The blood supply to the heart is greater than that of other body tissues since the heart has a constant metabolic demand that must be satisfied to keep the heart pumping at all times.

Coronary Artery Structure

The coronary arteries originate from the left side of the heart descending from the aorta. There are multiple coronary arteries derived from the larger right and left coronary arteries. For example, important coronary arteries that branch off from the larger arteries include the left anterior descending (LAD) coronary and the right posterior coronary.

Coronary arteries run both along the surface of the heart and deep within the myocardium, which has the greatest metabolic demands of all the heart tissues due to its muscle content. Epicardial coronary arteries, which run along on the surface of the heart, are capable of autoregulating vasodilation and vasoconstriction to maintain coronary blood flow at appropriate levels to fit the metabolic demands of the heart muscle. These vessels are relatively narrow and thus vulnerable to blockage, which may cause a myocardial infarction. Subendocardial coronary arteries run deep within the myocardium to provide oxygen throughout the muscle tissue of the cardiac wall.

Systole and Diastole

In systole, the ventricular myocardium contracts, generating high intraventricular pressure and compressing the subendocardial coronary vessels while allowing the epicardial coronary vessels to remain fully open. With the subendocardial coronary vessels compressed, blood flow essentially stops below the surface of the myocardium.

In diastole, the ventricular myocardium contracts, lowering the intraventricular pressure and allowing the subendocardial vessels to become open again. Due to the high pressures generated in the ventricular myocardium during systole, most myocardial tissue perfusion occurs during diastole. Additionally, catecholamines such as norepinephrine, which normally cause vasoconstriction will instead cause vasodilation within the coronary arteries. This mechanism is due to beta-adrenergic receptors in the coronary arteries and helps enable the increased cardiac output associated with fight-or-flight responses.

Myocardial Infarctions

A myocardial infarction (heart attack) may be caused by prolonged ischemia (oxygen deprivation) in the heart, which occurs due to blockage of any of the coronary arteries. Since there is very little unnecessary blood supply to the myocardium, blockage of these vessels can cause serious damage. When these vessels become blocked, the myocardium becomes oxygen-deprived, a condition called ischemia. Brief periods of ischemia in the heart are associated with intense chest pain called angina, which may either be transient if the clot breaks up on its own or stable if it does not. As the time period of ischemia increases, the hypoxic conditions cause muscle tissue to die, causing myocardial infarction (heart attack).

Myocardial infarction is one of the most common causes of death worldwide. The clots that cause the infarction are usually the result of ruptured atherosclerotic plaques that break off and occlude the coronary arteries, but arterial thrombosis from injury or pooled blood may also cause a heart attack. The tissues of the heart do not regenerate, so those that survive a myocardial infarction will generally have scar tissue in their myocardium and may be more susceptible to other heart problems in the future.

Operation of Atrioventricular Valves

The atrioventricular valves separate the atria from the ventricles and prevent backflow from the ventricles into the atria during systole.

A heart valve allows blood flow in only one direction through the heart, and the combination of the atrioventricular and semi-lunar heart valves determines the pathway of blood flow. Valves open or close based on pressure differences across the valve. The atrioventricular (AV) valves separate the atria from the ventricles on each side of the heart and prevent the backflow of blood from the ventricles into the atria during systole.

Subvalvular Apparatus

The subvalvular apparatus describes the structures beneath the AV valves that prevent the valves from prolapsing. Valve prolapse means that the valves do not close properly, which may cause regurgitation or backflow of blood from the ventricle back into the atria, which is inefficient. The subvalvular apparatus includes the chordae tendineae and the papillary muscles. The AV valves are anchored to the wall of the ventricle by chordae tendineae (heartstrings), small tendons that prevent backflow by stopping the valve leaflets from inverting. The chordae tendineae are inelastic and attached at one end to the papillary muscles and at the other end to the valve cusps.

Papillary muscles are finger-like projections from the wall of the ventricle that anchor the chordae tendineae. This connection provides tension to hold the valves in place and prevent them from prolapsing into the atria when they close, preventing the risk of regurgitation. The subvalvular apparatus has no effect on the opening and closing of the valves, which is caused entirely by the pressure gradient of blood across the valve as blood flows from high pressure to low pressure areas.

The Mitral Valve

The mitral valve is on the left side of the heart and allows the blood to flow from the left atrium into the left ventricle. It is also known as the bicuspid valve because it contains two leaflets (cusps). The relaxation of the ventricular myocardium and the contraction of the atrial myocardium causes a pressure gradient that allows for rapid blood flow from the left atrium into the left ventricle across the mitral valve. Atrial systole (contraction) increases the pressure in the atria, while ventricular diastole (relaxation) decreases the pressure in the ventricle, causing the pressure-induced flow of blood across the valve. The mitral annulus, a ring around the mitral valve, changes in shape and size during the cardiac cycle to prevent backflow. The ring contracts at the end of the atrial systole due to the contraction of the left atrium around it, which aids in bringing the leaflets together to provide firm closure during ventricular systole.

The Tricuspid Valve

The tricuspid valve is the three-leaflet valve on the right side of the heart between the right atrium and the right ventricle and stops the backflow of blood between the two. The tricuspid valve functions similarly to the bicuspid valve except that three chordae tendineae connect the cusps of the valve to three papillary muscles, rather than the pair that connects the bicuspid valve. Blood passes through the tricuspid valve the same as it does through the bicuspid valve, based on a pressure gradient from high pressure to low pressure during systole and diastole.

The reason that the valves have different numbers of leaflets is not fully understood but may arise from differences in tissue structure and pressure that occur during fetal development.

Operation of Semilunar Valves

The semilunar valves allow blood to be pumped into the major arteries while preventing the backflow of blood from the arteries into the ventricles.

The semilunar valves are located at the connections between the pulmonary artery and the right ventricle, and the aorta and the left ventricle. These valves allow blood to be pumped forward into the arteries but prevent the backflow of blood from the arteries into the ventricles. These valves do not have subvalvular apparatus and are more similar to the semilunar valves in veins and lymphatic vessels than to atrioventricular (AV) valves.

The semilunar valves act in concert with the AV valves to direct blood flow through the heart. When the atrioventricular valves are open, the semilunar valves are shut and blood is forced into the ventricles. When the AV valves shut, the semilunar valves open, forcing blood into the aorta and pulmonary artery. The mechanism for this process depends on blood pressure gradients in the heart, which provide the force that pushes blood through the semilunar valves.

The Aortic Valve

The aortic valve separates the left ventricle from the aorta and has three cusps. During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle exceeds the pressure in the aorta, the aortic valve opens and blood flows from the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle drops rapidly, and the valve closes due to a lack of pressure imposed on them from the left ventricle. Blood pressure within the aorta following systole also causes the closing of the valve. The closing of the aortic valve produces a sound that is a component of the second heart sound.

The Pulmonary Valve

The pulmonary valve (also called the pulmonic valve), which also has three cusps, separates the right ventricle from the pulmonary artery. Similar to the aortic valve, the pulmonary valve opens in ventricular systole when the pressure in the right ventricle exceeds the pressure in the pulmonary artery. When ventricular systole ends, pressure in the right ventricle drops rapidly, and the pressure in the pulmonary artery forces the pulmonary valve to close. The closure of the pulmonary valve also produces a sound, however, it is softer than the aortic sound because the blood pressure in the right side of the heart is lower compared to the left side, due to the differences between pulmonary and systemic circulation.

Valve Problems

Valves are vulnerable to several conditions that impair their normal functions. Two of the most common problems with the semilunar valves are stenosis and regurgitation.  Valve stenosis refers to a narrowing of the valves, which prevents the valve from opening fully, causing an obstruction of blood flow. Valve stenosis is often caused by calcium buildup and scarring from rheumatic fever and may cause cardiac hypertrophy and heart failure. Valve regurgitation is backflow through the valves that occurs when they cannot close completely. It is the cause of most heart murmurs and is generally a minor problem, but if severe enough, it can cause heart failure. Stenosis and regurgitation can occur in both the semilunar and atrioventricular valves.

Systemic and Pulmonary Circulation

The cardiovascular system has two distinct circulatory paths, pulmonary circulation and systemic circulation.

The cardiovascular system is composed of two circulatory paths: pulmonary circulation, the circuit through the lungs where blood is oxygenated; and systemic circulation, the circuit through the rest of the body to provide oxygenated blood. The two circuits are linked to each other through the heart, creating a continuous cycle of blood through the body.

Pulmonary Circulation

Pulmonary circulation is the movement of blood from the heart to the lungs for oxygenation, then back to the heart again. Oxygen-depleted blood from the body leaves the systemic circulation when it enters the right atrium through the superior and inferior venae cavae. The blood is then pumped through the tricuspid valve into the right ventricle. From the right ventricle, blood is pumped through the pulmonary valve and into the pulmonary artery. The pulmonary artery splits into the right and left pulmonary arteries and travel to each lung.

At the lungs, the blood travels through capillary beds on the alveoli where gas exchange occurs, removing carbon dioxide and adding oxygen to the blood. Gas exchange occurs due to gas partial pressure gradients across the alveoli of the lungs and the capillaries interwoven in the alveoli. The oxygenated blood then leaves the lungs through pulmonary veins, which return it to the left atrium, completing the pulmonary circuit. As the pulmonary circuit ends, the systemic circuit begins.

Systemic Circulation

Systemic circulation is the movement of blood from the heart through the body to provide oxygen and nutrients to the tissues of the body while bringing deoxygenated blood back to the heart. Oxygenated blood enters the left atrium from the pulmonary veins. The blood is then pumped through the mitral valve into the left ventricle. From the left ventricle, blood is pumped through the aortic valve and into the aorta, the body’s largest artery. The aorta arches and branches into major arteries to the upper body before passing through the diaphragm, where it branches further into the iliac, renal, and suprarenal arteries which supply the lower parts of the body.

The arteries branch into smaller arteries, arterioles, and finally capillaries. Gas and nutrient exchange with the tissues occurs within the capillaries that run through the tissues. Metabolic waste and carbon dioxide diffuse out of the cell into the blood, while oxygen and glucose in the blood diffuse out of the blood and into the cell. Systemic circulation keeps the metabolism of every organ and every tissue in the body alive, with the exception of the parenchyma of the lungs, which are supplied by pulmonary circulation.

The deoxygenated blood continues through the capillaries which merge into venules, then veins, and finally the venae cavae, which drain into the right atrium of the heart. From the right atrium, the blood will travel through the pulmonary circulation to be oxygenated before returning gain to the system circulation, completing the cycle of circulation through the body. The arterial component of systemic circulation the highest blood pressure in the body. The venous component of systemic circulation has considerably lower blood pressure in comparison, due to their distance from the heart, but contains semi-lunar valves to compensate. Systemic circulation as a whole is a higher pressure system than pulmonary circulation simply because systemic circulation must force greater volumes of blood farther through the body compared to pulmonary circulation.

The nervous system regulates the cardiovascular system with the help of baroreceptors and chemoreceptors. Both receptors are located in the carotids and aortic arch. Also, both have afferent signals through the vagus nerve from the aortic arch and afferent signals through the glossopharyngeal nerve from the carotids.

• Baroreceptors are more specifically located in the carotid sinus and aortic arch. They respond quickly to changes in blood pressure.
• A decrease in blood pressure or blood volume causes hypotension, which leads to a decrease in arterial pressure, which creates a decrease in the stretch of the baroreceptors and decreases afferent baroreceptor signaling. This decrease in afferent signaling from the baroreceptor causes an increase in efferent sympathetic activity and a reduction in parasympathetic activity, which leads to vasoconstriction, increase heart rate, increase contractility, and an increase in BP. The vasoconstriction increases TPR in the equation MAP=CO*TPR to bring pressure (MAP) back up.
• An increase in blood pressure or blood volume causes hypertension which increases the stretch of the baroreceptors
• Chemoreceptors come in 2 types: peripheral and central. Peripheral chemoreceptors are specifically located in the carotid body and aortic arch. They respond to oxygen levels, carbon dioxide levels, and pH of the blood. They become stimulated when oxygen decreases, carbon dioxide increases, and the pH decreases. Central chemoreceptors are located in the medulla oblongata and measure the pH and carbon dioxide changes of the cerebral spinal fluid.

Autoregulation

Autoregulation is the method by which an organ or tissue maintains blood flow despite a change in perfusion pressure. When blood flow becomes decreased to an organ, arterioles dilate to reduce resistance.

• Myogenic theory: Myogenic regulation is intrinsic to the vascular smooth muscle. When there is an increase in perfusion, the vascular smooth muscle stretches, causing it to constrict the artery. If there is a decrease in pressure to the arteriole, then there is decreased stretching of the smooth muscle, which would lead to the relaxation of the smooth muscles and dilation of the arteriole.
• Metabolic theory: Blood flow is closely related to metabolic activity. When there is an increase in metabolism to muscle or any tissue, there is an increase in blood flow to that location. Metabolic activity creates substances that are vasoactive and stimulate vasodilation. The increase or decrease in metabolism leads to an increase or decrease in metabolic byproducts that cause vasodilation. Increased adenosine, carbon dioxide, potassium, hydrogen ion, lactic acid levels, and decreased oxygen levels, and increased oxygen demand all lead to vasodilation. Adenosine is from AMP, which derives from the hydrolysis of ATP and increases during hypoxia or increased oxygen consumption. Potassium is increased extracellularly during metabolic activity (muscle contraction) and has a direct effect on relaxing smooth muscles. Carbon dioxide is produced as a byproduct of the oxidative pathway and increases with metabolic activity. Carbon dioxide diffuses to vascular smooth muscle and triggers an intracellular pathway to relax the vascular smooth muscle.
• Heart: Metabolites that cause coronary vasodilation include adenosine, NO, carbon dioxide, and low oxygen.
• Brain: The primary metabolite controlling cerebral blood flow is carbon dioxide. An increase in arterial carbon dioxide causes vasodilation of cerebral vasculature. A decrease in arterial carbon dioxide causes vasoconstriction of the cerebral vasculature. Hydrogen ions do not cross the blood-brain barrier and thus are not a factor in regulating cerebral blood flow. A decrease in oxygen pressure in arteries causes vasodilation of the cerebral arteries; however, an increase in oxygen pressure in arteries does not cause vasoconstriction.
• Kidneys: Autoregulation of the kidneys is myogenic and with tubuloglomerular feedback. In severe cases of hypotension, kidney arterioles constrict, and renal function is lost.
• Lungs: Hypoxia of the lungs causes vasoconstriction, creating a shunt away from poorly ventilated areas of the lung and redirects perfusion to ventilated portions of the lung.
• Skeletal muscle: Adenosine, potassium, hydrogen ion, lactate, and carbon dioxide all increase during exercise and cause vasodilation. When resting, the skeletal muscle is controlled extrinsically by sympathetic activity and not by metabolites.
• Skin: Regulation of the skin occurs through sympathetic stimulation. The purpose of regulating blood flow in the skin is to regulate body temperature. In a warm environment, skin vasculature dilates due to a decrease in sympathetic stimulation. In cold environments, skin vasculature constricts due to an increase in sympathetic activity. During fever, the regulation of the body temperature is at a higher setpoint.

The starling equation can explain the capillary fluid exchange. This equation describes the forces of oncotic and hydrostatic pressure on the movement of fluid across the capillary membrane. Edema can result from an increase in capillary pressure (heart failure), a decrease in plasma proteins (liver failure), an increase in the interstitial fluid due to lymphatic blockage, or an increase in capillary permeability due to infections or burns.

Heart Circulation

Coronary circulation is the circulation of blood in the blood vessels of the heart.

Coronary circulation is the circulation of blood in the blood vessels of the heart muscle. The vessels that deliver oxygen-rich blood to the myocardium are known as coronary arteries. The vessels that remove the deoxygenated blood from the heart muscle are known as cardiac veins. The blood supply to the heart is greater than that of other body tissues since the heart has a constant metabolic demand that must be satisfied to keep the heart pumping at all times.

Coronary Artery Structure

The coronary arteries originate from the left side of the heart descending from the aorta. There are multiple coronary arteries derived from the larger right and left coronary arteries. For example, important coronary arteries that branch off from the larger arteries include the left anterior descending (LAD) coronary and the right posterior coronary.

Coronary arteries run both along the surface of the heart and deep within the myocardium, which has the greatest metabolic demands of all the heart tissues due to its muscle content. Epicardial coronary arteries, which run along on the surface of the heart, are capable of autoregulating vasodilation and vasoconstriction to maintain coronary blood flow at appropriate levels to fit the metabolic demands of the heart muscle. These vessels are relatively narrow and thus vulnerable to blockage, which may cause a myocardial infarction. Subendocardial coronary arteries run deep within the myocardium to provide oxygen throughout the muscle tissue of the cardiac wall.

Systole and Diastole

In systole, the ventricular myocardium contracts, generating high intraventricular pressure and compressing the subendocardial coronary vessels while allowing the epicardial coronary vessels to remain fully open. With the subendocardial coronary vessels compressed, blood flow essentially stops below the surface of the myocardium.

In diastole, the ventricular myocardium contracts, lowering the intraventricular pressure and allowing the subendocardial vessels to become open again. Due to the high pressures generated in the ventricular myocardium during systole, most myocardial tissue perfusion occurs during diastole. Additionally, catecholamines such as norepinephrine, which normally cause vasoconstriction will instead cause vasodilation within the coronary arteries. This mechanism is due to beta-adrenergic receptors in the coronary arteries and helps enable the increased cardiac output associated with fight-or-flight responses.

Myocardial Infarctions

A myocardial infarction (heart attack) may be caused by prolonged ischemia (oxygen deprivation) in the heart, which occurs due to blockage of any of the coronary arteries. Since there is very little unnecessary blood supply to the myocardium, blockage of these vessels can cause serious damage. When these vessels become blocked, the myocardium becomes oxygen-deprived, a condition called ischemia. Brief periods of ischemia in the heart are associated with intense chest pain called angina, which may either be transient if the clot breaks up on its own or stable if it does not. As the time period of ischemia increases, the hypoxic conditions cause muscle tissue to die, causing myocardial infarction (heart attack).

Myocardial infarction is one of the most common causes of death worldwide. The clots that cause the infarction are usually the result of ruptured atherosclerotic plaques that break off and occlude the coronary arteries, but arterial thrombosis from injury or pooled blood may also cause a heart attack. The tissues of the heart do not regenerate, so those that survive a myocardial infarction will generally have scar tissue in their myocardium and may be more susceptible to other heart problems in the future.

Operation of Atrioventricular Valves

The atrioventricular valves separate the atria from the ventricles and prevent backflow from the ventricles into the atria during systole.

A heart valve allows blood flow in only one direction through the heart, and the combination of the atrioventricular and semi-lunar heart valves determines the pathway of blood flow. Valves open or close based on pressure differences across the valve. The atrioventricular (AV) valves separate the atria from the ventricles on each side of the heart and prevent the backflow of blood from the ventricles into the atria during systole.

Subvalvular Apparatus

The subvalvular apparatus describes the structures beneath the AV valves that prevent the valves from prolapsing. Valve prolapse means that the valves do not close properly, which may cause regurgitation or backflow of blood from the ventricle back into the atria, which is inefficient. The subvalvular apparatus includes the chordae tendineae and the papillary muscles. The AV valves are anchored to the wall of the ventricle by chordae tendineae (heartstrings), small tendons that prevent backflow by stopping the valve leaflets from inverting. The chordae tendineae are inelastic and attached at one end to the papillary muscles and at the other end to the valve cusps.

Papillary muscles are finger-like projections from the wall of the ventricle that anchor the chordae tendineae. This connection provides tension to hold the valves in place and prevent them from prolapsing into the atria when they close, preventing the risk of regurgitation. The subvalvular apparatus has no effect on the opening and closing of the valves, which is caused entirely by the pressure gradient of blood across the valve as blood flows from high pressure to low pressure areas.

The Mitral Valve

The mitral valve is on the left side of the heart and allows the blood to flow from the left atrium into the left ventricle. It is also known as the bicuspid valve because it contains two leaflets (cusps). The relaxation of the ventricular myocardium and the contraction of the atrial myocardium causes a pressure gradient that allows for rapid blood flow from the left atrium into the left ventricle across the mitral valve. Atrial systole (contraction) increases the pressure in the atria, while ventricular diastole (relaxation) decreases the pressure in the ventricle, causing the pressure-induced flow of blood across the valve. The mitral annulus, a ring around the mitral valve, changes in shape and size during the cardiac cycle to prevent backflow. The ring contracts at the end of the atrial systole due to the contraction of the left atrium around it, which aids in bringing the leaflets together to provide firm closure during ventricular systole.

The Tricuspid Valve

The tricuspid valve is the three-leaflet valve on the right side of the heart between the right atrium and the right ventricle and stops the backflow of blood between the two. The tricuspid valve functions similarly to the bicuspid valve except that three chordae tendineae connect the cusps of the valve to three papillary muscles, rather than the pair that connects the bicuspid valve. Blood passes through the tricuspid valve the same as it does through the bicuspid valve, based on a pressure gradient from high pressure to low pressure during systole and diastole.

The reason that the valves have different numbers of leaflets is not fully understood but may arise from differences in tissue structure and pressure that occur during fetal development.

Operation of Semilunar Valves

The semilunar valves allow blood to be pumped into the major arteries while preventing the backflow of blood from the arteries into the ventricles.

The semilunar valves are located at the connections between the pulmonary artery and the right ventricle, and the aorta and the left ventricle. These valves allow blood to be pumped forward into the arteries but prevent the backflow of blood from the arteries into the ventricles. These valves do not have subvalvular apparatus and are more similar to the semilunar valves in veins and lymphatic vessels than to atrioventricular (AV) valves.

The semilunar valves act in concert with the AV valves to direct blood flow through the heart. When the atrioventricular valves are open, the semilunar valves are shut and blood is forced into the ventricles. When the AV valves shut, the semilunar valves open, forcing blood into the aorta and pulmonary artery. The mechanism for this process depends on blood pressure gradients in the heart, which provide the force that pushes blood through the semilunar valves.

The Aortic Valve

The aortic valve separates the left ventricle from the aorta and has three cusps. During ventricular systole, pressure rises in the left ventricle. When the pressure in the left ventricle exceeds the pressure in the aorta, the aortic valve opens and blood flows from the left ventricle into the aorta. When ventricular systole ends, pressure in the left ventricle drops rapidly, and the valve closes due to a lack of pressure imposed on them from the left ventricle. Blood pressure within the aorta following systole also causes the closing of the valve. The closing of the aortic valve produces a sound that is a component of the second heart sound.

The Pulmonary Valve

The pulmonary valve (also called the pulmonic valve), which also has three cusps, separates the right ventricle from the pulmonary artery. Similar to the aortic valve, the pulmonary valve opens in ventricular systole when the pressure in the right ventricle exceeds the pressure in the pulmonary artery. When ventricular systole ends, pressure in the right ventricle drops rapidly, and the pressure in the pulmonary artery forces the pulmonary valve to close. The closure of the pulmonary valve also produces a sound, however, it is softer than the aortic sound because the blood pressure in the right side of the heart is lower compared to the left side, due to the differences between pulmonary and systemic circulation.

Valve Problems

Valves are vulnerable to several conditions that impair their normal functions. Two of the most common problems with the semilunar valves are stenosis and regurgitation.  Valve stenosis refers to a narrowing of the valves, which prevents the valve from opening fully, causing an obstruction of blood flow. Valve stenosis is often caused by calcium buildup and scarring from rheumatic fever and may cause cardiac hypertrophy and heart failure. Valve regurgitation is backflow through the valves that occurs when they cannot close completely. It is the cause of most heart murmurs and is generally a minor problem, but if severe enough, it can cause heart failure. Stenosis and regurgitation can occur in both the semilunar and atrioventricular valves.

Systemic and Pulmonary Circulation

The cardiovascular system has two distinct circulatory paths, pulmonary circulation and systemic circulation.

The cardiovascular system is composed of two circulatory paths: pulmonary circulation, the circuit through the lungs where blood is oxygenated; and systemic circulation, the circuit through the rest of the body to provide oxygenated blood. The two circuits are linked to each other through the heart, creating a continuous cycle of blood through the body.

Pulmonary Circulation

Pulmonary circulation is the movement of blood from the heart to the lungs for oxygenation, then back to the heart again. Oxygen-depleted blood from the body leaves the systemic circulation when it enters the right atrium through the superior and inferior venae cavae. The blood is then pumped through the tricuspid valve into the right ventricle. From the right ventricle, blood is pumped through the pulmonary valve and into the pulmonary artery. The pulmonary artery splits into the right and left pulmonary arteries and travel to each lung.

At the lungs, the blood travels through capillary beds on the alveoli where gas exchange occurs, removing carbon dioxide and adding oxygen to the blood. Gas exchange occurs due to gas partial pressure gradients across the alveoli of the lungs and the capillaries interwoven in the alveoli. The oxygenated blood then leaves the lungs through pulmonary veins, which return it to the left atrium, completing the pulmonary circuit. As the pulmonary circuit ends, the systemic circuit begins.

Systemic Circulation

Systemic circulation is the movement of blood from the heart through the body to provide oxygen and nutrients to the tissues of the body while bringing deoxygenated blood back to the heart. Oxygenated blood enters the left atrium from the pulmonary veins. The blood is then pumped through the mitral valve into the left ventricle. From the left ventricle, blood is pumped through the aortic valve and into the aorta, the body’s largest artery. The aorta arches and branches into major arteries to the upper body before passing through the diaphragm, where it branches further into the iliac, renal, and suprarenal arteries which supply the lower parts of the body.

The arteries branch into smaller arteries, arterioles, and finally capillaries. Gas and nutrient exchange with the tissues occurs within the capillaries that run through the tissues. Metabolic waste and carbon dioxide diffuse out of the cell into the blood, while oxygen and glucose in the blood diffuse out of the blood and into the cell. Systemic circulation keeps the metabolism of every organ and every tissue in the body alive, with the exception of the parenchyma of the lungs, which are supplied by pulmonary circulation.

The deoxygenated blood continues through the capillaries which merge into venules, then veins, and finally the venae cavae, which drain into the right atrium of the heart. From the right atrium, the blood will travel through the pulmonary circulation to be oxygenated before returning gain to the system circulation, completing the cycle of circulation through the body. The arterial component of systemic circulation the highest blood pressure in the body. The venous component of systemic circulation has considerably lower blood pressure in comparison, due to their distance from the heart, but contains semi-lunar valves to compensate. Systemic circulation as a whole is a higher pressure system than pulmonary circulation simply because systemic circulation must force greater volumes of blood farther through the body compared to pulmonary circulation.

The nervous system regulates the cardiovascular system with the help of baroreceptors and chemoreceptors. Both receptors are located in the carotids and aortic arch. Also, both have afferent signals through the vagus nerve from the aortic arch and afferent signals through the glossopharyngeal nerve from the carotids.

• Baroreceptors are more specifically located in the carotid sinus and aortic arch. They respond quickly to changes in blood pressure.
• A decrease in blood pressure or blood volume causes hypotension, which leads to a decrease in arterial pressure, which creates a decrease in the stretch of the baroreceptors and decreases afferent baroreceptor signaling. This decrease in afferent signaling from the baroreceptor causes an increase in efferent sympathetic activity and a reduction in parasympathetic activity, which leads to vasoconstriction, increase heart rate, increase contractility, and an increase in BP. The vasoconstriction increases TPR in the equation MAP=CO*TPR to bring pressure (MAP) back up.
• An increase in blood pressure or blood volume causes hypertension which increases the stretch of the baroreceptors
• Chemoreceptors come in 2 types: peripheral and central. Peripheral chemoreceptors are specifically located in the carotid body and aortic arch. They respond to oxygen levels, carbon dioxide levels, and pH of the blood. They become stimulated when oxygen decreases, carbon dioxide increases, and the pH decreases. Central chemoreceptors are located in the medulla oblongata and measure the pH and carbon dioxide changes of the cerebral spinal fluid.

Autoregulation

Autoregulation is the method by which an organ or tissue maintains blood flow despite a change in perfusion pressure. When blood flow becomes decreased to an organ, arterioles dilate to reduce resistance.

• Myogenic theory: Myogenic regulation is intrinsic to the vascular smooth muscle. When there is an increase in perfusion, the vascular smooth muscle stretches, causing it to constrict the artery. If there is a decrease in pressure to the arteriole, then there is decreased stretching of the smooth muscle, which would lead to the relaxation of the smooth muscles and dilation of the arteriole.
• Metabolic theory: Blood flow is closely related to metabolic activity. When there is an increase in metabolism to muscle or any tissue, there is an increase in blood flow to that location. Metabolic activity creates substances that are vasoactive and stimulate vasodilation. The increase or decrease in metabolism leads to an increase or decrease in metabolic byproducts that cause vasodilation. Increased adenosine, carbon dioxide, potassium, hydrogen ion, lactic acid levels, and decreased oxygen levels, and increased oxygen demand all lead to vasodilation. Adenosine is from AMP, which derives from the hydrolysis of ATP and increases during hypoxia or increased oxygen consumption. Potassium is increased extracellularly during metabolic activity (muscle contraction) and has a direct effect on relaxing smooth muscles. Carbon dioxide is produced as a byproduct of the oxidative pathway and increases with metabolic activity. Carbon dioxide diffuses to vascular smooth muscle and triggers an intracellular pathway to relax the vascular smooth muscle.
• Heart: Metabolites that cause coronary vasodilation include adenosine, NO, carbon dioxide, and low oxygen.
• Brain: The primary metabolite controlling cerebral blood flow is carbon dioxide. An increase in arterial carbon dioxide causes vasodilation of cerebral vasculature. A decrease in arterial carbon dioxide causes vasoconstriction of the cerebral vasculature. Hydrogen ions do not cross the blood-brain barrier and thus are not a factor in regulating cerebral blood flow. A decrease in oxygen pressure in arteries causes vasodilation of the cerebral arteries; however, an increase in oxygen pressure in arteries does not cause vasoconstriction.
• Kidneys: Autoregulation of the kidneys is myogenic and with tubuloglomerular feedback. In severe cases of hypotension, kidney arterioles constrict, and renal function is lost.
• Lungs: Hypoxia of the lungs causes vasoconstriction, creating a shunt away from poorly ventilated areas of the lung and redirects perfusion to ventilated portions of the lung.
• Skeletal muscle: Adenosine, potassium, hydrogen ion, lactate, and carbon dioxide all increase during exercise and cause vasodilation. When resting, the skeletal muscle is controlled extrinsically by sympathetic activity and not by metabolites.
• Skin: Regulation of the skin occurs through sympathetic stimulation. The purpose of regulating blood flow in the skin is to regulate body temperature. In a warm environment, skin vasculature dilates due to a decrease in sympathetic stimulation. In cold environments, skin vasculature constricts due to an increase in sympathetic activity. During fever, the regulation of the body temperature is at a higher setpoint.

The starling equation can explain the capillary fluid exchange. This equation describes the forces of oncotic and hydrostatic pressure on the movement of fluid across the capillary membrane. Edema can result from an increase in capillary pressure (heart failure), a decrease in plasma proteins (liver failure), an increase in the interstitial fluid due to lymphatic blockage, or an increase in capillary permeability due to infections or burns.