Physiological Mechanisms

Circulation

By

Dr Smita Bhatia BP-5, II floor,

Shalimar Bagh (West) Delhi 110088

Contact: 27483738 Email: smitabhatia@edscientia.com

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Circulation Learning objectives Blood

Functions of bloodConstituents of blood

Blood groupsHeart: Structure and function

The cardiac muscleChambers of the heartHeart and circulationCardiac cycleCoronary circulationElectrocardiogram (ECG)Heart sounds

Blood vessels: structure and functionsCapillary exchange

Blood pressure Measurement of blood pressure Factors affecting blood pressure

Control of blood pressureNeural regulationHormonal regulation Autoregulation

HemostasisLymph

Blood

A unicellular organism can derive nutrients and oxygen directly from the environment, and

eliminate wastes into it. But, in a multicellular organism, all the constituent cells are not

directly in contact with the environment. So to perform these functions a special fluid

circulates the nutrients and oxygen (O2) to each cell and takes away carbon dioxide (CO2) and

wastes. This fluid is known as blood. Also assisting in this function is the interstitial fluid, i.e.

the fluid present in-between cells (plasma—the fluid component of blood is a part of interstitial

fluid as they are interchangeable to a certain extent. See filtration and reabsorption in the

capillaries at the tissue level).

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Functions of blood

• Transport: It is responsible for carrying O2 from the lungs to the body cells and CO2 from

the cells to the lungs. It also transports hormones from the endocrine glands to the target

cells, nutrients from the gastrointestinal tract to various cells and wastes to be eliminated

from the body.

• Homeostasis: It is responsible for the maintenance of the internal body environment. Blood

helps maintain temperature by carrying heat away from the cells and by losing heat through

the skin (from the capillaries). It maintains the pH by buffers present in the blood.

• Osmotic balance: Osmotic balance in the cells is maintained by the blood. It maintains

blood volume in the body as it can prevent its own loss by clotting and by other

mechanisms (hemostasis — vasoconstriction/platelet plug formation/blood coagulation).

• Defense: The white blood cells in the blood protect the body from various diseases by

destroying microorganisms using a variety of mechanisms.

Constituents of blood Blood consists of a fluid portion called plasma (55% of total volume) and cells (45% of the

total volume). Fig 1: Blood constituents

Plasma (55%) Cells (45%)

Water Solutes Red blood cell (RBC) White blood cell (WBC) Platelets or erythrocyte or leucocyte (1,50,000 (91.5%) (8.5%) (4.8 – 5.4 x 106/mm3) (5000–10,000/mm3) –4,00,000/mm3)

Proteins (7%) Other solutes (1.5%)

• Albumins (54%) • Globulin (38%) • Fibrinogen (7%) • Others (1%)

• Electrocytes • Nutrients • Regulatory substances • Gases • Wastes

Plasma

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Water

It is the solvent for the various solutes and medium for suspension of various constituents of

blood.

Solutes

Proteins:

Albumins

• Smallest plasma proteins

• Produced in the liver

• Exert osmotic pressure which helps maintain the osmotic balance between blood and

tissues and maintains the blood volume

• Function as transport proteins for fatty acids, certain fat-soluble hormones (steroids) and

certain drugs.

Globulins

• Most of them are produced by the hepatocytes.

• There are three types:

o α-globulins include high density lipoproteins which transport lipids (extra cholesterol

from the body cells to the liver to be eliminated). Thyroxine-binding globulin

(transports thyroxine), cortisol-binding globulin (transports cortisol) and vitamin B12-

binding globulin (transports vitamin B12).

o β-globulins include transferrin (transports iron), low density lipoproteins and very low

density lipoproteins (transport cholesterol from the liver to the body cells).

o γ-globulins are antibodies which are produced by plasma cells derived from B-

lymphocyte.

Fibrinogen

• Protein needed for blood clotting

• Produced by hepatocytes.

Other solutes:

Electrolytes

• Inorganic salts; Cations, such as Na+, K+, Ca2+ and anions like Cl-, HCO3-, HPO42-, SO4

2.

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• Maintain the osmotic pressure of blood.

• Maintain the excitability of cell membranes, participate in blood clotting (Ca2+) and act as

buffers.

Nutrients

• Products of digestion like amino acids, glucose, fatty acids, glycerol and vitamins.

Regulatory substances

• Enzymes produced by cells responsible for catalyzing various chemical reactions. <link to

enzymes in chapter on Digestion>

• Hormones produced by the endocrine glands are carried to the target organs where they

produce the desired effect. <link to chapter on Hormonal control>

• Growth factors

• Vitamins <link to vitamins in chapter on Digestion>

Gases

• Oxygen (O2): mostly associated with haemoglobin in RBC. Carried from lungs to the body

cells to be utilized for various cellular activities.

• Carbon dioxide (CO2): mostly presents as HCO3- ions in the plasma, carried to the lungs

where it is exhaled.

• Nitrogen (N2): In plasma; no known function.

Wastes

• These include urea, uric acid, creatinine (from creatine), ammonia, bilirubin, urobilin.

Cells: Fig 2: Types of cells in blood

< External link http://cache.eb.com/eb/image?id=91871&rendTypeId=34>

Erythrocytes

Leucocytes

Platelets

Eosinophil BasophilNeutrophil

LymphocyteMonocyte

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Erythrocytes: Also known as red blood cells (RBCs) because of the red colour due to the presence of iron-

containing red pigment — haemoglobin.

• There are 5–5.5 million RBCs/mm3 of blood in a male and 4.5–5 million /mm3 of blood in

a female.

• RBCs are biconcave discs without nucleus. This shape and lack of nucleus increases the

space available for transporting oxygen. The cell membranes are strong and flexible. The

biconcave shape (larger surface area for their volume) of RBCs facilitates their distortion

without damage while squeezing through narrow capillaries.

• RBCs lack mitochondria, endoplasmic reticulum and other organelles.

• They cannot reproduce or synthesize proteins.

• They generate energy glycolytically (anaerobically) so they do not use up any oxygen that

they carry.

• Since they cannot synthesize any new proteins for cell repair, their life is very short (120

days).

• Every day many RBCs are destroyed and replaced by new ones (haematopoiesis; see

external link: http://en.wikipedia.org/wiki/Hematopoiesis).

• The products of their destruction are removed or recycled. Worn out RBCs break down

while passing through the narrow capillaries of the spleen. These damaged RBCs are

removed from circulation and phagocytosed by the macrophages in the spleen, liver or red

bone marrow.

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Haemoglobin (Hb) <link to respiration>

Structure The haemoglobin of the RBCs is made up of into heme and globin portions. It consists of four heme groups each containing an iron atom and four polypeptide chains that constitute the globin part. In the adult, haemoglobin (HbA) these polypeptide chains are of α and β type (2α and 2β chains) so the adult haemoglobin molecule is written as Hbα2β2, with the α chain containing 141 amino acids and the β chain containing 146 amino acids. Fetal haemoglobin (HbF) contains 2 α and 2 γ chains forming its globin part. The γ chain differs from the β chain in 37 amino acids. Fetal Hb has a greater affinity for O2 than adult Hb. Haemoglobin from the destroyed RBCs has the following fate:

Haemoglobin

Globin Heme

Breaks down into Amino acids

Iron non-iron part Reused for synthesizing Combines with Converted into a green new proteins transferrin in the blood pigment biliverdin Transported to

spleen / liver / muscle Stored in these organs as Converted into an ferritin and hemosiderin orange pigment, bilirubin Transported by transferrin to bone marrow when needed Used by precursor RBCs for the Transported to the liver by synthesis of haemoglobin blood

Secreted with bile juice Bile juice in small intestine Some of it is absorbed Some part is not absorbed Reaches the large intestine Converted to urobilinogen by bacteria

Iron transport and storage Iron absorbed in the small intestine is transported by the

blood by a β globulin, apotransferrin, which combines with iron to form transferrin. Iron is then released to be deposited in the hepatocytes, muscle cells or the macrophages of spleen and liver. In the cell cytoplasm this iron combines with a protein, apoferritin, to form ferritin. Most of the iron is stored in this form. When all the apoferritin is converted to ferritin the extra iron is stored as hemosiderin. Whenever iron is needed in the body it is released from this storage pool and delivered to the cells where it is needed, e.g. erythroblasts in the red bone marrow, by transferrin.

Enterohepatic circulation

Some of it is absorbed into the blood, converted Some part is not absorbed into a yellow pigment (urobilin) and carried to the kidneys Excreted by the kidneys as a yellow Converted to stercobilin by Pigment in the urine bacteria in the large intestine

Excreted with feces (the characteristic colour and odor of the fecal matter is due to stercobilin)

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Production of RBCs (Erythropoiesis)

• RBCs, like all other blood cells are formed in the red bone marrow of an adult. RBCs are derived from the pleuripotent stem cells along specific lines:

Pleuripotent stem cell Myeloid stem cell Colony forming unit: Erythrocytes (CFU-E), progenitor cells, not capable of dividing, committed to differentiating into RBCs Basophilic erythroblast (Prorubricyte) Polychromatophillic erythroblast (Rubricyte, haemoglobin synthesis starts here) Acidophilic erythroblast (Normoblast, haemoglobin synthesis is maximum here)

loss of nucleus, most endoplasmic reticulum and mitochondria Reticulocyte (34% haemoglobin, with some endoplasmic reticulum and mitochondria) Reticulocytes released into blood stream

mature in 1-2 days

Erythrocytes

• At any given point of time 0.5 to 1.5% of blood cells are reticulocytes. This is known as the reticular count.

Hematocrit • 45% of the total blood volume is represented by RBCs (hematocrit). • Males have an average hematocrit of 47% and females have an average of 42%. • Males have a higher hematocrit because testosterone stimulates the secretion of

erythropoietin which in turn stimulates RBC synthesis. • A reduction in hemtocrit indicates anaemia.

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White blood cells or leucocytes: These are cells with nuclei and other cells organelles. They are of two types, granulocytes and agranulocytes

Leucocytes (White blood cells)

Granulocytes Agranulocyte (Have chemical-filled vesicles in their (Have very fine vesicles that are not visible cytoplasm that look like granules when stained) under a light microscope when stained) Neutrophils Eosinophils Basophils Lymphocytes Monocytes(60-70%) (2-4%) (0.5-1%) (20-25%) (3-8%) Of total WBCs Of total WBCs Of total WBCs Of ALL WBCs Of total WBCs

Lymphocyte

Monocyte

Basophil

Eosinophil

Neutrophil

Neutrophils: Granules stain with both basic and acidic dyes. Nucleus is multi-lobed with

lobes connected with thin strands of chromatin. Responsible for destruction of microorganisms

by phagocytosis, by using lysozymes, defensins and oxidants.

Eosinophils: granules stain with acidic dyes like eosin. Nucleus bilobed or kidney shaped.

Destroy certain parasitic worms, phagocytose antigen-antibody complexes.

Basophils: granules stain with basic dyes. Nucleus is irregular or kidney shaped and obscured

by the thick granules. Responsible for the inflammatory response in allergic reactions.

Lymphocytes: Circular nucleus with very little cytoplasm around it. These are the only blood

cells that can divide even after they leave the bone marrow. They leave the bone marrow and

differentiate into T lymphocytes, B lymphocytes and natural killer cells. T lymphocytes are

responsible for destroying viruses, cancer cells and transplanted tissue cells. B lymphocytes

form plasma cells which produce antibodies to destroy foreign antigens. Killer cells destroy

infectious microbes and certain tumour cells.

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Monocytes: Kidney shaped or horse-shoe shaped nucleus. Monocytes differentiate into

macrophages which can be of two types:

1. Fixed macrophages which reside in a particular tissue and phagocytose foreign matter e.g.

the macrophages in the spleen, alveolar macrophages in the lung alveolar epithelium,

reticuloendothelial (Kupffer) cells in the liver.

2. Wandering macrophages which do not reside in a particular tissue but keep moving

throughout the body and aggregate at the site of infection or inflammation.

Production of WBCs

• White blood cells are also produced in the red bone marrow.

Pleuripotent stem cell

Myeloid stem cell Lymphoid stem cell Eosinophilic Neutrophillic Basophilic Monoblast T lymphocyte B lymphocyte myeloblast myeloblast myeloblast myeloblast Eosinophil Neutrophil Basophil Monocyte T lymphocyte B lymphocyte Plasma

Begin their development in the red bone marrow

Since WBCs are involved in protecting the body from diseases, many WBCs leave the blood

stream to aggregate at the site of infection or inflammation. These WBCs leave the blood

stream by squeezing through spaces between endothelial cells in a blood vessel. This process is

known as emigration (earlier known as diapidesis)

Lymphocytes keep circulating between the blood stream and interstitial fluid and lymph. But

granulocytes and monocytes do not return to the blood stream after once leaving it.

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WBCs, like other nucleated cells of the body, have certain specific protein antigens protruding

from their surface. These are called major histocompatibility (MHC) antigens (RBCs lack

them).

Platelets (Thrombocytes): They are also formed in the red bone marrow from the haemopoeitic (pluripotent) stem cells

that give rise to the myeloid stem cell.

Production of Platelets

Pleuripotent stem cell

Myeloid stem cell

Megakaryoblast

Megakaryocyte

Fragmentation (takes place in the bone marrow)

Platelets (Thrombocytes)

Platelets have no nuclei but have special vesicles. They cannot reproduce and have a short life

of 5-9 days. Worn out platelets are removed by macrophages in the spleen and liver. Platelets

have certain special characteristics that facilitate their functioning in hemostasis, such as

• Residual endoplasmic reticulum and Golgi bodies that synthesize various enzymes and

store large quantities of Ca2+ ions.

• Mitochondria and enzymes that synthesize ADP and ATP.

• Certain enzymes that are responsible for the synthesis of prostaglandins like Thromboxane

A2.

• A protein called fibrin-stabilizing factor (Factor XIII, see blood coagulation) that helps

strengthen a blood clot.

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• Actin, myosin and another contractile protein, thrombosthenin (in their cytoplasm) that

cause the platelets to contract.

• A growth factor (Platelet Derived Growth Factor—PDGF) that can cause proliferation of

vascular endothelial cells, vascular smooth muscle fibres and fibroblasts to help repair the

damaged blood vessel.

• Serotonin which is a vasoconstrictor

• Large amounts of a phospholipid (in their membranes), the platelet factor, which

participate in blood clotting,

The red bone marrow in adults is located

in the microscopic spaces between the

trabeculae of the spongy part of the

bones, e.g. the epiphyses of femur and

humerus bones, of the pelvic and pectoral

girdles, the vertebrae and the ribs. During

embryonic life RBCs are formed in the

yolk sac, liver, spleen and red bone

marrow of bones. In an adult, as the age

increases the production of RBC

decreases as the red bone marrow gets

converted into yellow marrow which

only stores fat.

Many factors, such as the haemopoeitic

growth factors regulate the formation of

blood cells through haematopoiesis.

Formation of RBCs is stimulated by such a

factor called erythropoietin produced by the

kidneys. Under conditions of hypoxia a

larger amount of erythropoietin is produced

that increases the number of RBCs produced

to counter the hypoxia. Thrombopoetin

produced by the liver cells stimulates the

formation of platelets (thrombocytes).

Cytokines produced by the bone marrow

cells, macrophages, fibroblasts, endothelial

cells and leucocytes stimulate the formation

of leucocytes. Two such cytokines are the

colony stimulating factors and interleukins.

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Blood groups RBCs have some antigens (glycolipid and glycoprotein molecules) called agglutinogens on the

surface that are important in identifying the blood groups. There are at least 100 different types

of antigens and 24 different types of blood groups. Within a particular blood group there may

be two or three different blood types. Out of the 24 different blood groups, there are two major

blood groups: ABO and Rh.

ABO blood group

This is based on the type of agglutinogen (a glycolipid) present on the surface of RBCs which

could be either A type (Group A), B (Group B), both A and B (Group AB) and none (Group

O). There are readymade antibodies circulating in the body against the antigen NOT present on

the surface of RBCs, e.g. a person with agglutinogen A will have circulating antibodies against

agglutinogen B.

Agglutinogen Circulating antibodies Blood group on RBC surface A Anti-B A B Anti-A B AB None AB None Anti-A, Anti-B O

The antibodies of the recipient attack the RBCs of the donor

that carry agglutinogens. For example, if a person (a

recipient) with blood group A (and antibodies of the anti-B

type) is given blood from a person (donor) with blood group

B, the anti-B antibodies of the recipient attack the RBCs of

the donor as they have agglutinogen B on their surface which

results in clumping (or agglutination) of the donors RBCs and their destruction. It is the

destruction products of these RBCs which accumulate in the body of the donor and are harmful

(even fatal).

The antibodies of the donor do not cause agglutination of the recipients’ RBCs (e.g. in case of a donor with blood group O and a recipient with blood group A or B or AB, because the donor’s antibodies get diluted by the recipient’s blood.

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Theoretically, a person with blood group AB can receive blood from any donor (any blood

group) as there are no circulating antibodies in the recipient’s body to attack the donor RBCs.

Thus a person with AB blood group is known as a universal recipient.

Also a person with blood group O can give blood to any person (with any blood group) as there

are no antigens present on the surface of the RBCs that can be attacked by the antibodies of the

recipient. Thus, a person with blood group O is called a universal donor.

In practice, however, this is more complicated because in addition to the A and B antigens,

many other antigens are present on the surface of RBCs that may cause agglutination. Thus it is

essential that a sample of blood from the donor be tested by mixing with a sample of blood

from the recipient to see if there is any agglutination of the RBCs. This is known as cross-

matching.

Rh Factor

Another antigen important for blood grouping is the Rh factor (so named because it was first

discovered in the Rhesus monkey). This factor is coded by three genes C, D and E and a person

having any one of these alleles in its dominant form will have this factor. Such a person is said

to have a Rh positive (Rh+ve) blood group and if all these alleles are in their recessive form

this factor is absent and the blood group is said to be Rh negative (Rh-ve). The Rh type of

blood grouping when combined with the A, B, O type of grouping the blood groups are

designated as A+ve, B+ve or A–ve and B–ve, etc.

Antibodies against the Rh antigen are not circulating in the plasma but are synthesized only

after exposure to the antigen.

External links

Blood groups types and transfusions

<http://nobelprize.org/educational_games/medicine/landsteiner/readmore.html>

Blood typing game

<http://nobelprize.org/educational_games/medicine/landsteiner/index.html>

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Haemolytic Disease of the Newborn or Erythroblastosis foetalis

This is a disease caused by the presence of an Rh+ve foetus in the uterus of an Rh-ve mother (where the gene for Rh factor comes from an Rh+ve father). When the mother’s body is exposed to the Rh antigen (especially during the birth of the first child) the mother’s body starts producing antibodies against the Rh antigen. Though the first child is not affected, if the second child is also Rh+ve then the already formed antibodies cross the placenta to attack the RBCs of the fetus causing hemolysis. Also, because of destruction of a large number of RBCs the fetal system responds by producing large number of RBCs at a fast pace so much so that instead of reticulocytes, erythroblasts are released into circulation (thus erythroblastosis foetalis). Such a situation does not arise for the A,B,O type of blood groups because the antibodies for these antigens cannot cross the placenta.

Heart: Structure and function Heart is a vital organ present in the thoracic cavity resting on the diaphragm. It is protected by

the rib cage, the sternum and the vertebral column.

Fig 3: Structure of the heart

Aorta

Left coronary artery

Right coronary artery

Pulmonary trunk

Left ventricle

Right atrium

Right auricle

Left auricle

Superior vena cava

Inferior vena cava

Left pulmonary veins

Right ventricle

The human heart is made up of four chambers – two atria which receive blood from different

parts of the body and two ventricles that are responsible for pumping the blood to different

parts of the body.

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The outer surface of the heart is covered by a protective covering called the pericardium.

Pericardium consists of two components:

1. Fibrous pericardium which is a thick outermost covering that protects and anchors the heart

and prevents its overstretching. It is made up of dense connective tissue.

2. Serous pericardium consists of a double membrane covering the heart. The outer membrane

called the parietal layer is associated with the fibrous pericardium and the inner membrane

called the visceral layer is associated with the surface of the heart forming the epicardium.

The small space between these two membranes, the pericardial cavity is filled with a fluid

(pericardial fluid) secreted by the cells of the membranes. The pericardial fluid provides

lubrication to the heart when it contracts and relaxes. Fig 4: Outer surface of the heart

The heart wall is made up of three layers

1. innermost endocardium

2. middle myocardium

3. outermost epicardium

The myocardium is the thickest layer of t

The endocardium is made up of the endo

provides a smooth lining to the inner surf

the endothelium of the blood vessels asso

to the heart valves. The epicardium is the

mesothelium and connective tissue.

Pericardium

Myocardium

:

he heart wall made

thelium and a layer

ace of the heart. Th

ciated with the hea

serous layer of the

Fibrous pericardium

Serous pericardium:

Endocardium parietal layer

Pericardial cavity

Serous pericardium: visceral layer

up of mainly cardiac mu

of connective tissue ben

e endothelium is contin

rt and it also provides a

pericardium consisting

Epicardium

scle cells.

eath it. It

uous with

covering

of

16

The cardiac muscle The cardiac muscle is a specialized type of muscle designed to carry out the specific functions

of the heart. It has certain distinctive characteristics to suit these functions. Cardiac muscle

fibres (each fibre is a cell):

• are striated

• are shorter and thicker than skeletal muscle fibres

• are mostly uninucleated, at times binucleated

• are branched

• also have A and I bands and Z-discs as in a skeletal muscle fibre. [<link to skeletal muscle

in muscular system>)

• have transverse tubules that are less numerous than in skeletal muscle fibres though they

are wider. Only one t- tubule is

present at the Z-disc in a

sarcomere.

Fig 5: Cardiac muscle fibres

Intercalated disc

• have scanty sarcoplasmic

reticulum (so a small amount of

Ca2+ is stored within the muscle

cell, most of it comes from the

extra cellular fluid during

contraction)

• have adjacent muscle fibres connected to each other by transverse thickenings of the

sarcolemma called the intercalated discs that serve to convey the force of contraction from

one cell to another and also serve to keep them together.

• intercalated discs also contain desmosomes that keep the fibres together,

• have gap junctions present between the cells that serve to convey the action potential from

one cell to another without any delay so that all the muscle cells in a network contract

together (muscle fibres of atria form one network and those of the ventricles form another).

• have numerous mitochondria in the sarcoplasm that help to generate ATP for contraction

aerobically (energy is not generated in the heart muscle anaerobically)

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Gap junction

They are tunnel like openings between adjacent cells. These are known as connexions and are

made up of tubular proteins. Molecules from one cell can pass to another through these. Fig 6: Gap junction

Cell 1 Cell 2

Connexons A gap junction

Chambers of the heart

The Atria: The left and right atria are the receiving chambers of the heart and are separated

from one another by a thin interatrial septum. The right atrium receives deoxygenated blood

from the major veins of the body, the superior and inferior venae cavae and the coronary sinus

that brings blood back from the heart tissue. <See coronary circulation>.

The left atrium receives oxygenated blood from the lungs via the four pulmonary veins. The

anterior inner walls of the atria are not smooth but have muscular ridges called pectinate

muscles. The atria empty the blood they receive into the ventricles of their side. The atria are

separated from ventricles by valves (the atrioventicular (AV) valves) that open into the

ventricles and prevent back flow of blood into atria when the ventricles contract. The left

atrium is separated from the left ventricle by the bicuspid (made up of two cusps) valve or the

mitral valve and the right atrium is separated from the right ventricle by the tricuspid (made up

of three cusps) valve.

Atria have extensions called auricles (shaped like dog’s ears) that increase their capacity to

hold blood.

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The Ventricles: These are the chambers that pump blood into the body. The left and right

ventricles are separated from one another by an interventricular septum. The left ventricle

pumps oxygenated blood to the body tissues through the aortic arch and the right ventricle

pumps deoxygenated blood into the lungs through the pulmonary aorta (which then divides

into the pulmonary arteries carrying blood to each lung; these are the only arteries that carry

deoxygenated blood). The opening of these major arteries is guarded by semilunar (SL) valves,

which prevent the back flow of blood into the ventricles when the ventricles relax. (Major

veins entering the atria do not have any valves because their openings constrict when the atria

contract.)

Heart and circulation

Fig 7: Circulatory pathways of the heart

Deoxygenated

blood

Aorta

Pulmonary artery Superior vena cava

To lungs

From lungs From lungs

m

Pulmonary valve

Atrioventricular valves

Inferior vena cava

D

Rightatrium

Right ventricle

eoxygenated blood

O

Left atriu

Pulmonary veins Left ventricle

Aortic valve

Aorta

xygenated blood

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The blood takes the following route with the heart receiving deoxygenated blood from the

body and pumping it into the lungs for oxygenation (called pulmonary circulation), receiving

oxygenated blood from the lungs and pumping it into the body (called systemic circulation).

Lungs

Pulmonary veins (oxygenated blood) Left atrium Aorta Bicuspid valve Left ventricle Aortic valve

Pulmonary circulation

Route of blood in the heart

Superior and inferior venae cavae and the coronary sinus

Right atrium

Tricuspid valve

Right ventricle

Body tissue Pulmonary valve

Pulmonary arteries (deoxygenated blood)

Systemic circulation

The left ventricle is more muscular than the right ventricle as it pumps blood with a greater

force to the tissues. The walls of the ventricles are not smooth but bear ridges called the

trabeculae carneae—cone shaped modifications of these, called the papillary muscles, have

cord-like extensions, the chordae tendinae, attached to the atrioventricular valves (the tricuspid

and the bicuspid valves) which prevent the valves from being pushed back into the atria when

the ventricles contract.

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Fig 8: Inner structure of the heart

Bicuspid valve

Tricuspid valve

Chordae tendinae

Papillary muscles

Trabeculae carneae

The atria and the ventricles form separate units which are electrically insulated from one

another by the dense connective tissue forming a fibrous skeleton which also anchors the heart

valves and cardiac muscle bundles.

The conducting and non-conducting cells of the heart

All the cells of the heart do not function as contractile cells. About 1% of the cells of the heart,

during its embryonic development, differentiate into specialized cells that are responsible for

generating and conducting an action potential. These cells are the conducting system cells.

They have certain special characteristics:

• They have automaticity, i.e. they automatically generate pacemaker potentials that

gives rise to an action potential.

• They have autorhythmicity, i.e. an inherent automatic rhythm of pacemaker potential

generation.

Since the heart beat originates in the heart muscle itself, such a heart is known as a myogenic

heart.

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C

S

t

1

f

t

t

bF

A

A

t

s

t

t

t

A pacemaker potential is generated by the opening of slow Ca2+ ion channels that gradually cause a slow depolarization resulting in the generation of action potential when the threshold is reached, the same effect can be achieved by a reduction in the permeability of the membrane to K+ ions so less K+ ions can move out.

omponents of the conducting system

inuatrial node or SA node: It is a group of conducting system cells located near the entry of

he superior vena cava in the right atrium. It has an inherent rate of potential generation of 90–

00 depolarizations/min. This acts as the pacemaker of the heart because it has the highest

requency of depolarization. The atria contract in response to the action potentials generated by

he SA node. In a normal individual its rate of depolarization is under inhibitory influence of

he parasympathetic nervous system (Vagus nerve) so the heart beat is set at about 72–75

eats/min. ig 9: Components of the conducting system (diagrammatic)

SA node

Left bundle branch

Bundle of His

AV node

rrows

triove

he inte

pread

his co

he atri

he ven

Right bundle branch

Purkinje fibres

show the spreading of the action potential from the SA node.

ntricular node or the AV node: This group of conducting system cells are present in

ratrial septum. The action potential is picked up by the AV node from the SA node as it

s through the atria. At the AV node the action potential slows down because the fibres of

mponent are much smaller. This ensures a delay of 0.1 sec between the contraction of

a and the ventricles—the nodal delay—so that all the blood in the atria is emptied into

tricles before the ventricles start contracting.

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Atrio-ventricular bundle or Bundle of His: This is located in the interventricular septum and

is the only electrical connection between the atria and ventricles. The ventricles cannot directly

pick up the action potential from the atria as the two are separated by an insulating fibrous

skeleton.

Right and left bundle branches: From the Bundle of His arise the left and right bundle

branches that carry the action potential down the interventricular septum towards the apex from

where the branches separate with the left branch moving along the left ventricle wall and the

right branch moving along the right ventricle wall.

Purkinje fibres: The left and right bundle branches give off fibres called the Purkinje fibres in

the wall of the ventricles that make contact with the non- conducting system (muscle) cells of

the ventricle. These fibres convey the action potential to the muscle cells of the ventricle

making them contract as a unit (through the gap junctions by which the muscle cells are

joined).

Each of these components have an inherent rate of depolarization with the SA node being the

fastest. So, normally, the SA node acts as the pace maker; but if the SA node stops working

other components can act as pacemakers but with a lower rate of depolarization e.g. the AV

node has a frequency of 40–50 depolarizations per minute and all the other components (the

Bundle of His, the bundle branches and the Purkinje fibres) have a frequency of 20–40

depolarizations per minute.

The non-conducting system: the cardiac muscle cells

These cells respond to an action potential (AP) by undergoing contraction. The AP in these

cells is generated by the following sequence of events resulting in contraction.

23

AP reaches the sarcolemma of a cardiac muscle fibre (from a conducting system cell)

Voltage-gated fast Na+ ion channels open (1) Na+ rushes in Fast depolarization As these Na+ ion channels start to close Slow Ca2+ ion channels open and some K+ ion channels close (2) Ca2+ ions move in and less K+ ions are allowed to go out Depolarized state is maintained for some time longer (250 msec) than in a skeletal muscle fibre (1 msec)) Membrane regains its polarized state due to closure of Ca2+ ion channels and opening of K+ ion channels (3)

Why does the cardiac muscle not show tetany? The cardiac muscle has a long refractory period (almost as long as the contraction period) so another contraction cannot be generated before the first one is over. That is why heart muscle does not show summation or tetany. This has a physiological significance that each contraction has to be followed by relaxation so that heart can receive blood. If it contracts again before it relaxes it would not be able to perform its function as a pump.

Fig 10: Action potential in relation to contraction in a non-conducting system cell

Depolarization Repolarization

(2)

(3)

Membrane potential

+ 20 mV

(1)

– 90 mV c

Refra

Co

Tim

0.3 se

ctory period

ntraction

e (seconds)

24

Fig 11: Pacemaker potential in a conducting system cell

Pacemaker potential

Action potential

Membrane potential

+ 10 mV

– 60 mV

Threshold

Time (seconds)

Cardiac cycle At an average normal heart rate of 72 beats/min, each heart beat lasts for 0.8 seconds. Each

heart beat consists of a period of contraction (systole) and a period of relaxation (diastole)

which comprises one cardiac cycle. The ventricular systole lasts for 0.3 sec. and ventricular

diastole lasts for 0.5 sec. (with the cardiac cycle lasting for a total of 0.8 sec). The atrial systole

and diastole overlap the ventricular diastole or systole, e.g. when the ventricles are in diastole,

for some part of it the atria are in systole and when the ventricles are in systole the atria are in

diastole.

The different parts of the cardiac cycle with the state of different chambers and valves are as

follows (considering the beginning of the cardiac cycle as time 0). Time 0 – 0.1 s 0.1 – 0.4 s 0.4 – 0.8 s Atria/ventricles Atrial systole

Ventricular diastole Atrial diastole Ventricular systole

Atrial diastole Ventricular systole

AV valves Open Closed Open Aortic and pulmonary valves

Closed Open Closed

Blood flow

Atria Ventricles Superior and inferior vena cavae to right atrium, pulmonary veins to left atrium, left ventricle to aortic arch, right ventricle to pulmonary arteries

Superior and inferior vena cavae to right atrium, pulmonary veins to left atrium, left atrium to left ventricle, right atrium to right ventricle

25

Phases of the cardiac cycle

Atrial systole and ventricular diastole (0–0.1 s). When the atria contract the ventricles relax so

that all the blood in the atria is pumped into the ventricles. During this time the atrioventricular

(bicuspid and tricuspid valves) remain open.

Ventricular systole and atrial diastole. As the ventricles start contracting and the atria relax,

due to the increase in pressure inside the ventricles, the atrioventricular valves close. The aortic

valves are already closed (they have not yet opened) so during this brief period in the

beginning of ventricular systole the ventricles are neither receiving blood from the atria nor are

they pumping any blood out into the major arteries. This period is called the period of

isovolumetric ventricular contraction.

As the contraction progresses further the pressure inside the ventricles increases further to push

the aortic (semilunar) valves open and blood is pumped into the major arteries. This is called

ventricular ejection.

Ventricular diastole and atrial diastole (Joint diastole). In the beginning of ventricular

diastole (when the atria are already in diastole), as the pressure in the ventricles starts to

decrease, the semilunar valves close (because the pressure in the aortic arch and pulmonary

aorta is greater than that in the ventricles). The atrioventricular valves are already closed (as

the pressure in the ventricles has not reduced so much as to cause their opening); at this stage

no blood is entering or leaving the ventricles. This is known as isovolumetric ventricular

relaxation.

As ventricles relax further and the pressure inside drops, the atrioventricular valves open and

blood starts pouring in from the atria. This is known as ventricular filling.

The atria keep receiving blood from the superior and inferior venae cavae and the pulmonary

veins. This blood keeps flowing into the relaxing ventricles. Whatever blood is left in the atria

is conveyed to the ventricles when the atria contract (atrial systole).

26

External link for cardiac cycle animation: <link> http://bcs.whfreeman.com/thelifewire/content/chp49/49020.html

http://anatimation.com/cardiac-cycle/cardiac-cycle-animation-and-diagram.html

Coronary circulation The heart does not derive oxygen from the oxygenated blood present in the left ventricle but is

supplied by special blood vessels called the coronary arteries arising from the aorta.

Fig 12a: Anterior view of heart Fig 12b: Posterior view of heart

Aorta

Pulmonary trunk Right atrium

Right coronary artery

Left coronary artery Coronary

sinus

Great cardiac vein

Left ventricle

There are two major branches, the right and the left coronary artery which further divide into

smaller arteries. These arteries form capillaries in the myocardium to supply oxygen and

nutrients to the heart tissue and to collect carbon dioxide and wastes. Blood is returned to the

heart by the coronary sinus that opens into the right atrium. There are many connections

between the different branches of the coronary arteries so that if one route is blocked the heart

muscle still receives oxygen and nutrients via another.

Electrocardiogram (ECG)

It is a recording of the electrical currents generated on the surface of the body because of the

action potentials in the different regions of the heart. It is NOT a recording of the action

potential in a heart muscle cell.

27

ECG is recorded by using an instrument called the electrocardiograph. The instrument uses 12

leads (electrical wires) placed on different regions of the body: 6 on the limbs and 6 on the

chest). With the recordings it is possible to find out if

• there is any conduction system disorder Fig 13: Components of a typical normal ECG

• there is any damage in any region of

the heart

• any of the heart chambers is enlarged

A typical normal ECG has the following

components:

• P wave: This is an upward dome-

shaped deflection corresponding to

the atrial depolarization.

• QRS complex: It is a complex made

up of a downward deflection (Q wave) followed by a spike shaped upward deflection (R

wave) and again a small downward deflection (S wave). This entire complex represents the

ventricular depolarization.

Since atrial repolarization occurs at the same time when ventricles are depolarizing, atrial

repolarization is not recorded.

• T wave: This is a small dome-shaped, upward deflection representing the ventricular

repolarization.

Since an EGG is recorded on a graph paper the intervals of each wave and the intervals in

between can be calculated, on the basis of which several conclusions can be drawn, e.g.

• Enlarged P wave indicates enlarged atria (may be due to a defective atrioventricular valve).

• Enlarged Q wave indicates a myocardial infarction.

• Enlarged R wave indicates enlarged ventricles.

• Flat T wave indicates insufficient oxygen supply to the heart muscle as in a coronary artery

disease.

• Enlarged or elevated T wave indicates high levels of K+ ions in blood (hyperkalemia).

28

• Elevated ST segment (above the base line) indicates an acute myocardial infarction.

• Depressed ST segment (below the baseline) indicates that the heart muscle is receiving

insufficient oxygen.

• Increased QT interval indicates damaged myocardium or myocardial ischemia (insufficient

oxygen supply) or conduction system disorders.

Heart sounds

Two prominent heart sounds can be heard through a stethoscope placed on the chest of a

person (auscultation). The first heart sound called lubb is a longer and louder sound made by

the turbulence of blood caused when the AV valves close in the beginning of ventricular

systole. The second sound dupp, is a dull, shorter sound produced by the turbulence of blood

caused by the closure of the semilunar valves at the beginning of the ventricular diastole.

Any abnormal heart sounds heard in addition to the two normal sounds are called heart

murmurs. The time of the heart murmur indicates the possible defect in the heart, e.g. a

murmur heard during systole indicates a stenotic (narrowed) semilunar valve or an insufficient

(leaky) AV valve. A murmur heard during diastole indicates an insufficient semilunar valve or

a stenotic AV valve.

29

Cardiac output. It is the volume of blood pumped by the ventricle (right or left) per minute. It is given

by: Stroke volume x heart rate = 70 ml x 75 beats/min = 5.25 L.

Stroke volume. The volume of blood pumped out at each systole by the ventricle (left or right). It is given

by: End diastolic volume – End systolic volume = 130 ml – 60 ml = 70 ml.

Cardiac reserve. The difference between the maximum cardiac output possible and the cardiac output at

rest. In a normal person during strenuous exercise the heart can pump four times the normal volume of

blood, i.e. the cardiac reserve is 400%. In trained athletes the cardiac reserve could be as high as 600%.

Frank-Starling’s Law of Heart. It states that the force of contraction of the heart is directly proportional

to the initial length of the cardiac muscle fibres. This means that, within a limit, if the cardiac muscle

fibres are stretched more during diastole (because of filling of the chambers with a larger amount of blood)

the heart will contract with a greater force during systole (to pump out this greater volume of blood). This

property of the cardiac muscle ensures that if the heart receives more blood from the body (venous return)

it pumps out a greater volume of blood.

Blood vessels: structure and functions

Blood vessels carrying blood from the heart to the body tissues are known as arteries. All the

arteries, except the pulmonary arteries, contain oxygenated blood. Large arteries form medium-

sized arteries which then branch into arterioles further branching into metarterioles that finally

form capillaries. Branches of arteries may join each other to form anastomoses that provide an

alternative route for blood flow if one branch gets blocked. Capillaries are the site of exchange

of gases, nutrients and waste material between the blood and the body tissues. Capillaries join

to form venules which in turn give rise to veins which carry blood back to the heart from the

body tissues. With the exception of pulmonary veins, which bring back oxygenated blood from

the lungs, all veins contain deoxygenated blood.

Fig 14: Comparative structure of blood vessels

Artery

Vein

Tunica interna

Lumen

Endothelium

Basement membrane

Arteries

The walls of arteries are made up of the following three layers:

1. Tunica externa consisting of elastic and collagen fibres.

Tunica externa

External elastic lamina

Tunica media Valve

Internal elastic lamina

Smooth muscle

30

2. Tunica media consisting of:

• Elastic fibres and circularly arranged smooth muscle fibres.

• External elastic lamina made up of elastic fibres that provide elasticity to the walls of

the arteries.

3. Tunica interna is the innermost layer of endothelial cells which are in contact with blood in

the lumen, and consists of

• A basement membrane

• Internal elastic lamina made up of elastic fibres

It is the smooth muscle fibres of the tunica media that contract or relax in response to various

stimuli (e.g. sympathetic stimulation causes them to contract and reduction in sympathetic

stimulation causes them to relax that results in vasoconstriction or vasodilation, respectively).

Large arteries: These are the major arteries, such as the aortic arch, the pulmonary artery, the

common carotid, which serve to carry blood to the various parts of the body. Their tunica

media have a lot of elastic fibres making these highly distensible. Due to this characteristic,

when blood is pumped from the heart

into these arteries they distend and

when the heart relaxes, their elastic tissue

causes them to return to their original

position pushing the blood forward into

the medium-sized arteries. So these

arteries are also known as elastic arteries

or conducting arteries.

Fig 15: Smooth muscle fibres in arteriole and metarteriole

Smooth muscle cell Arteriole

Metarterioles

Medium-sized arteries: These are also known as the muscular arteries because their tunica

media contains many muscle fibres and a few elastic fibres. Since they help to distribute blood

to the various body parts they are also known as the distributing arteries. An example of this

type of artery is the femoral artery in the thigh region.

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Arterioles: These are branches of the medium-sized arteries which give rise to metarterioles.

The walls of arterioles have the same structure as that of the medium-sized arteries though in

very fine arterioles there may be only an endothelial lining surrounded by some smooth muscle

fibres. Since arterioles can dilate or constrict they can regulate the flow of blood to the

capillary bed. They are also known as resistance vessels because they can alter the resistance to

blood flow.

Metarterioles: Metarterioles arise from arterioles and give rise to capillaries. Rings of smooth

muscle, called the precapillary sphincters, are present at the junction of metarterioles and

capillaries. These precapillary sphincters keep contracting and relaxing intermittently to

increase and decrease the blood flow through the capillaries. This contraction and relaxation of

the sphincters is called vasomotion. (No such sphincters are present at the other end of the

metarterioles where they join a venule).

Fig 16: Arteriole, metarteriole, veins, venules and capillary network showing direction of blood flow

Venule

Direction of blood flow

Direction of blood flow

Precapillary sphincter

Arteriole

Artery

Vein

Capillaries

Metarteriole

32

Capillaries: These are the finest blood vessels that are the site for exchange of material

between the blood and body tissues, so they are also known as exchange vessels. The walls of

capillaries are made up of a layer of endothelial cells resting on a basement membrane.

Types of capillaries

There are three types of capillaries found in the body:

1. Continuous capillaries, e.g. in skeletal and smooth muscle, lungs and connective tissue. In

these the endothelial cells form a continuous sheet of cells and there are only intercellular

clefts between them.

2. Fenestrated capillaries,e.g. in kidneys, villi of small intestine, some endocrine glands.

These capillaries have fenestrations (pores) in the cell membrane of the endothelial cells.

3. Sinusoids, e.g. in liver, spleen, red bone marrow and some endocrine glands. These are

wide capillaries with an incomplete basement membrane. The endothelial cells have large

pores and large intercellular clefts.

33

Fig 17: Capillary wall types

Fenestrated capillary

Continuous capillary

Sinusoid

Basement membrane

Endothelial cell

Lumen

Nucleus of endothelial cell

Intercellular cleft

Basement membrane

Endothelial cell

Nucleus of endothelial cell

Intercellular cleft (fenestration)

Lumen

Basement membrane (incomplete)

Endothelial cell

Nucleus of endothelial cell

Intercellular cleft (fenestration) Lumen

Venules: Capillaries join to form venules. Venules have a tunica interna made up of

endothelial cells and a tunica media consisting of a few smooth muscle fibres. Endothelium of

venules is very porous and allows exchange of material. White blood cells also reach a site of

infection by emigrating through venules.

Veins: Have the same three layers in their walls as the arteries, but veins have a larger lumen

compared to an artery of the same diameter. They are different from arteries in the following

features.

1. Tunica interna is thinner with very thin layers of smooth muscle and elastic fibres.

2. Tunica media is thinner. The internal and elastic laminae are absent.

3. Tunica externa forms flap-like valves in most veins to prevent the backflow of blood.

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Capillary exchange

The exchange of material between the blood in the capillaries

and the cells of the body takes place in the capillary bed by

three mechanisms.

1. Diffusion: Where the substances move from a region of

higher concentration to a region of lower concentration.

Substances such as CO2, O2, wastes, nutrients, hormones, are exchanged by this

mechanism. The degree of diffusion of material is different in different types of capillaries.

Many materials, inclduing CO2, O2, lipid soluble substance, hormones, wastes, can cross

the capillaries through the intercellular clefts or fenestrations in fenestrated capillaries but

proteins and cells cannot. In the sinusoids as in the liver cells or bone marrow, proteins

(those synthesized by the hepatocytes) and cells (found in the bone marrow) can also pass

through.

In the brain, capillaries are continuous type, and only selected molecules can pass through

the capillary walls because here the endothelial cells are joined to each other by tight

junctions to form the blood–brain barrier. This barrier is absent in certain regions of the

brain, e.g. pineal gland, pituitary gland, and the hypothalamus.

A venous sinus, e.g. the coronary sinus of the heart has a thin endothelial wall, no smooth muscle and dense connective tissue in place of tunica media and tunica externa.

2. Transcytosis: This is a mechanism for the transport of those substances across the capillary

wall which cannot diffuse through it, e.g. insulin. Here the molecule is picked up by the

endothelial cell from the blood on the luminal side by pinocytosis. This vesicle then moves

across the endothelial cell to be exocytosed on the other side (interstitial fluid) of the

endothelial cell.

35

Fig 18: Transcytosis

Pinocytotic vesicle Molecule taken in by pinocytosis

Lumen of capillary

Interstitial fluid

Molecule released into the interstitial fluid by exocytosis endothelial cell

3. Bulk flow. It is the movement of substances together in one direction, i.e. from a region of

high pressure to a region of low pressure. Fluid containing many molecules, ions etc.,

moves out of the capillaries into the interstitial fluid at the arterial end. This process is

called filtration. Most of this fluid is reabsorbed at the venular end of the capillaries

because the pressure differences here are reversed. This process is called resorption. Four

factors affecting these two processes (known as Starling’s forces) are:

i. Hydrostatic pressure in the capillaries (HPC) due to the presence of blood in the

capillaries. It causes the fluid to move out of capillaries.

ii. Osmotic pressure in the capillaries (OPC) due to ions and proteins in the blood causes

fluid to move into the capillaries.

iii. Hydrostatic pressure in the interstitial fluid (HPIF) causes the fluid to move out of the

interstitial spaces into the capillaries.

iv. Oncotic pressure in the interstitial fluid (OPIF) causes the fluid to move into the

interstitial spaces (out of capillaries).

36

Fig 19: Direction of movement of fluid due to different factors

Interstitial fluid

HPIF OPc HPc OPIF

Capillary

At the arterial end of capillaries HPC = 35 mmHg HPIF = 0 mmHg (because the fluid is in open space)

Net filtration pressure of 35 mmHg (35–0) causes the movement of fluid out of the capillaries (into the Interstitial spaces).

OPc = 28 mmHg

Net difference of 25 mmHg (28–3) causes the movement of fluid into the capillaries.

OPIF = 3 mmHg (because a very small amount of ions and proteins are present in the fluid in the interstitial spaces)

Due to a pressure difference of 35 mmHg fluid moves out of capillaries and due to a pressure

difference of 25mm Hg fluid moves into the capillaries so there is a net movement of fluid out

of the capillaries because of a pressure difference of 10 mmHg (35 mmHg – 25 mmHg). i.e.

there is a net filtration because of which the cells get oxygen and nutrients while the wastes and

CO2 are released into the interstitial fluid from the cells.

At the venular end of capillaries

Movement of fluid out of the capillaries (into the interstitial spaces) because of a pressure difference of 15 mmHg—[a]

HPC = 15 mmHg HPIF = 0 mmHg Movement of fluid into the

capillaries because of a pressure difference of 25 mmHg (28 mmHg–3 mmHg)—[b]

OPC = 28 mmHg OPIF = 3 mmHg

37

Since [b] is greater than [a] there is a net movement of fluid into the capillaries because of a

pressure difference of 10 mmHg (25 mmHg–I5 mmHg), i.e., there is a net absorption of fluid

into the capillaries at the venular end. The pressure difference causing filtration at the arterial

end is same as that causing absorption at the venular end (10 mmHg) so most, but not all, of

the fluid that filters out is reabsorbed. Whatever extra fluid is left in the interstitial spaces is

returned to the heart via the lymphatic ducts. This near equilibrium of the filtered and absorbed

fluid is known as Starling’s law of capillaries.

Blood pressure

Any fluid when enclosed in a tube exerts pressure on its walls. Similarly, blood exerts pressure

on the walls of blood vessels. Clinically, blood pressure is the pressure exerted by the blood on

walls of the arteries. As the blood keeps flowing from the major arteries to the capillary bed

the blood pressure keeps decreasing because of the resistance offered to blood flow. The

pressure in an artery during a cardiac cycle can be shown as:

Fig 20: Pressure in an artery during a cardiac cycle

Systolic pressure

Diastolic pressure

Pressure increase caused by aortic valve closure

120

Pressure (mm Hg)

80

Time

As the ventricles start contracting more blood is added to the arteries (which are never empty).

This causes a rise in the blood pressure till the end of systole to a value of 120 mmHg. When

the ventricles start relaxing the pressure starts reducing as the pumping force of the heart is

withdrawn and the blood flows ahead. A slight increase in pressure (the hump in the curve) is

seen due to the closure of the aortic valves after which the pressure steadily drops to the

diastolic value of 80 mmHg. The difference between the systolic (120 mmHg) and diastolic

38

pressure (80 mmHg) is known as the pulse pressure as it is this difference that causes the pulse

to be felt (in the superficial arteries). The mean arterial pressure is not an average of the

systolic and diastolic pressure values because the heart remains in diastole for a longer time

(0.5 s in a cardiac cycle) than it remains in systole (0.3 s in a cardiac cycle).

The mean arterial pressure can be calculated by the following formula:

Mean arterial pressure = diastolic pressure + 1/3 (systolic pressure – diastolic pressure) = 80 + 1/3 (120 – 80)

= 93.33 mmHg Measurement of blood pressure

Blood pressure can be measured using an instrument known as the sphygmomanometer

(sphygmo = pulse, manometer = pressure measuring

instrument). It consists of a cuff made of cloth that is

wrapped around the upper arm to measure the blood

pressure in the brachial artery. The cuff is attached to a

rubber bulb through a tubing which is used for inflating the

cuff. It is also attached to a mercury column, which is used

for reading the pressure in the cuff. A screw attached to the

rubber bulb is used for releasing the air from the cuff to

reduce the pressure. A stethoscope is used for hearing

sounds in the brachial artery.

Stethoscope

Fig 21: Sphygmomanometer

Principle of working of the sphygmomanometer

When the cuff is wrapped around the arm and inflated, it compresses the brachial artery to stop

the flow of blood through it. When the pressure in the cuff is above the systolic pressure, blood

does not flow at all through the compressed artery— Curve A.

When the pressure in the cuff is reduced slightly below the systolic pressure the artery opens

slightly and blood flows through this narrow opening intermittently (only for that period in the

39

cardiac cycle when the systolic pressure is higher than the cuff pressure). A soft intermittent

sound is heard at this cuff pressure. This pressure is an indication of the systolic pressure,

though it is slightly lower than the actual systolic pressure — Curve B.

On further reducing the cuff pressure, as the artery opens up further, blood flows through it

with a greater turbulence so the sounds are louder and intermittent— Curve C.

On further reduction in the cuff pressure when the diameter of the artery is near normal and the

turbulence is minimum, the sounds become very dull— Curve D.

Fig 22:

Curve A Curve B Curve C Curve D Curve E

Dotted line shows cuff pressure

When the pressure is reduced below the diastolic pressure no sound is heard as the artery is

completely open. When no sound is heard the reading in the mercury column corresponds to

the diastolic pressure (though it is slightly lower than the actual diastolic pressure) — Curve E.

All sounds heard during measurement of blood pressure are called Korotkoff sounds.

40

Factors affecting blood pressure Cardiac output

An increased cardiac output increases blood pressure and vice versa. Cardiac output is

determined by the stroke volume and heart rate. Any factor causing a change in the stroke

volume or heart rate would affect the blood pressure, e.g. during exercise the heart rate and

stroke volume both increase resulting in increased blood pressure.

Blood volume

A normal person has about 5 litres of blood in the body. An increase in the volume of blood

causes an increase in blood pressure and vice versa. Blood volume may increase under certain

circumstances such as increased Na+ and water retention due to increased Na+ intake. Blood

volume may decrease under certain other conditions, e.g. dehydration or loss of blood due to

haemorrhage.

Elasticity of arterial walls

When blood is pumped into the already filled arteries, during ventricular systole the arteries

distend due to the elasticity of their walls. When the ventricles relax this extra pressure from

the ventricles is removed and the arteries return to their original position due to elastic recoil.

This serves to push the blood ahead. If this elasticity decreases, the arterial walls do not distend

adequately and blood pressure increases. The elasticity of arterial walls reduces with age.

Viscosity of blood

Blood pressure increases with increase in blood viscosity (as during dehydration) because

resistance to blood flow increases. A reduced blood viscosity as in anaemia or reduced plasma

protein concentration reduces blood pressure.

Peripheral resistance or systemic vascular resistance

It is the resistance offered by all blood vessels to blood flow. Since the major arteries and all

veins have a large lumen they do not offer much resistance to blood flow but considerable

resistance is offered by narrower blood vessels like the arterioles, metarterioles, capillaries and

41

venules. Greater the resistance, greater the blood pressure. Peripheral resistance itself varies

with:

1. Size of the lumen of the vessel. If the vessel is narrower resistance is more.

R α 1/r4, where R is resistance to blood flow and r is the radius of the blood vessel.

2. Length of blood vessel. Longer the blood vessel greater the resistance offered. (Obese

people have a higher blood pressure because they have an increased blood vessel length

due to the extra blood vessels in the adipose tissue, in addition to other factors).

Control of blood pressure Blood pressure is regulated both by the nervous system and the endocrine system. Neural regulation

There is a specialized group of neurons in the medulla forming the cardiovascular (CV) centre.

It has three types of neurons: 1. Neurons that stimulate the heart (cardiostimulatory neurons).

2. Neurons that inhibit the heart (cardioinhibitory neurons).

3. Neurons that control the blood vessel diameter (vasomotor centre). These can cause

vasodilation or vasoconstriction by decreasing or increasing the sympathetic impulses.

The cardiovascular centre receives inputs from:

1. Upper brain regions, such as the cerebral cortex, the limbic system and the hypothalamus.

2. Baroreceptors, which perceive blood pressure in the blood vessels and atria.

3. Chemoreceptors, which perceive the levels of H+ ions, CO2, and O2 in the blood.

The cardiovascular centre sends outputs to the heart through the

• Parasympathetic fibres to the heart (Vagus nerve; cardioinhibitory nerve) which results in

an inhibition of heart (reduced heart rate and contractility).

• Sympathetic fibres to the heart (cardioaccelerator nerves) which stimulate the heart

(increase the heart rate and contractility).

• Sympathetic fibres to blood vessels. When impulses in these fibres increase

vasoconstriction occurs in most blood vessels, in the blood vessels of the heart and skeletal

42

muscle sympathetic stimulation causes vasodilation. Reduced impulses in the sympathetic

fibres cause vasodilation, in most blood vessels.

Under normal resting conditions the sympathetic fibres sending signals to the smooth muscle

fibres of the blood vessels are under some degree of stimulation so the blood vessels are

always slightly constricted (and not totally dilated to their normal diameters). This state of

tonic constriction is known as the vasomotor tone.

Under conditions of strenuous exercise, sympathetic stimulation of blood vessels increases to

cause vasoconstriction in areas such as abdominal viscera, and vasodilation in skeletal muscle

and heart (so that more blood is made available to these organs).

Inputs to the CV centre from higher brain regions (link to earlier heading)

• Inputs from the limbic system cause the stimulation of heart (increased heart rate and

contractility) e.g., when one is preparing for a race.

• During exercise, when the body temperature rises, inputs from the hypothalamus

(thermoregulatory centre) cause the CV centre to facilitate vasodilation in the capillaries of

the skin to lose heat.

Inputs to the CV centre from baroreceptors

Baroreceptors or pressoreceptors are present in the walls of the carotid sinus and the aortic arch

(See diagram of chemoreceptors in chapter on respiration <link>).

Those in the carotid sinus are supplied by the sensory fibres of the Glossopharyngeal (IX)

nerve. These monitor the pressure of blood going into the brain region. Baroreceptors in the

aortic arch are supplied by the sensory fibres of the Vagus (X) nerve and are concerned with

monitoring the pressure of blood going to the body tissues. These baroreceptors perceive

changes in blood pressure and send signals to the CV centre to regulate blood pressure.

43

Increase in blood pressure Perceived by the baroreceptors Signals sent to the CV centre in the medulla Increased parasympathetic impulses from the cardioinhibitory neurons Reduction in sympathetic impulses from vasomotor neurons Reduced heart rate and contractility Vasodilation Reduced (restored to normal) blood pressure Decreased blood pressure Perceived by baroreceptors Impulses sent to the CV centre Increased sympathetic impulses Increased sympathetic impulses From the cardioaccelerator neurons from the vasomotor neurons Increased heart rate and contractility Vasoconstriction Increased (resorted to normal) blood pressure This relationship between blood pressure and heart rate is known as Marey's Law of Heart. Baroreceptors are also present in the right atrium and

the venae cavae. They are also innervated by the

sensory fibres of the Vagus (X) nerve.

Sympathetic stimulation of

veins causes vasoconstriction

(as in the arteries) so that

venous return increases and

heart rate and contractility

increase (Starling’s Law of

Heart) to restore (increase) the

blood pressure.

When pressure in the right atrium or venae cavae increases (due to increased venous return) Perceived by baroreceptors in the right atrium and the venae cavae Signals sent to the CV centre Increased sympathetic impulses from the cardioaccelerator neurons

44

Increased heart rate and contractility which shows that greater volume of blood is pumped out

when the venous return is more. This is known as Bainbridge reflex (related to Starling’s Law

of Heart).

Inputs to the CV centre from chemoreceptors

Close to the baroreceptors in the carotid sinus and the aortic arch are present chemoreceptors

that are sensitive to the levels of H+ ions, CO2 and O2 in the blood. They perceive these

changes and send impulses to the CV centre to adjust the heart rate and contractility and the

vasomotor tone to meet the demands of the body tissue.

Increase in levels of H+ ions or CO2 Perceived by chemoreceptors Signals sent to the CV centre Increased sympathetic signals to the heart and blood vessels Increased heart rate and contractility Vasoconstriction Increased blood pressure Increased delivery of blood to tissues Increased delivery of O2 to tissues Reduced (restored to normal) levels of H+ ions and CO2

These chemoreceptors also send signals to the respiratory centre (link to respiration chapter:

control of respiration) to adjust the rate of breathing according to the heart rate.

Hormonal regulation

Many hormones regulate the blood pressure by changing the heart rate or blood vessel

diameter or by changing the factors that affect blood pressure.

Epinephrine and nor epinephrine. These hormones are produced from the adrenal medulla

and axon terminals of sympathetic nerve fibres. They increase the heart rate and contractility

and cause vasoconstriction in the blood vessels of abdominal viscera and skin and vasodilation

of cardiac and skeletal muscle blood vessels.

45

Antidiuretic hormone (ADH) or vasopressin. This hormone is produced by the

hypothalamus and stored and released by the posterior lobe of pituitary. It causes increased

water reabsorption in kidney tubules and vasoconstriction resulting in increased blood

pressure. (Alcohol intake causes reduced secretion of ADH resulting in vasodilation and

reduced blood pressure.)

Renin-angiotensin- aldosterone system. A reduced blood volume (and reduced blood

pressure) reduces the blood flow to kidneys which stimulates the cells of the juxtaglomerular

apparatus to secrete an enzyme renin which acts in the following manner.

Reduced blood supply to kidney tubule

Stimulation of Angiotensinogen in

juxtaglomerular cells blood (from liver)

Secertion of renin

Angiotensin I

Angiotensin converting enzyme in lungs

Angiotensin II

Stimulation of adrenal cortex Vasoconstriction Secretion of aldosterone Increased Na+ reabsorption in kidney tubules Increased water retention

Increased blood volume

Increased/restored blood flow

Increased blood pressure

to kidney tubules

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Atrial natiuretic peptide or factor (ANP or ANF). This is a hormone secreted by the right

atrial cells in response to an increased blood volume in the right atrium.

Increased blood volume (or venous return)

Stimulation of cells in the right atrium

Secretion of ANP or ANF

Increased Na+ loss from kidney tubules Vasodilation

Reduced blood volume Reduced venous return Histamines and kinins. Histamine is produced by mast cells and kinins are present in plasma.

Both cause vasodilation (reduced blood pressure) and play an important role in inflammatory

responses.

Parathyroid hormone. This is secreted by the parathyroid gland and causes vasodilation

(reduces blood pressure).

Calcitriol. This is the active form of vitamin D. It causes vasoconstriction (increased blood

pressure). Autoregulation

Some substances produced by the blood vessel walls and blood cells regulate blood pressure by

regulating the diameter of the blood vessels. These substances are called vasoactive

substances. Such changes are especially important in different regions of the brain where blood

supply is increased to a particular area which is active during a particular activity, e.g. blood

supply to the speech area increases while talking. Vasoactive substances can be

vasoconstrictors or vasodilators:

Vasodilators

• K+ ions, H+ ions, lactic acid,

adenosine(All these are produced when

O2 levels are low so vasodilation should

occur locally to supply more blood and

oxygen)

• Nitric oxide (endothelium derived

relaxation Factor: EDRF)

Vasoconstrictors

• Eicosanoids (Thromboxane A2, PGF2α )

• Angiotensins

• Endothelins

• Serotonin from platelets

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Hemostasis

It is the prevention of blood loss from the body in case of any injury and is achieved by three

mechanisms:

1. Vascular constriction. This is an immediate response following injury to or rupturing of a

blood vessel. It reduces the flow of blood from the ruptured vessel. It is caused by:

• Nervous reflexes initiated by pain or other impulses originating from the traumatized

blood vessel or tissues.

• Myogenic (originating in the smooth muscle layer of the blood vessel) contraction of

blood vessel caused by direct damage to the blood vessel wall, especially in larger

blood vessels.

• In small blood vessels vasoconstriction is brought about by Thromboxane A2, a

vasoconstrictor produced by platelets.

This local vascular spasm reduces the loss of blood in the beginning following which

platelet plug formation and blood clotting prevent further loss of blood.

2. Platelet plug formation. Whenever there is a small hole in a blood vessel it is sealed by a

platelet plug formed by aggregation of

platelets at the site of damage. The following

steps are involved in platelet plug formation:

T

• Platelets contact and stick to the damaged

blood vessel’s exposed collagen fibres

beneath the endothelium. This is known

as platelet adhesion. A protein produced

by the endothelial cells and platelets

called the von Willebrand Factor (VWF)

is necessary for the adhesion of platelets

at the site of injury.

• As a result of adhesion the platelets

become activated and their characteristics

Fig 23: Platelet plug formation

hromboxane A2

ADP

Platelet aggregation

Platelet release reaction

Platelet adhesion

48

change and they become irregular by developing projections which help the platelets to

contact each other. Then they begin to release the contents of their granules. This is

known as platelet release reaction.

• The released ADP and Thomboxane A2 activates the neighbouring platelets also, which

then becomes sticky and adhere to already activated platelets. This is known as platelet

aggregation which results in a platelet plug formation. This platelet plug is reinforced

by fibrin threads when a clot is formed.

3. Blood clotting. Whenever there is an injury to a vessel or tissue the blood forms a clot

consisting of threads of fibrin that entrap the cells of blood. The final part of the process

of formation of these fibrin threads is given below:

Prothrombin Thrombin

Prothrombinase or Prothrombin activator

Certain substances in the blood, called clotting factors, are res

clot. The factors involved in the process of blood clotting are

the blood. They are synthesized in the liver. They are number

XIII (except number VI which has not been assigned). Clotting factors Factor Name I Fibrinogen II Prothrombin III Tissue factor or thromboplastin IV Calcium V Proaccelerin (Labile factor) VII Proconvertin (Stable factor) VIII Antihemophilic factor A, Antihemophilic globulin IX Antihemophilic factor B, Plasma thromboplastin comp

X Stuart-Prower factor XI Plasma thromboplastin antecedent, Anti-hemophilic f

XII Hageman factor, Glass factor XIII Fibrin stabilizing factor, Laki-Lorand factor HMW-Kininogen

High molecular weight kininogen

Kallikrein

Fibrinogen Fibrin (clot)

ponsible for the formation of a

present in their inactive form in

ed in Roman numerals from I to

onent, Christmas factor

actor C

49

One factor gets activated under certain conditions and it activates another factor, which in turn

activates another one, forming a cascade. There are two pathways by which fibrin threads (a

clot) are formed — intrinsic and extrinsic — but the final part of the process (formation of

fibrin from prothrombin) is common to both. The intrinsic pathway is so named because all the

factors necessary for the formation of a clot are present in blood (intrinsic to it). In the extrinsic

pathway, one factor, the tissue thromboplastin or tissue factor is derived from injured tissue

and is extrinsic to blood. These two pathways can occur independently or together to form a

clot.

The formation of prothrombinase or prothrombin activator occurs by the combination of

activated factor X (X a) and factor V in the presence of Ca2+ ions.

Intrinsic pathway XII XII a

Thrombin

PF =

HMW-Kininogen, Kallikrein

XI XI a

IX IX a

Exposed collagen in a damaged blood vessel (or any such electronegatively charged surface e.g., glass)

VIII VIII a X X a, V

Ca2+, PFThrombin

V a Prothrombin Thrombin platelet factor

Fibrinogen Fibrin

Loose clot

Ca2+, PF

XIII a XIII

PF, Ca2+

Stabilized clot

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Extrinsic pathway Damaged tissue Tissue thromboplastin or tissue factor (Factor III) VII VII a

Blood plasma devoid of clotting factors is known as serum

IX IX a VIII VIII a X X a, V

Thrombin

PF, Ca2+ V a

Prothrombin Thrombin Fibrinogen Fibrin XIII

PF, Ca2+

XIII a

Loose clot

Positive feedback effects of thrombin

PF = platelet factor

Stabilized Clot

External link <For details on coagulation factors visit :

http://en.wikipedia.org/wiki/Coagulation#Coagulation_factors>

The cascade of blood clotting is further

stimulated by thrombin by a positive feedback

where once thrombin is formed in small amounts

it causes its own formation by:

• activating factor V to V a, which

enhances the formation of

prothrombinase (initially inactive factor

V combines with X a to form prothrombinase).

Role of vitamin K in clotting Vitamin K is needed for the synthesis of prothrombin and factors VII, IX and X in the liver. Liver itself helps in the absorption of this vitamin which is lipid soluble and requires bile for its absorption. Through this vitamin can also be synthesized by bacteria in the large intestine.

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• activating factor XI and VIII (in the beginning inactive factor VIII catalyses the

activation of factor X to X a in the presence of factor IX a).

• activating platelets which then stimulate blood clotting by releasing the platelet factor.

Once formed the clot retracts because of the contraction of platelets. On retraction, some serum

oozes out and the broken ends of the blood vessel are brought together to reduce further loss of

blood. Then the blood vessel can be repaired by formation of new fibroblasts and endothelial

cells.

After the vessel is repaired the clot is dissolved. Dissolution of clot is known as fibrinolysis. It

is brought about by an enzyme called plasmin (fibrinolysin) which is formed from its inactive

precursor plasminogen. This activation is catalyzed by thrombin and a tissue plasminogen

activator.

Why blood does not clot in uninjured vessels

There are three mechanisms that prevent

clotting in an uninjured vessel:

1. Plasma protein tissue factor pathway

inhibitor secreted by the endothelial cell binds to the tissue factor and VII a complex, so

that they cannot activate factor X (that is why only a small amount of thrombin is formed

by extrinsic pathway if it operates alone).

Platelet aggregation in uninjured areas of blood vessels is prevented by the presence of prostacyclin, another eicosanoid.

2. Thrombin binds to an endothelial cell receptor called thrombomodulin.

Bound thrombin binds to another plasma protein, Protein C

Protein C is activated

Activated Protein C in combination with another plasma protein, inactivates factor VIII

a and factor V a and inactivates the inhibitor of tissue plasminogen activator, increasing

the formation of plasmin (so that if a small amount of fibrin is formed it is broken down

by plasmin).

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3. An anticoagulant antithrombin II or III combines with another anticoagulant produced by

endothelial cells, and heparin to inactivate various clotting factors.

Lymph

Lymph is a clear pale yellow fluid formed from the interstitial fluid. It flows in lymphatic

vessels where it finds its way through the lymphatic capillaries. They act as one-way carriers

for lymph because lymph can enter these capillaries from the interstitial fluid but cannot leave

the capillaries to return into the interstitial spaces. These lymphatic capillaries are also made up

of endothelial cells which overlap one another and have intercellular spaces. These spaces open

up when the pressure of fluid in the interstitial spaces is more than in the capillaries. When

there is more fluid in these capillaries, the intercellular spaces close so that no more fluid can

enter or leave the capillaries. The endothelial cells are anchored to the surrounding tissues by

anchoring filaments.

Fig 24: Lymph draining into lymphatic capillary from interstitial fluid

Intercellular space opening into lymphatic capillary

Lymphatic capillary

Anchoring filament

Tissue cells

Interstitial fluid

Endothelial cells in the lymph capillary

Lymph entering lymph capillary

53

These capillaries form larger lymphatic ducts to eventually return the lymph to the blood.

Lymph takes the following route:

Lymph capillaries Lymphatic vessels Lymph nodes Lymphatic trunks Lymphatic ducts Join the blood vessels (at the junction of the internal jugular and subclavian vein) Lymphatic vessels also contain valves (as in the veins) to prevent backflow.

Functions of lymph

• Returns the fluid to blood

• Carries lost proteins (those that manage to escape the capillaries) and large particulate

matter away from the tissue spaces which cannot be removed by absorption into the blood

capillaries.

• Carries products of digestion especially fats in lacteals of the small intestine.

• Pathogens such as bacteria are removed by the lymph from tissue and when lymphatics

enter the lymph nodes these bacteria are destroyed.

Disorders of the cardiovascular system Anemia

It is a condition of reduced haemoglobin content either because of a reduction in the number of

RBCs or reduced content of haemoglobin per RBC. Different factors cause different types of

anemia.

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• Iron deficiency anemia: It is caused by insufficient intake or absorption or excessive loss of

iron. Women are more prone to this type of anemia because of loss of blood during

menstruation and increased demands of iron during pregnancy.

• Pernicious anemia: This is caused by insufficient intake or absorption of folic acid

(Vitamin B12) which is necessary for RBC production. Absorption of folic acid is affected

if the gastric glands do not produce enough intrinsic factor.

• Haemorrhagic anemia: This is caused by excessive loss of blood.

• Aplastic anemia: This occurs when the bone marrow fails to produce red blood cells due to

certain toxins, gamma irradiation or drugs.

• Thalassemia: It is a genetic disorder where the RBCs are fragile or the haemoglobin

synthesis is not adequate affecting the oxygen carrying capacity. The RBCs are microcytic

and hypochromic.

• Hemolytic anemia: In this condition the RBCs are fragile and undergo hemolysis with their

breakdown products accumulating in the body adversely affecting the kidneys. This is

caused by parasites or toxins or due to some genetic defect.

• Haemophilia: It is a disorder where the blood does not clot easily. It is a genetic disorder

where the clotting factors are not produced in adequate amounts. Haemophilia A or the

classic haemophilia is caused by the absence of clotting factor VIII; haemophilia B is

caused by the absence of clotting factor IX; and haemophilia C is caused by the absence of

clotting factor XI. Haemophilia A and B primarily occur in males because they are sex-

linked recessive disorders.

• Sickle-cell anemia: This is a genetic disorder where there is a defective gene for

haemoglobin synthesis. Instead of the normal haemoglobin, Hb-S is synthesized which

forms crystals when it gives up oxygen to the tissues causing the RBCs to become sickle-

shaped. These RBCs are then destroyed. This gene is found in populations inhabiting those

regions of the world where malaria is prevalent because the sickle-shaped RBCs are

resistant to malarial parasite. A person with one sickle cell gene and one normal gene (a

carrier) is more resistant to malaria.

Leukemia

It is a malignant disease where WBCs are produced in uncontrolled numbers.

55

Polycythemia

It is an abnormal increase in the number of RBCs. It may be caused by hypoxia as at high

altitudes or unchecked production of RBCs (a type of tumour).

Leucocytopenia

It is a reduction in the number of WBCs caused by damage to the bone marrow by irradiation

or certain drugs.

Myocardial ischemia

It is the weakening (not death) of cardiac cells due to insufficient oxygen supply caused by a

blocked coronary artery.

Myocardial infarction or heart attack

It is the death of heart tissue because of lack of oxygen caused by blockade in the coronary

artery. The infarcted tissue becomes non contractile and may interfere with the conduction of

the impulse. The extent of damage and the consequences depend upon the location and size of

the infarcted area.

Arteriosclerosis

It is a group of disorders where there is a thickening of the arterial wall and loss of elasticity.

One of such disorders is atherosclerosis where there is a formation of an atherosclerotic

plaque. Its formation is initiated by factors such as high levels of low-density lipoproteins,

cytomegalovirus, prolonged high blood pressure, diabetes mellitus and cigarette smoke. It

starts with an injured endothelium where there is an aggregation of platelets and phagocytes. In

the inner layer of the arterial wall cholesterol and triglycerides get deposited. Macrophages

also get collected here. Smooth muscle cells, collagen fibres etc. start proliferating abnormally.

The plaque thus formed narrows the lumen of the artery obstructing blood flow. It also

provides a rough surface for the platelets to aggregate and stimulate blood clotting

(thrombosis). A thrombus thus formed may move away from its formation site (such a

thrombus is called an embolus) and may obstruct small blood vessels, which could be fatal.

Angina pectoris

It is the chest pain associated with tightness caused by ischemia of heart muscle. Common

cause is constriction of coronary arteries due to stress or due to strenuous exercise particularly

after a heavy meal when the blood flow is diverted towards the digestive tract.

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Coronary artery disease (CAD)

It is a disorder that affects the coronary artery due to atherosclerosis which results in a reduced

blood flow to the myocardium. Many risk factors make a person prone to CAD. These include

genetic factors, smoking, obesity, diabetes mellitus, high cholesterol levels and a sedentary

lifestyle.

Arrhythmias

It is a disorder of the conduction system of the heart where the heart may beat too slowly

(bradycardia), too fast (tachycardia) or irregularly. Arrhythmias may be caused by substances

that stimulate the heart (e.g. caffeine, alcohol, cocaine) or due to a congenital defect.

57