BLOOD COMPOSITION AND CIRCULATION

BLOOD COMPOSITION AND CIRCULATION

1.   BLOOD COMPOSITION AND CIRCULATION

1.1.    Blood
Blood is a kind of fluid connecting tissue that circulates regularly to provide nutrition, oxygen, and to remove waste product from the body. Blood is largely made up of liquid in which many cells and proteins are suspended to make it viscous than pure water. 
The liquid found in blood is termed as plasma, contributing approximately half (55%) of the blood content. Plasma contains proteins that perform numerous functions and also contains glucose and other dissolved nutrients.
The next half (45%) content of blood tissue is made up of blood corpuscles like
•     Red blood corpuscles (Erythrocytes); 4.7 to 6.1 million (male), 4.2 to 5.4 million (female)
•     White blood corpuscles (Leukocytes);  4,000–11,000 leukocytes
•     Platelet corpuscles (Thrombocytes); 200,000–500,000 thrombocytes
1.2.    Erythrocytes
These are the most common type of blood cells that act as the principal element for O2 transport in vertebrates. During blood circulation, they take up oxygen from lungs or gills and release it into tissues.
The erythrocytes contain a large amount of a cytoplasmic protein, haemoglobin. It is an iron-containing metalloprotein that can bind oxygen and gives the red colour to these cells. The membrane of these cells is composed of proteins and lipids that provide essential physiological cell functions like deformability and stability.
The mature red blood cells of humans are flexible and of oval biconcave shaped, they also lack a cell nucleus and most organelles to provide maximum space for haemoglobin. In a human body, around 2.4 million erythrocytes are generated per second in the bone marrow and each of them circulates 100–120 days in the body until they are recycled by macrophages, in the spleen. The condition where RBC count is higher named as polycythaemia and low-level count termed as anaemia.
The roles of RBCs in the body of an individual are
•    Oxygen transport from lungs to whole body tissues.
•    They release ATP under shear stress to dilate the blood vessels for lowering of blood pressure.
•    They also release S-nitrosothiols at the time of deoxygenation of haemoglobin to dilate blood vessels to allow more blood to flow.
•    Using L-arginine as a substrate they also synthesize nitric oxide enzymatically, that may regulate the minimal vascular activity.
•    RBCs also produce hydrogen sulfide, as a signalling molecule to relax vessel walls. 
•     The free radicals are also produced by the haemoglobin upon pathogenic lysis of RBCs, which kills the pathogen by degrading their cell wall and other structures.

1.3.    Leukocytes
These are the colourless nucleated cells that lack haemoglobin but able to localize. The leucocytes are also having a unique feature to defend the body against infections by ingesting or by destroying infectious agents via antibodies production.
A healthy adult human has 4,500 to11, 000 WBCs per cubic millimetre that makes about 1 % of total blood volume. However, the number of cells fluctuates during a day, like lowers while resting and higher during exercise. The increase in the mean value of leukocytes is known as leukocytosis and the decreased value is termed as leukopenia.
These cells are divided into five classes based on morphological characteristics appeared during staining.
•    Neutrophils (40% - 75%)            
•    Eosinophils (1% - 6%)
•    Basophils (less than 1%)            
•    Monocytes (2%-10%)
•    Lymphocytes (20%-45%)
Neutrophils, Eosinophils, and Basophils are collectively known as granulocytes because of granules residing in their cytoplasm. Remaining cells like Monocytes and lymphocytes are called as (agranulocytes) mononuclear cells.
1.3.1.    Neutrophils
The granulocytes filled with microscopic granules, containing enzymes that digest microorganisms so that's why also known as a polymorphonuclear leukocyte. Neutrophils migrate into the extravascular tissues and activated by chemoattractants at the injury site, where they ingest the bacteria by phagocytosis and release the enzymes to destroy them.
1.3.2.    Eosinophils
The Eosinophils are specialized cells of the immune system having the bilobed nucleus and cytoplasm filled with numerous granules containing enzymes and proteins. These cells migrate into the extravascular tissues through blood and survive there for weeks. The chemoattractants direct the movement of Eosinophils to phagocyte the bacteria. These cells do not ingest the bacteria but they do exert cytotoxic effects on them.
1.3.3.    Basophils
They make up about 0.5% of the total number of leukocytes and circulate in the blood and also found throughout many tissues. These cells protect the body by killing bacteria and other parasites. When these cells are stimulated by complexes of antigens that are bound to IgE (antibody); they cause inflammatory reactions by releasing histamine and heparin.
1.3.4.    Monocytes
These are the largest leukocytes that mature into macrophages upon entering the bloodstream. Then they migrate to the tissues like liver, lymph nodes, and lungs and stay for several days or years. Monocytes are active phagocytes and ingest particulate matter. These cells also ingest and process antigens and play a crucial role in antigen presentation.
1.3.5.    Lymphocytes

These types of leukocytes are fundamentally important immune cells that determine the specificity of the immune response to the infectious agent. Lymphocytes are found in both circulation and central lymphoid organs like spleen, tonsils, and lymph nodes.
These cells are categorized into two types; B-cells and T-cells. Both cells originate from stem cells in the bone marrow so that's why initially similar in appearance. Some of them migrate to the thymus and mature into T cells; while others remain in the bone marrow and develop into B cells. These immune cells are responsible for immunologic “memory”, that facilitate the more rapid and vigorous response upon the second encounter with the same antigen. The high count of lymphocytes is termed as lymphocytosis whereas low count is known as lymphopenia.

1.4.    Thrombocytes
These are anucleated cell fragments called platelets produced in bone marrow by cytoplasmic fragmentation of megakaryocytes. They exhibit a significant role in blood clotting by sticking to the lining of blood vessels. These are biconvex discoid structures of 2–3 µm diameters. Non-mammalian thrombocytes circulate as intact mononuclear cells. The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20. The condition of elevated levels of thrombocytes is known as thrombocytosis and decreased value condition is termed as thrombocytopenia.
1.5.    Haematopoiesis
Hematopoiesis sometimes also named as hemopoiesis or hemopoiesis. It is the process of formation of blood cells from hematopoietic stem cells. A healthy adult person produces approximately 1011–1012 new blood cells daily in order to maintain equilibrium levels in the circulation. The site of hematopoiesis varies as the individual develop from the embryo to the fully mature adult as shown in the table below
Foetus                     0–2 months (yolk sac)
                                2–7 months (liver, spleen)
                                5–9 months (bone marrow) Red bone marrow
    Infant                    Bone marrow (practically all bones)
    Adult                  Vertebrae, ribs, sternum, skull, sacrum and pelvis, proximal ends of the femur      


Haematopoietic stem cells (HSCs) are present in the medullary region of the bone (i.e. bone marrow). These stem cells exhibit their unique ability to differentiate into all different mature blood cells and to self-renewal. During their proliferation (division), few of the daughter cells remain as HSCs to maintain their pool and the other daughter's cells become myeloid or lymphoid progenitor cells. The pool of progenitor cells is heterogeneous. It may be of either long-term self-renewing HSC or short-term self-renewing HSC (transient).

The bone marrow is composed of stromal cells and a microvascular network. The adipocytes, fibroblasts, endothelial cells and macrophages are collectively called as stromal cells. These cells secrete some extracellular molecules to form an extracellular matrix; the molecules are collagen, glycoproteins (fibronectin and thrombospondin) and glycosaminoglycans (hyaluronic acid and chondroitin derivatives). These stromal cells also secrete numerous growth factors for stem cell survival. The stem cell factor (SCF) and Jagged proteins expressed on stroma and their respective receptors c-Kit and notch expressed on stem cell are critical to maintaining stem cell viability and production in the stroma. 
Haemopoiesis begins with stem cell proliferation which includes self-renewal and differentiation.  The selection of a cell to commit for either stem cell or progenitor cell depends on the chance and on the external signals reception. Earlier they express low levels of transcription factors, determining their fate. Many transcription factors are involved in the regulation of cell lineage differentiation like, PU-1 commits cells to the myeloid lineage and GATA-1 involved in erythropoietic and megakaryocytic lineage commitments.
These biomolecules are collectively termed as hematopoietic growth factors, which are simply the glycoprotein hormones that regulate the differentiation, maturation and function of the cell forming from the lineages.
Some common growth factors are listed below in the table according to their related cell lineages and also represented by the schematic diagram shown here.


Lymphoid precursor cells initially undergo special differentiation (in the thymus or bone marrow) and later in the major lymph nodes as well as in the bone marrow. Remaining precursor cells are derived from myeloid progenitor cells of bone marrow through the process of proliferation, maturation, and release into the bloodstream. 
Erythropoietin and thrombopoietin are the two hormones, which involved in myelopoiesis. 
Thrombopoietin (mainly from the liver) triggers the development of megakaryocytes that give rise to platelets and erythropoietin promotes the maturation and proliferation of erythrocytes, that is secreted by the liver in the foetus, and chiefly by the kidney after birth in response to hypoxia (oxygen deficiency).
The life span of a red blood cell is around 120 days so why they regularly exit from arterioles in the spleen, where old RBC’s are sorted out and destroyed (hemolysis). 

The iron-containing group (heam) of haemoglobin released during hemolysis and broken down into bilirubin to recycle the iron. Ferritin is one of the chief forms of the body iron store that resides mainly in the intestinal mucosa, liver, bone marrow, red blood cells, and plasma. Ferritin contains binding pockets for approximately 4500 Fe3+ ions and it serves as rapidly available stores of iron.
The iron deficiency inhibits the haemoglobin synthesis and causes hypochromic microcytic anaemia and the Iron overload commonly damage the liver, pancreas and myocardium (hemochromatosis).
Vitamin B12 (cobalamin) and folic acid are also critical for erythropoiesis and their deficiencies may lead to hyperchromic Anemia, but decreased cobalamin absorption does not lead to symptoms until many years later because of large storage. However, folic acid deficiency leads to symptoms within a few months.

1.6.    Anemias
The term Anemia is concerned with the deficiency of haemoglobin in the blood, either due to lack of red blood cells or due to haemoglobin crisis in the RBC’s. There are so many kinds of Anemias are observed in the human population, Some of them are 
1.6.1.    Blood Loss Anemia: After an effective haemorrhage, the body recovers the fluid portion of the plasma in 1 to 3 days, but the concentration of red blood cells remains low.
1.6.2.    Aplastic Anemia:  Lack of functioning bone marrow (bone marrow aplasia)  because of genetic defect or on intense exposure to g-rays, X-rays and sensitive chemicals of drugs or industries. The symptoms of aplastic Anemia are similar to those of Megaloblastic Anemia, occurs due to the insufficiency of folic acid, vitamin B12 and other vitamin B compounds.
1.6.3.    Hemolytic Anemia: The abnormality of RBC’s make them fragile that's why cells rupture easily during circulation and the mean life span is reduced and the steady state not maintained. Like in hereditary spherocytosis,  sickle cell Anemia.
In severe Anemia, the blood viscosity may fall to 1.5 times than the normal value of about 3 and leads to increased blood flow in the peripheral blood vessels and cardiac output (increased pumping workload on the heart). On excessive demand for oxygen in tissues (extreme hypoxia)  like during intense exercise, it may lead to acute cardiac failure due to extreme pumping workload.
1.7.    Polycythemia
Polycythemia is an abnormal physiological state in which the proportion of red blood cells increases in the blood volume. The absolute polycythemias are categorized as
1.7.1.    Primary polycythemia: It occurs when excess red blood cells are produced because of abnormal bone marrow. Like Polycythemia vera (PCV), polycythemia rubra vera (PRV), or erythremia that exhibit symptoms like headaches, vertigo, abnormally enlarged spleen or liver and high blood pressure or formation of blood clots.
1.7.2.    Secondary polycythemia: Natural or artificial increases in the production of erythropoietin cause increased erythropoiesis, also called as physiologic polycythemia. The conditions which cause the physiological polycythemia are high altitudes, Hypoxic disease, phlebotomy (bloodletting), Neoplasms and use of anabolic steroids.
The increased levels of RBC greatly increase the viscosity of the blood that decreases the rate of venous return to the heart that conversely increase the blood volume to increase venous return.
The regulating mechanisms can usually offset the tendency for increased blood viscosity to increase peripheral resistance and arterial pressure. However; these regulations fail beyond certain limits and leads to hypertension. That leads to the increased quantity of blood in venous plexus, give rise to the ruddy complexion with a bluish (cyanotic) tint to the skin.

1.8.    Blood plasma
Blood plasma is the pale yellow liquid portion of blood, which is 92 percent water and constitutes about 55 percent of blood volume. Plasma is a protein-salt solution that normally holds the cellular components of the whole blood in suspension, that is why it is also known as the extracellular matrix of blood cells. 
This intravascular fluid contains 6–8% proteins (like; serum albumins, globulins, and fibrinogen), glucose, clotting factors, electrolytes (Na+, Ca+2, Mg+2, HCO3, Cl, etc.), hormones, and carbon dioxide.
Plasma also serves as the protein reserve and the exchange medium for vital electrolytes to maintain the proper osmotic balance in the body, crucial for cell and protects the body from infection.
1.8.1.    Composition and function
The composition of the plasma is listed below in the table where the function of each individual component also given opposite to them.

1.9.    Blood volume
Blood volume is simply the total volume occupied by the blood components (plasma and RBC’s) in the body of an individual animal. Blood volume can be calculated as given below 

Here, BV stands for blood volume, PV for plasma volume and HC stands for hematocrit (RBC fraction of the blood). In a typical adult human, the amount of blood volume is approximately 5 litres. However, the blood volume in females is generally less than blood volume of males.  Blood volume of an individual is regulated by the kidneys.
Blood volume can also be determined by estimating the amount of water and sodium ingested and excreted by the kidneys into the urine or lost through the gastrointestinal tract, lungs and skin. However, the amounts of water and sodium gain or loss are highly variable.
The kidneys regulate the amount of water and sodium into the urine to regulate the intravascular blood volume. The blood is filtered at the glomerular capsule of the nephron, excretory unit of the kidney.
The filtrate obtained at proximal convoluted tubule (PCT) contains ions, water and other substances that pass through the Henle’s loop, distal convoluted tubule (DCT) and collecting tubules (CT). During this, the concentration of ions like sodium, glucose and water alters because of their reabsorption. The transport of sodium is regulated by angiotensin II (Ang II), by increasing the sodium transport that leads to sodium retention. Aldosterone is the other hormone that induces the sodium reabsorption from the tubular fluid. Another pituitary secretion i.e. antidiuretic hormone (ADH/ vasopressin) also helps to maintain the blood water level by increasing water reabsorption from the late distal tubules and collecting tubules. Apart from this hormonal regulation of sodium and water retake the renal blood pressure and the rate of filtration also play a significant role in blood volume maintenance.
The activated renin-angiotensin-aldosterone (RAAS) system reduces the loss of water into the urine to expand the blood volume. The activation of this system takes place during heart failure to retain the body. 
1.10.    Blood groups
Although all blood is made of the likely basic elements, that are similar but not the same at all.  The types of blood are determined on the basis of the presence or absence of inherited antigenic substances that are found on the surface of red blood cells. These antigens are may be proteins, carbohydrates, glycoproteins or glycolipids depending on the type of blood. Some of them can be found on the surface of other cells of various tissues. Approximately 35 human blood group types have been recognized by the International Society of Blood Transfusion (ISBT). These 35 blood groups have sum of 600 antigens out of which any 30 types can determine a complete blood group.
The determinants of blood types are inherited from both parents, among which the two most important are ABO and Rh D antigen. The ABO antigens determine the A, B, AB and O blood types, whereas the Rh D antigens predict the –ve, +ve or null status of the groups determined by ABO antigens.
The all blood types are classified in the eight blood groups, four out of eight are determined on the basis of RBC antigens (A &B) and the latter four are seems to be their subtypes, determined by the presence or absence of the Rh antigen along with them. The basic concept behind blood grouping is shown in the figures below

All people synthesize a precursor carbohydrate, called the H antigen that is attached to lipids or proteins on red blood cells. The H antigen then specified later into A and B blood group antigens by the action two glycosyltransferases. The blood group A glycan by 1,3GalNAc transferase and the blood group B glycan by 1, 3-Gal transferase.
While the O genes code inactive glycosyltransferase. Therefore, express unmodified H antigen but the A and B genes co-dominates with copies of both genes and represents the blood group AB.
like this these O-linked glycoproteins with their exposed sugar residues determines the antigen type.

Some individuals may not possess a functional H gene, therefore lacks H antigen and hence why they cannot produce A and B antigens. Because of this, they produce anti-A, anti-B, and anti-H antibodies and exhibit a new phenotype, called the "Bombay phenotype" after it was first discovered in the Bombay. These individuals are healthy but if they ever required a blood transfusion, the antibodies present in their serum for all A, B and H  antigens highly increases the risk of having an acute haemolytic transfusion reaction and it can be avoided only by using blood products from a donor having the Bombay phenotype.
The Rh antigens are transmembrane proteins having exposed loops on the surface of red blood cells. They may be helpful in the transport of carbon dioxide and ammonia across the plasma membrane. They are named after the rhesus monkey from which these antigens were first identified. A red blood cell may express numerous Rh antigens and call as "Rh-positive", designated as “D”. However, the cells that do not express such antigen are called as "Rh-negative". The frequency of this antigen in a population is about 15%.
The major significance of the Rh system in human population is to avoid the risk of RhD incompatibility between mother and its developing foetus. If the developing baby of an Rh –ve mother gets an RhD allele from its father it will show Rh +ve phenotype. During parturition in such cases, there is often leakage of the baby's RBCs into the mother's blood and the mother immune system develops antibodies against it. That antibody does not affect that child but on further pregnancies, if a baby gets such phenotype, then the IgG antibodies produced against the RhD antigen can cross the placenta and attack the RBCs of the baby and cause the Anemia and jaundice. This hemolytic disease of the newborn is specially termed as erythroblastosis fetalis that may kill the fetus or even the newborn infant.
1.11.    Hemostasis
Hemostasis is the normal physiological response of a body that occurs during a haemorrhage, to prevent and stop the bleeding (outflow of blood) by vasoconstriction and coagulation. It seems to be the first stage of wound healing that involves blood transformation from a liquid to a gel.
It can be also achieved in other ways if it does not occur naturally during surgery or medical treatment. Hemostasis is harder to achieve under shock and stress that increases the risk of haemorrhage. However, it can be achieved by many chemical, mechanical or physical agents. 
Generally, the endothelial cells of blood vessels prevent blood clotting and platelet aggregation with a heparin-like molecule, thrombomodulin, with nitric oxide and prostacyclin respectively. But if an injury occurs in the endothelial cells, they stop such secretions that prevent coagulation and aggregation and instead secretes Von Wille brand factor to initiate the hemostasis.
The process of hemostasis is divided into three major steps:-
1.11.1.     Vascular spasm- The very first response to the injury in which damaged vessels will constrict to reduce the amount of blood flow to limit the blood loss. It is triggered by factors like the direct injury to vascular smooth muscles, secretion of endothelial cells and platelets and the reflexes initiated by local pain receptors. Vascular constriction is more effective in smaller blood vessels but its intensity increases with the amount of damage. This process is mediated by vaso-constrictors like thromboxane, released at the site of the injury and the epinephrine from adrenal glands. 
1.11.2.     Platelet plug formation – After vascular spasm, the platelets aggregates near damaged endothelium to form a plug when activated by a glycoprotein, Von Wille brand factor present in blood plasma. As the platelets adhere on the collagen fibers of a wound, they become stickier and spiked and then release adenosine diphosphate (ADP), serotonin and thromboxane A2 to activate the more platelets to aggregate and to secrete. 
This leads to the enhanced vascular spasms and creation of a platelet plug. After the plug formation, the clotting factors found in plasma begins the process of clotting with the formation of collagen fiber, fibrin. Fibrin forms a mesh all around the platelet plug to hold the plug and make it stronger by trapping the RBCs and WBCs. Aspirin inhibits platelet activation by inhibiting the action of thromboxane.

The vascular spasm and the platelets plug forming processes collectively called as primary hemostasis.
1.11.3.     Blood coagulation –The blood has many clotting factors in an inactive state that are activated after endothelial vascular damage in a cascade manner, known as clotting cascade (shown in the figure below).
The blood clots are made from fibers of fibrin that are derived from an inactive precursor called fibrinogen. 
The fibrinogen molecule contains caps on its ends that mask fibrin-to-fibrin binding sites but the enzyme thrombin (derived from prothrombin) converts the fibrinogen to fibrin by removing that caps, leads to polymerization of fibrin monomers with the help of calcium. The polymerized fibrin fibers make a loose mesh-like network that is further stabilized by clotting factor XIII and this mesh then traps blood cells to form the blood clot that stops the flow of blood. This is known as the secondary hemolysis.
In the complete cascade of blood clotting, the thrombin is seemed to be a critical factor that regulates the complete process. The regulatory pathway is classified in the two categories on the basis of the mode of damage (1) the intrinsic pathway and (2) the extrinsic pathway.
The intrinsic pathway is triggered by the component of the blood itself that stimulates the activation of a cascade of clotting factors that finally activates the factor X. The activated factor X act as an enzyme and converts the prothrombin to thrombin, that initiates the clotting cascade.
Whereas in the extrinsic pathway the damage of tissue outside of the blood vessel triggers the clotting pathway by the activation of tissue thromboplastin, that also activates the factor X by catalysis. The activated X factor then initiates the clotting cascade.

Some other aspects are also used in the case of haemorrhage to prevent the excess loss of blood rather than the natural means of hemostasis, which are
•    Chemical / topical agents- These are often used in surgery settings to stop bleeding but they require the normal hemostatic pathway to be properly functional like Microfibrillar collagen
•    Pressure dressing- This kind approach is used in improper medical attention to slow the bleeding from a wound and allowing more time to get to a medical setting. 
•    Sutures and ties- The sutures and ties allow the skin to be joined back together and to assist the platelets to initiate the hemostasis at a quicker pace by reducing the surface area. 
•    Physical agents- These agents are mostly used in surgical settings as well as after surgery that absorbs the blood and allows to coagulate faster. They also give off chemical responses to decrease the time for initiating clotting pathway. Like gelatin sponge
Some physiologically abnormal conditions are also observed in the human population, in which the normal clotting system does not work properly. In these conditions, the individual requires personal attention regarding such conditions. Some of them are listed below
Haemophilia: The condition in which the person suffers from excessive blood loss due to the abnormal coagulation pathway. This could be caused by a deficiency of any of the clotting factors, however, 80% of all haemophiliacs are deficient in factor VIII.  
Thrombosis: The abnormal condition of hyper blood clotting that may cause embolisms, where blood lodges into a vein or artery and blocks the circulation.
Thrombocytopenia: The condition of lower numbers of platelets where the micro-tears of capillaries and arteries do not repair and allows blood to seep into the tissues. In this condition, the purple blotches (thrombocytopenia purpura) appears on the skin. 
Vitamin K deficiency: Vitamin K is required for the maturation of several clotting factors like factor X and prothrombin. So the deficiency of vitamin K inhibits the clotting mechanism that leads to excessive bleeding.
1.12.    Clot Removal 
The blood clots are designed to be temporary because after the clot formation vessel repair begins, in which marginal epithelial cells of the injury undergo cell division and fill the gap due to the injury. The process of repair also required fibroblast cells, which repair the basement membrane of the vessel. After the healing of vessels, the blood clot is no longer needed and subsequently removed in the following way:
The clot stimulates the secretion of tissue plasminogen activator (TPA) from the surrounding vascular epithelium that catalyzes the conversion of plasminogen to plasmin, which dissolves the clots. Or we can say the clot calls for its own destruction by initiating the activation of plasmin as shown below

The substances or agents that have the tendency to inhibit or block the process of  blood clot formation are known as anti-coagulants, that are
1.12.1.    Heparin 
•    Produced primarily in the liver and lung (usually obtained from pigs or cows).
•     Inhibiting the activity of thrombin. 
•     Used to prevent clotting in IVs (heplock) or in other clinical approaches.
1.12.2.    Coumadin (dicoumarol, warfarin) 
•    Taken orally in small doses for long-term control of blood clotting. 
•    Inhibiting the processing of vitamin K 
•    It is a slow acting agent requiring days to show the effect. 
1.12.3.    Citrates  
•    Citrates chelate the calcium ions and thus inhibits the fibrin polymerization. 
•    used in long term blood storage. 
•    Because of calcium chelating, it also disrupts the processes like nerve transmission and muscle contraction. 
1.13.     Comparative Anatomy of Heart
The heart is a muscular organ found in animals to pump the blood through the blood vessels of the circulatory system. It is made up of cardiac muscles and located in the middle compartment of the mediastinum, present in the thoracic cavity. The cardiac muscles that are different from the skeletal and smooth muscles, adjust the rate of muscular contraction to maintain a regular pumping rhythm. The heart is mainly composed of chambers, the valves, and the electrical nodes.
The anatomy of the heart is different among the animal kingdom; some of the major structures are discussed here for better understanding of the evolution of the circulatory system in vertebrates.
1.13.1.    Fish 
Fish is the earliest animal to be considered as vertebrate and it possesses the simplest type of true heart. That is a two-chambered organ, one of which is atrium and another one is ventricle.  These two chambers are interconnected via a rudimentary valve. Here the blood is pumped from the ventricle through the conus arteriosus (largest artery) to the gills where the blood receives oxygen and releases carbon dioxide. Blood then circulate to the organs of the body for the exchange of nutrients, gases and wastes and returns to the atrium through the sinus venosus. The heartbeat rates of fish are 60-240 per minute and depend upon the species and the temperature of water. 

1.13.2.    Amphibians and Reptiles 
Amphibians and reptiles have a three-chambered heart consisting of two atria and one ventricle. (The crocodile is said to have a four-chambers but the ventricles are not completely separated.) Blood pumped out from the ventricle through two vessels, either through pulmonary arteries leading to the lungs or through a forked aorta leading to the rest of the body. The oxygenated blood returning from the lungs through the pulmonary vein reaches the left atrium, while the deoxygenated blood returning from the body through the sinus venosus reaches the right atrium. Both atria pour into the single ventricle, which causes the mixing of both oxygen-rich and oxygen-depleted blood means the organs do not get oxygen saturated blood like in the animals with the four-chambered heart but it is sufficient for these cold-blooded organisms.
The heart rate of amphibians and reptiles directly depends on the environmental temperature. As shown below in the table

1.13.3.    Mammals and Birds 
Mammalian and avian hearts are made up of four chambers – two atria and two ventricles and seem to be the most efficient system in which the deoxygenated and oxygenated blood are not mixed. It also meets the larger oxygen supply required in warm-blooded organisms for thermoregulation.

The heart is a myogenic organ composed of cardiac muscles; it is called as myogenic because its contraction is regulated by muscles forming the organ rather than other stimuli like nerve innervations. This myogenic is acquired due to the inherent property of the cardiac muscles to regulate their own contraction.
1.13.4.     Circulatory routes
The circulation of blood in a mammalian body is done by pumping of heart in which following processes occur.
•    The heart receives deoxygenated blood collected from the whole body through two larger veins in the right atrium, that are superior vena cava (comes from the tissues situated superior to heart) and inferior vena cava (comes from the tissues situated below the heart).
•    The deoxygenated blood from the right atrium is passed to the right ventricle by the contraction in the atrial muscles that lead to the opening of mitral valves (tricuspid).
•    The deoxygenated blood of the right ventricle is pumped by the ventricular contraction through the pulmonary artery to the lungs.
•    The deoxygenated blood reach lungs where gaseous exchange (of O2 and CO2) occurs and the blood became oxygenated.
•    The oxygenated blood comes back to the left atrium of the heart via the pulmonary vein.
•    The oxygenated blood of left atrium is passed to left ventricle via the opening of other mitral valves (bicuspid) due to the auricular contraction.
•    The oxygenated blood residing in the left ventricle is finally pumped again to the whole body due to a strong ventricular contraction in the left of the heart.
•    The oxygenated blood pumped out of heart via arteries, initiates from the largest one, known as the aorta.
The figure shown below is depicting the routes of circulation in which the blood is pumped or received by heart two times, i.e. one through the whole body systems and other through the lungs. This twice circulation of blood in a body is termed as double circulation, in which one is systemic and the second is the pulmonary circulation.

1.14.    Heart composition
A typical mammalian heart is composed of cardiac muscles that form the following structures.
1.14.1.    Heart layers: The walls of the heart is made of three layers that are Epicardium, Myocardium and Endocardium respectively outer to inner direction. The myocardium is the most bulky layer out of all three layers. This combined muscular wall is also surrounded by a membranous layer known as pericardium that covers the whole heart to reduce the contact of heart from nearby organs and to provide optimum space for contractions. 
1.14.2.    Heart valves; the heart of a typical mammalian organism is four-chambered that are separated by a specific muscular structure, septa. The septa that separate the upper chambers (auricle/ atrium) from lower chambers (ventricles) are known as atrio-ventricular septa and comprised of mitral valves. There are two kinds of mitral valves in each septa that is a flap-like structure involved in the prevention of backward flow of blood.
*     Bicuspid valve- situated in the left atrioventricular septa.
*    Tricuspid valve- situated in the right atrioventricular septa.
Besides these, some valves of hemispherical shape are also situated in each exit site of the heart that is known as semi-lunar valves.
*    3 semilunar valves at the origin of the pulmonary artery.
*    3 semilunar valves at the origin of the aorta.
1.15.    Regulation of contraction
As prescribed above the heart is a myogenic organ that does not require any external stimulation to maintain its regular rhythm of contraction. But during some special condition, the contraction rhythm is altered by other external stimulations.
 1.15.1.    Intrinsic regulation
The own regulation of cardiac muscle contraction is mediated by some specialised cardiac fibers that are spread all around the cardiac muscles, that are
*    Sino-Atrial node (S.A. Node): This is a specialised center made up of cardiac fibers that are situated on the dorsal surface of the right atrium and generate a stimulus itself that is passed further to the A.V. node. This is initially critical for the rhythm regulation of the contraction. Hence called as Pacemaker.
*    atrio-ventricular node (A.V. Node): It is also made up of special cardiac fibres that are situated near the middle septa or atrio-ventricular septa. It receives the stimuli generated from S.A. node and passes it to a bundle of cardiac fibers known as the bundle of His.
*    Bundle of His:  It is a bundle or group of cardiac fibers situated in the middle septa that separate the right and left chambers. It receives the stimuli from the A.V. node and passes it further to the whole cardiac muscles.
*    Purkinje fibers: The fibers innervated in the whole cardiac muscles to mediate the supply of stimuli passed on from the bundle of His.
1.15.2.    Extrinsic regulation
Although the heart is myogenic in nature means it regulates its own contraction in normal condition but during extreme condition, the regulation of heart contraction is achieved by some external stimuli.
Central nervous system: The central nervous system can influence the heart contraction rhythm via two means
*    Medulla oblongata- The part of the brain that regulates the heart rate during abnormal conditions.
*    Vagus nerve- The nerve of the central nervous system that decreases the heart contraction rate during special conditions by the release of a neurotransmitter, acetylcholine.
*    Hormonal regulation- The catecholamines (both epinephrine and norepinephrine) increases the heart rate, called Tachycardia.
1.16.    Cardiac cycle and ECG
The cardiac cycle includes all the events occur during a single heartbeat. This includes the systole (contraction) and diastole (relaxation) in cyclic manners that are respectively, atrial systole, ventricular systole, and joint diastole (of both atria and ventricles).
•    Atrial systole: The contraction of atrial walls to pass the blood to the relaxed ventricles. 
•    Ventricular systole: The contraction of ventricular walls to pump out the blood out of the heart. During this, atria remain in the relaxed (diastolic) state. During this state, the mitral valves remain closed but the semilunar valves are open to facilitate the pumping.
•    Relaxation phase: the time at which all four chambers of the heart remains in a relaxed state to allow the incoming of blood into all chambers. During this state, the mitral valves also remain open but the semilunar valves are closed to avoid backflow of pumped blood.
1.16.1.    Electrocardiography (ECG)
The recording of heart activity in an individual by receiving the electrical signals with the help of electrodes. In this process, the electrodes detect the tiny electrical changes on the skin raised due to depolarization of cardiac muscles during each heartbeat.

In a traditional twelve angles ECG, ten electrodes are placed on the limbs and on the chest of the patient and then measures the overall magnitude of the cardiac electrical potential from twelve different angles ("leads"). These measurements are recorded over a period of time and used to plot a graph of voltage versus time. The procedure used in the graph plotting is known as an electrocardiogram and the graph obtained is termed as electrocardiograph.  The ECG with respect to a cardiac cycle is described in the diagram shown below.

The ECG graph plot as seen in the above figure has waveforms that are P, Q, R, S, and T respectively. These waves represent the different phases like
*    P wave- for atrial contraction
*    PR segment-for the time the electrical impulse takes to travel from the sinus node through the AV node.
*    QRS complex- for ventricular depolarization and contraction
*    ST segment - represent the time period of depolarized ventricles.
*    T wave - stands for ventricular repolarization.
*    U wave - hypothesized for the repolarisation of the interventricular septum and even more often is completely absent.
1.16.2.    Heart Sounds
The sounds of a normal heartbeat that is caused by blood pushing on the valves of the heart. The sounds are of two types, which are
*    Lubb- The sound that comes first in the heartbeat and is comparatively longer of the two heart sounds. It is produced by the closing of the mitral or AV valves at the beginning of ventricular systole.
*    Dupp- The shorter and sharper sound caused by the closing of the semilunar valves after ventricular systole. 
Any additional sounds like liquid rushing or gurgling indicate the defects in the atrial or ventricular septum or leakage in the valves.
1.16.3.    Cardiac Output
Cardiac output is the volume of blood pumped by the heart in a minute. The average value is around 5 to 5.5 litres per minute at a resting state. That is calculated by using the following equation
Cardiac output = Stroke Volume x Heart Rate
Where stroke volume is the amount of blood (in millilitres) pumped into the aorta due to single ventricular systole and heart rate referred to as the heart beats per minute. 
1.16.4.    Blood pressure
The pressure exerted by the blood on the inner walls of the blood vessels due to the contraction and relaxation of the heart. Usually, the term blood pressure is used for the pressure applied on the walls of arteries and in human beings, it is measured from the upper arm. The instrument used for the measurement of blood pressure is known as a sphygmomanometer.
The blood pressure is determined by the following four factors.
*    Blood Volume        
*    Elasticity of blood vessels        
*    Cardiac Output         
*    Peripheral Resistance
Hence the blood pressure can be calculated as
Blood Pressure (BP) = Cardiac Output x Systemic Vascular Resistance (SVR) 
Blood pressure is generally expressed in terms of the systolic (maximum) pressure over diastolic (minimum) pressure in millimetres of mercury (mm Hg). The value of normal resting blood pressure in an adult is considered as 120/80 mm of Hg by National Institute of Health (NIH).
Blood pressure keeps the flow of blood through all the vessels so that the cells of the body can receive oxygen and nutrients. During the contraction of the heart, the pressure exerted in the blood vessels increases and it decreases when the heart relaxes between two heartbeats. 
During hypertension, the small blood vessels in vital organs are affected over time and they become scarred, harden and inelastic that could lead to organ damage or failure, heart attacks and strokes. During hypotension, the pressure of blood gets abnormally low to pump effectively through the vital organs and the organs could not receive optimal blood supply. The reduced blood supply leads to the inefficient metabolism and energy production and generates problems like fainting, dizziness and seizures etc. To avoid such problems regarding blood pressure, it is critically regulated by two mechanisms.


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