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Heart muscles,as a pump and functions of valves

4 chambers:
Right and left atria
Right and left ventricles

4 valves:
Biscuspid valve between lft atrium and lft ventricles
Trcuspid valve between rt atrium and rt ventricles
2 semilunar valves ; one between lft ventricle and aorta and the other is between rt ventricle and pulmonary arteries

3 types of muscle:
Atrial muscle
Ventricular muscle
Specialized muscle:Excitatory muscle and conductory muscle

-Cardiac muscles are striated muscle with actin and myosin filaments sliding along side of each other as skeletal muscle.

The cardiac muscles are interconnected with each other by intercalated discs. At intercalated discs the membrane of cells fuses forming gap junctions through which adjacents cells can communicate with each other. These intercalated discs allows action potentail of one muscle cell to pass to other cells. By this way the whole heart muscle acts as a single unit. This property of heart muscle is called Syncytium.
2 types: Atrial and ventricular syncytium

-Atrium and ventricles are not directly connected. They are separated by fibrous tissues which insulates atria and ventricles.
-The impulses from atria are conducted to ventricles though specialezed conductive tissues called A-V bundle.
-Because of this insulation between atria and ventricles , atria contracts a short time ahead of ventricles.

Action potential in cardiac muscles

RMP: -85 mV
Peak/spike potential: +20 mV
After spkie potential it remains depolarised for about 0.2 sec called plateau phase and then only repolarization occurs. Plateau is the characteristics of heart muscle. Because of plateau ventricular muscles remains in contraction for 15 times longer duration than skeletal muscles.

Causes of plateau in Cardiac muscles

1.The cause of action potential in cardiac muscle is by opening of 2 types of channels:
a. fast Na ions channels
b. slow Na- Ca ions channels ( not present in skeletal muscles)

Slow Na-Ca ion channels opens slowly and remains opened for longer time, so large number of Na, Ca ions enters causing prolonged duration of depolarization and this causes plateau phase. The Ca ions that have influxed during plateau causes cardiac muscle contraction. But for skeletal muscle contraction Ca ions comes from sarcoplasmic reticulum .

2.After depolarization K ion permeability through cardiac mucle membrane decreases by 5 folds. So+ve ions remains inside the cell casuing plateau.

Velocity of conduction in cardiac muscles

Atrial , ventricular: 0.3 - 0.5 m/sec
Purkinje fiber: 4 m/sec

Refractory period: ventricles 0.25 – 0.30 sec (till plateau) ; atrium 0.15 sec

Relative refractory period: 0.05 sec, strong stimuli required for premature beats formation

Excitation – contraction coupling

-It is the mechanism by which action potential causes myofibrils to contract.

-It is same as skeletal skeletal muscle only one source of Ca ions: from sarcoplasmic reticulum

-When action potential reaches T tubules it causes releae of Ca ions from t tubules itself and cisternae of sarcoplasmic reticulum.

-The difference is that there are two Ca ions source: one is from cisternae of sarcoplasmic reticulum and the another is from T tubules itself. Because of the extra Ca from T tubules the cardiac muscles contraction is strong. The diameter of T tubules is bigger and it also contains large number of negative ions which binds Ca ions and releases when action potential reaches T tubules.

Duration of contraction:

contraction begins just a few milliseconds after action potential starts and continues till few milliseconds after end of action potential.

Atrial: 0.2 sec

Ventricle: 0.3 sec

The Cardiac Cycle

The events that occurs from beginning of heart beat to the beginning of next is called cardiac cycle.

Action potential is generated in SA node , it is located in the superior lateral wall of right atrium near the opening of superior venacava. Then it travels through atria and then though A-V bundle into ventricles. At A-V node there is delay in conduction of 0.1 sec, because of this atria contracts prior to ventricles and so pumps blood in ventricles and then ventricles contracts and pumps blood out.

Diastole and systole:

Diastole is the phase of cardiac cycle during which heart remains relaxed and is filled with blood .

Systole is the phase during which heart remains contracted and pumps blood out.

Relationship of heart sounds to heart pumping

First heart sound:
is due to closure of A-V valves when ventricle starts to contract

Second heart sounds:
closure of aortic and pulmonary valves at end of systole

Relationship between left ventricular volume and intraventricular pressure during diastole and systole.

Preload and afterload

Preload is the pressure with which the ventricle starts to contract and is the end diastolic volume

Afterload is the pressure/load against which the ventricle has to contract and is the systolic pressure.

Regulation of heart pumping

1.Intrinsic regulation of heart pumping (Frank starling mechanism):
Within physiologic limit, the greater the heart muscle stretched during blood filling, greater is the force of contraction and greater quantity of blood is pushed into aorta. This is known as Frank-starling mechanism.

2.Control of heart by autonomic nervous system:
-sympathetic stimulation causes increase heart rate and increased force of contraction
-parasympathetic/vagus stimulation decreases heart rate

Effect of K & Ca on heart function

Inc. K ions in ECF:
-heart becomes dilated, flaccid
-HR decreases
-slows/blocks conduction of impulses through A-V node
-decreases the RMP

Inc Ca ions: opposite to Inc K ions
-spastic contraction

Dec Ca ions:

Effect of temperature on heart function

Dec temperature:
decrease heart rate ; is due to less ions are permaeble to heart muscles membrane at low temp

Moderate inc temp:
contractile strength increased but high temp causes fatigue of muscle by inc metabolism.

Rhythmical Excitation of Heart

Excitatory & conductive system of heart

-sinoatrial /SA node, where impulse is generated
-internodal pathways conducts impulses to Atrio ventricular/A-V node
-A-V node delays impulse passing to ventricles
-A-V bundle conducts impulses from atria to ventricles
-lft and rt bundle branch of purkinje fiber carries impulses to all parts of ventricles.

SA node

-is a small, flat , ellipsoid strip of specialized cardiac muscle
-is located in superior posterolateral wall of rt atrium below and lateral to opening of SVC
-is directly connected to atrial muscle fiber, so AP generated in SA node immediately spreads to atria
-it is the pacemaker of heart
-RMP: -55 to -60 mV ( in ventricle is -85 to -90 mV), SA node is leaky to Na, Ca ions
-heart muscle have 3 types of pump: fast Na pump, slow Na-Ca pump, K pump
-in SA node fast Na pump is inactive and AP is due to slow Na- Ca pump & K pump
-SA node is self excitatory: this is due to high Na ions concentration in ECF and its membrane is leaky to Na ions . Because of this +ve Na ions enters itself and causes RMP to more than threshold leading to AP.
-Threshold: -40 mV

A-V node

-located in the posterior wall of rt atrium immediately behind tricuspid valve
-it delays the impulse conduction from atria to ventricles
-this delays allow atria to empty its content into ventricles before ventricles contract.
-it causes delay of 0.09 sec and another 0.04 sec is due to penetrating portion of AV bundle, also it takes 0.03 sec for impulse to come fromSA node to Av node. Total delay is 0.16 sec.
-slow conduction is due to dec gap junctions between conducting cells.

Ventricular purkinje system

-there is rapid transmission through ventricles due to specialized purkinje fibers.
-velocity is 1.5- 4 m/s and this is 6 time that in usual ventricle muscles
-high level of permeability at gap junctions
-impusle from SA node goes to ventricles only through purkinje fibers
-there is complete insulation between atria and ventricles except at AV bundle
-impulse travels in one direction only from Sa node to ventricles.

Control of excitation & conduction in heart

-SA node is the pacemaker of heart, discharging impulse at 70-80/min
-AV node, purkinje fiber can also exhibit intrinsic rhythmic excitation as SA node
-AV node can discharge impulse at rate of 40-60/min and purkinje at 15-40 /min if they are not stimulated from outside source.

- The dicharge rate of SA node is faster than the self excitatory discharge rate of others. Each time SA node discharges, its impulses is conducted through AV node and purkinje fibers and also depolarises their membrane. The depolarisation occurs before their membrane can reach to self excitatory threshold thus SA node inhibits impulse generation from AV node and purkinje fiber. Thus SA node is known as the pacemaker of heart.

Abnormal/Ectopic pacemakers

-Pacemaker elsewhere than SA node is known as ectopic pacemakers
-When SA node is not functioning at that time impulse is generated from AV node

-If there is AV block impulse will be generated from purkinje at rate of 15-40/min but atria will be beating normally. Purkinje will self generate impluse only after 5-20 sec because previously its function was suppressed by SA node. So during this time ventricles will not function and there will be lack of blood to brain and person faints and after sometime regains consciousnes. This is known as Stokes Adams Syndrome

Control of heart rhythm by autonomic nervous system

-Parasympathetic/vagus nerve mainly supplies SA node and AV node
-Sympathetic mainly supplies ventricles and also others.

-Vagus stimulation decreases heart rate and sometime even block heart and this is due to Ach release .Ach increases the permeability of K ions and makes membrane hyperpolarised(-65 to -75 mV)

-Sympathetic nerve increases heart rate by releasing norepinephrine which increases permeability to Na and Ca ions.


Increment in blood pressure above a level that is harmful to the organs of the body

Optimal 120/ 80

Normal 130 /85

High normal 130–139 /85–89

Stage 1 (mild) 140–159 90–99

Stage 2 (moderate) 160–179/ 100–109

Stage 3 (severe) 180 /110

Isolated systolic hypertension140/ 90

Malignant HTN= accelerated HTN+papilledema

Hypertension can broadly be divided into :

BENIGN HYPERTENSION: 90 – 95% of cases.

Rapidly rising blood pressure that if untreated leads to end organ failure and death within 1 or 2 years.
Clinically - Severe hypertension - diastolic pressure over 120 mm Hg, renal failure, and retinal hemorrhages and exudates, with or without papilledema.

MORPHOLOGY: Blood vessels show fibrinoid necrosis or concentric hyperplasia of smooth muscle-cells – Hyperplastic arteriosclerosis -- onion-skin changes. These hyperplastic changes are accompanied by fibrinoid deposits and acute necrosis of the vessel walls, referred to as necrotizing arteriolitis, particularly in the kidney.


Essential Hypertension
Secondary Hypertension


Acute glomerulonephritis,
Chronic renal disease,
Polycystic disease,
Renal artery stenosis,
Renal artery fibromuscular dysplasia,
Renal vasculitis,
Renin-producing tumors


Adrenocortical hyperfunction (Cushing syndrome, primary aldosteronism, congenital adrenal hyperplasia, licorice ingestion)
Hypothyroidism (myxedema)
Hyperthyroidism (thyrotoxicosis)
Exogenous hormones (glucocorticoids, estrogen [including pregnancy-induced and oral contraceptives]

Sympathomimetics and tyramine-containing foods, monoamine oxidase inhibitors
Pregnancy-induced (Pre eclampsia)


Coarctation of aorta,
Polyarteritis nodosa (or other vasculitis),
Increased intravascular volume,
Increased cardiac output,
Rigidity of the aorta
Increased intracranial pressure
Sleep apnea

BP regulation

Complications of HTN

Hypertensive Encephalopathy and Cerebral Atrophy
Sub arachnoid and intracerebral hemorrhage

Hypertensive Retinopathy

Hypertensive Cardiomyopathy

Hypertensive nephropathy: Nephrosclerosis and chronic renal failure

Exacerbation of atherosclerosis

Aortic dissection and aneurysm formation

Resorption, fibrosis

Hyaline Arteriolosclerosis

Morphology - homogeneous pink hyaline thickening of wall of arterioles

Clinical significance - benign hypertension and diabetes mellitus

Renal glomerulus and afferent arteriole with hyaline intimal thickening. This is caused
by either diabetes or "benign" hypertension.

Arteriole with marked hyaline intimal thickening.

This kidney has fine cobblestone-like surface. This is arterionephrosclerosis, which is
caused by small areas of infarction from the hyaline arteriolar thickening.

Hyperplastic Arteriolosclerosis

Morphology - concentric, onion skin thickening of walls of arterioles

Clinical significance - associated with malignant or accelerated hypertension

Pathogenesis - vasoconstriction

Hyperplastic Arteriolosclerosis. The renal artery at left has a concentric,
onion-skin-like thickening.

Kidney in malignant hypertension. It is atrophic, has irregular small infarcts, and a
more coarsely irregular cortical surface than in the arterionephrosclerosis seen earlier.

Hypertensive Heart Disease

Left ventricular hypertrophy in the absence of other cardiovascular pathology and a history of hypertension

Wall thickness greater than 2.0 cm

Heart weight greater than 500 grams

Myocyte hypertrophy with interstitial fibrosis

The heart at right is normal. The enlarged one at left is from a hypertensive patient.
Note that it is not only enlarged, but also somewhat rounded and dilated.

Left ventricular hypertrophy in hypertension. It is about 2.5 cm thick; normal is
less than 1.5 cm thick.

The cardiac myocytes undergo hypertrophy (enlargement) but not hyperplasia.

Tissue repair

Stages of wound healing



Granulation tissue (soft callus)

Scar – Fibrosis (hard callus)

Remodeling & Wound strength

Healing – replacement by connective tissue

Regeneration – Repair of injured tissue by parenchymal cells of the same type

Cell cycle

5 phases of cell cycle

G0( Quiescent phase)
G1( Pre synthetic phase)
S( phase of DNA synthesis)
G2( premitotic growth phase)
M( mitotic phase)

Transition between the phases regulated by cyclins and CDKs( cyclin dependent kinases)

The kinases on activation will phosphorylate proteins, form mitotic spindles, cause dissolution of nuclear membranes and chromosome condensation

CDK inhibitors like TP53 are important for buying time for DNA repair, or to induce apoptosis if the DNA cannot be repaired.

Proliferative Potential

Labile cells - continuously dividing
Epidermis, mucosal epithelium, GI tract epithelium etc

Stable cells - low level of replication
Hepatocytes, renal tubular epithelium, pancreatic acini

Permanent cells - never divide
Nerve cells, cardiac myocytes, skeletal mm

Polypeptide growth factors

Most Important Mediators affecting Cell Growth

Present in serum or produced locally

Exert pleiotropic effects; proliferation, cell migration, differentiation, tissue remodeling

Regulate growth of cells by controlling expression of genes that regulate cell proliferation

Angiogenesis: bFGF, VEGF

Scar formation: TGBβ, PDGF, FGF

Remodelling: metalloproteinases


Types of signaling between cells:

Gap junctions
Autocrine signalling
Paracrine signalling
Endocrine signalling

Receptors of growth factors and cytokines:

Ion channels eg Ca++ channels
Receptors with intrinsic kinase activity, eg Ras, which activates the IP3/DAG pathway
G protein coupled receptors, which either increase or decrease the cGMP in the cell- Gs and Gi respectively

Repair by connective tissue

Occurs when repair by parenchymal regeneration alone cannot be accomplished

Involves production of Granulation Tissue

replacement of parenchymal cells with proliferating fibroblasts and vascular endothelial cells

Extracellular matrix

ECM, esp basement mb is very crucial to healing

ECM has collagen, elastin, proteoglycans and hyaluronan, which act as scaffolding for tissue repair

The collagen and laminin of basement mb, and the adhesive glycoprotein of the ECM like fibronectin and laminin hold the cells via integrins in the cell mb.

Note: proteoglycans are proteins linked to glycosaminoglycans( GAG) like dermatan sulphate and heparan sulphate while hyaluronan is not linked to any proteins.

Components of the process of fibrosis

Angiogenesis - New vessels budding from old
Fibrosis, consisting of emigration and proliferation of fibroblasts and deposition of ECM
Scar remodeling, tightly regulated by metalloproteinases like collagenase, elastase, etc and protease inhibitors

Epidermal Wound healing

Induction of acute inflammatory response by an initial injury

Parenchymal cell regeneration

Migration and proliferation of parenchymal and connective tissue cellsBasement membrane crucial to wound healing: collagen in the bm binds to cells via proteins like integrins, fibronectin and laminin.

Synthesis of ECM proteins

Remodeling of parenchymal elements to restore tissue function
Remodeling of connective tissue to achieve wound strength

Healing by First Intention

Focal Disruption of Basement Membrane and loss of only a few epithelial cells e.g. Surgical Incision

Chronological events in wound healing

24 hrs: neutrophils infiltrate, clot formation, increases mitosis in the basal cells which deposit new basement membrane and meet in the midline beneath the clot.

Day 3: macrophages replace neutrophils, granulation tissue formation, epithelial cell proliferation and collagen deposition

Day 5: neovascularisation and collagen deposition peaks, epithelium matures

2 weeks: the WBC and blood vessels decrease

1 month: tensile strength of the scar increased due to cross linking of collagen, wound contraction due to myofibroblasts dermal appendages like hair follicles and sweat glands are destroyed forever

Healing by Second Intention

Larger injury, abscess, infarction Process is similar but Results in much larger Scar and then CONTRACTION

Wound Strength

After sutures are removed at one week, wound strength is only 10% of unwounded skin (Walker’ Law)
By 3-4 months, wound strength is about 80% of unwounded skin (Walker’s Law)

Granulation tissue

Healing Skin wound


Protective response of the body to cell injury to remove the noxious stimulus that caused the injury in the first place.

Acute or Chronic if the noxious stimulus persists.

Acute inflammation lasts for minutes to days while chronic inflammation may persist from days to years
Inflammation and repair are the important steps in healing process but the inflammation can cause harm to our native tissues, eg

Autoimmune diseases
Constrictive pericarditis

Cardinal signs of inflammation:

Calor: hot
Rubor: red
Dolor: pain
Tumor: swelling
Function laesa

CellularComponents of inflammation:


Polymorphonuclear cells( neutrophils)


B cells and humoral immunity
T cells and cell mediated immunity
Monocytes and macrophages
Smooth muscle cells
Mast cells
Natural killer cells

Events in Acute Inflammation:

1.Vascular Events

Vascular dilatation: histamine, bradykinin

Increased vascular permeability and exudation:

Endothelial cell contraction( early) and retraction( late)
Direct endothelial injury: toxins, burn, etc
Leucocyte dependent endothelial injury
Increased transcytosis
Neoangiogenesis: increased gap junctions

2.Cellular events:

Neutrohils initially
Monocytes after 6-24 hours
Rolling and margination
Adhesion: interaction between selectins, integrins and cell adhesion molecules like VCAM
Transmigration by diapedesis


Chemokines: bacterial peptides, C5a, LTB4( Leukotreine), IL 8( interleukin)
Actin myosin interactions in the leucocyte are responsible for diapedesis

Phagocytosis and degranulation

Opsonisation: c3b, IgG, collectins
Oxidative burst

How do neutrophils kill?

Oxidative burst resulting in free radicals

2O2+NADPH ....NADPH.....2O2- ions+NADP+H+

2O2- ions+ 2H+ .....oxidase........ H2O2

H2O2+ Cl-...myeloperoxidase....... HOCl-

Dead organisms digested by lysosomal hydrolases

Bacterial killing also aided by lysozymes and defensins, the latter increase the permeability of bacterial cell.

Body’s defense against free radical injuries

Catalase which neutralises H2O2 into water and O2
Superoxide Dismutase
Glutathione Peroxidase
Antioxidant Vitamins like vitamin A, C and E

Disorders of cellular events of inflammation

Adhesion deficiency
Myeloperoxidase deficiency: Chediak Higasi disease
NADPH Oxidase deficiency: chronic granulomatous diseases

Chemical mediators of inflammation


Preformed mediator so released early on
Secreted by mast cells and basophils
Secreted in response to
cross linking of IgE during reexposure to allergen in type I hypersensitivity
Anaphylotoxins: C3a, C5a

Substance P: responsible for pain

Chemical mediators of inflammation

Kinin Cascade:

Coagulation factor XIIa activates Prekallikrein into Kallikrein
Kallikrein activates HMWK( High Molecular Weight Kininogen) into Bradykinin

Coagulation cascade:

Fibrinolytic cascade: tPA activates plasmin

Complement cascade:

Proteases that are nine in number: c1 to c9

Activated by
classic pathway due to Ag-Ab complexes
alternative pathway by microbial LPS or endotoxins

One activated complement activates another
C3a and C5a are anaphylotoxins
C5a is a chemokine
C3b along with IgG work as opsonins
C5b to C9 make the MAC: membrance attack complex

Lysosomal proteases, endonucleases and antiproteases to protect the cells against own enzyme, eg α antitrypsin.

NO( previously called EDRF) by NO synthase

Reactive oxygen species

Arachidonic acid metabolites


Interleukins: more than 20 types


Colony stimulating factors eg GM-CSF

IL 1 and TNFα are responsible for all the acute phase response including fever, cachexia, neutrophil aggregation, septic shock and synthesis of acute phase reactants from liver( eg CRP, ceruloplasmin)

Chronic Inflammation

Outcomes of acute inflammation can either be resolution, chronic inflammation or scarring

Persistence of noxious stimulus causes chronic inflam.

Eg. Chronic viral hepatitis, syphilis, TB and fungi( delayed hypersensitivity), silicosis and other pneumoconioses, autoimmune diseases, etc

Interference in the healing process

3 main components

Mononuclear cell( macrophages) infiltration
Tissue destruction
Repair: by either tissue regeneration or fibrosis

Tissue injury in chronic inflammation is caused by Radical oxygen species, proteases and tissue plasmin activator( tPA)

Fibrosis is a common component in chronic inflammation caused by cytokines like PDGF, FGF, TGFβ, VEGF, etc

Granulomatous inflammation

Type IV hypersensitivity

Attempt at walling off the noxious material

CD4 T helper lymphocyes crucial in recruiting monocytes which turn into macrophages( epitheloid cells) and giant cells

Granuloma with caseous necrosis seen in TB

Other examples are

tuberculoid leprosy
syphilitic gumma
fungal infections like histoplasmosis, blastomyces, cryptococcosis, coccidioides
foreign body like suture materials
pneumoconiosis like silicosis
idiopathic like sarcoidosis

Morphology of a granuloma

lymphocytes( esp CD4 type T helper cells)

macrophages( epitheloid cells, so called because of their resemblance to squamous cells)

epitheloid giant cells formed by the fusion of many epitheloid cells with multiple nucleus in different patterns of arrangement like horseshoe pattern in Langhan’s giant cell seen in TB granuloma.

Necrotic material in centre in case of caseous granuloma as seen in TB

Morphologic types of inflammation


Exudative Inflammation: excess fluid. TB lung.
Suppuration/Purulent – Bacterial - neutrophils
Fibrinous – pneumonia – fibrin
Serous – excess clear fluid – Heart, lung
Haemorrhagic – b.v.damage - anthrax.

Chronic inflammation:

with healing.
Granulomatous – clusters of epitheloid* cells eg. TB, Fungus, Foreign body.

Lewis Triple Response:

Flush: capillary dilatation.
Flare: arteriolar dilatation.
Wheal:exudation, edema.

Gastric Ulcer:


Mouth Aphthous ulcer:

Acute Enteritis:


Neutrophil Margination:

Vascular changes:

Pneumonia - Exudation:

Chronic Inflammation:

Serous Inflammation - Effusion :

Fibrinous Inflammation:

Purulent - Inflammation:

Chronic Inflammation:

Lung Abscess