Red blood cell cycle:

RBCs enter the blood at a rate of about 2 million cells per second. The stimulus for erythropoiesis is the hormone erythropoietin, secreted mostly by the kidney. RBCs require Vitamin B12, folic acid, and iron. The lifespan of RBC averages 120 days. Aged and damaged red cells are disposed of in the spleen and liver by macrophages. The globin is digested and the amino acids released into the blood for protein manufacture; the heme is toxic and cannot be reused, so it is made into bilirubin and removed from the blood by the liver to be excreted in the bile. The red bile pigment bilirubin oxidizes into the green pigment biliverdin and together they give bile and feces their characteristic color. Iron is picked up by a globulin protein (apotransferrin) to be transported as transferrin and then stored, mostly in the liver, as hemosiderin or ferritin. Ferritin is short term iron storage in constant equilibrium with plasma iron carried by transferrin. Hemosiderin is long term iron storage, forming dense granules visible in liver and other cells which are difficult for the body to mobilize.

Some iron is lost from the blood due to hemorrhage, menstruation, etc. and must be replaced from the diet. On average men need to replace about 1 mg of iron per day, women need 2 mg. Apotransferrin (transferrin without the iron) is present in GI lining cells and is also released in the bile. It picks up iron from the GI tract and stimulates receptors on the lining cells which absorb it by pinocytosis. Once through the mucosal cell iron is carried in blood as transferrin to the liver and marrow. Iron leaves the transferrin molecule to bind to ferritin in these tissues. Most excess iron will not be absorbed due to saturation of ferritin, reduction of apotransferrin, and an inhibitory process in the lining tissue.

Erythropoietin Mechanism:

Myeloid (blood producing) tissue is found in the red bone marrow located in the spongy bone. As a person ages much of this marrow becomes fatty and ceases production. But it retains stem cells and can be called on to regenerate and produce blood cells later in an emergency. RBCs enter the blood at a rate of about 2 million cells per second. The stimulus for erythropoiesis is the hormone erythropoietin, secreted mostly by the kidney. This hormone triggers more of the pleuripotential stem cells (hemocytoblasts) to follow the pathway to red blood cells and to divide more rapidly.

It takes from 3 to 5 days for development of a reticulocyte from a hemocytoblast. Reticulocytes, immature rbc, move into the circulation and develop over a 1 to 2 day period into mature erythrocytes. About 1 to 2 % of rbc in the circulation are reticulocytes, and the exact percentage is a measure of the rate of erythropoiesis.

Excitability ( Bathmotropism ) : Excitability means the ability of cardiac muscle to respond to signals. Here we are talking about contractile muscle cells that are excited by the excitatory conductive system and generate an action potential.

Cardiac action potential is similar to action potential in nerve and skeletal muscle tissue , with one difference , which is the presence of plateau phase . Plateau phase is unique for cardiac muscle cells .
The  resting membrane potential for cardiac muscle is about -80 mV.
When the cardiac muscle is stimulated an action potential is generated . The action potential in cardiac muscle is composed of four phases , which are :

1. Depolarization phase (Phase 0 ) :

A result of opening of sodium channels , which increase the permeability to sodium , which will lead to a rapid sodium influx into the cardiac muscle cell.

2. Repolarization : Repolarization in cardiac muscle is slow and triphasic :

a. Phase 1 (early partial repolarization ) : A small fast repolarization , results from potassium eflux and chloride influx.
b. Phase 2 ( Plateau ) : After the early partial depolarization , the membrane remains  depolarized , exhibiting a plateau , which is a unique phase for the cardiac muscle cell. Plateau is due to opening of slow calcium-sodium channels , delay closure of sodium channels , and to decreased potassium eflux.
c. Phase 3  ( Rapid repolarization) :  opening of potassium channels and rapid eflux of potassium.
d. Phase 4 ( Returning to resting level) in other words : The phase of complete repolarization. This due to the work of sodium-potassium pump.

Absolute refractory period:

Coincides wit phase 0,phase1 , and phase 2 . During this period , excitability of the heart is totally abolished . This prevents tetanization of the cardiac muscle and enables the heart to contract and  relax to be filled by blood ..

Relative refractory period : 

Coincides with the rapid repolarization and allows the excitability to be gradually recovered .
Excitation contraction relationship : Contraction of cardiac muscle starts after depolarization and continues about 1.5 time as long as the duration of the action potential and reaches its maximum at the end of the plateau. Relaxation of the muscle starts with the early partial repolarization.

Factors , affecting excitability of cardiac muscle:

I. Positive bathmotropic effect :

1. Sympathetic stimulation : It increase the heart , and thus reduces the duration of the action potentia; . This will shorten the duration of the absolute refractory period , and thus increase the excitability .
2.  Drugs : Catecholamines and  xanthines derivatives .
3. Mild hypoxia and mild ischemia
4. Mild hyperkalemia as it decreases the K+ efflux and opens excess Na+ channels .
5. Hypocalcemia

II. Negative bathmotropic effect :

1. Parasympathetic stimulation: The negative bathmotropic effect is limited to the atrial muscle excitability , because there is no parasympathetic innervation for the ventricles. Parasympathetic stimulation decreases the heart rate , and thus increases the duration of cardiac action potential and thus increases the duration of the absolute refractory period.
2. moderate to severe hypoxia
3. hyponatremia , hypercalcemia , and severe hyperkalemia.

Clinical Physiology : Extrasystole is a pathological situation , due to abnormal impulses , arising from ectopic focus .It is expressed as an abnormal systole that occur during the early diastole .
Extrasystole  is due to a rising of excitability above the normal , which usually occurs after the end of the relative refractory period ( read about staircase phenomenon of Treppe)

Heart is a hollow muscular organ , that is located in the middle mediastinum  between the two bony structures of the sternum and the vertebral column ( a very important location for applying Cardiopulmonary Resuscitation - CPR- ) .
It has a shape of clenched fist , which weighs about 300 grams ( with mild variation between male and female ).
  Heart has an apex that is anteriorly , inferiorly , and leftward oriented , and a base , that is posteriorly , superiorly and rightward oriented   .
 In addition to its apex and base the heart has anterior , posterior and left surfaces.
 
 The wall of the heart is composed of three layers :
 
1. Endocardium : The innermost layer , which lines the heart chambers and is in direct contact with the blood . It is composed of endothelial cells that are similar to those , that line the blood vessels , and of connective tissue too. 
 Endocardium has a smooth surface that prevents blood clotting, as it ensures laminar blood flow .

 Clinical Physiology 
 Endocarditis is the inflammation of the endocardium , which is resistant to antibiotic treatment and difficult to cure.Endocarditis usually involves heart valves and chordae tendineae too.

 2. Myocardium  : The middle layer of the cardiac wall . It is the thickest among the three layers , and is composed of two types of cardiac muscles :
a. contractile muscle cells (form about 98-99% of the cardiac muscle ) .
 b- non-contractile muscle cells ( form about 1-2 % of the cardiac muscles and are the cells that form excitatory-conductive system of the heart).
 The cardiac muscle cells are similar to the skeletal muscles in that they are striated , but similar to the smooth muscles in being involuntary and connected to each others via gap junctions , that facilitate conduction of electrical potential from one cell to the others. Desmosomes adhere cardiac muscle cells to each others .

 3- Epicardium :  is the outermost and protective layer of the heart . It is composed of connective tissue , and form the inner layer of the pericardium ( visceral pericardium - see bellow).

 Pericardium: 
The heart is surrounded by a fluid-fill sac , which is known as pericardium . Pericardium is composed of two layers ( doubled layer membrane ) , between which a fluid-fill pericardial cavity exist .

 The outer layer is called fibrous pericardium , while the inner layer is called serous pericardium , which is subdivided into parietal pericardium and visceral pericardium . The visceral pericardium is the previously mentioned outermost layer of heart ( epicardium) .
Pericardial sac plays an important role in protection of heart from external hazards and infections , as it fixes the heart and limits its motion. It also prevents excessive dilation of the heart.

Clinical physiology: 

When there is excessive fluid in the pericardial cavity as a result of pericardial effusion , a cardiac tamponade will develop . cardiac tamponade means compression of the heart within the pericardial sac , which will prevent the relaxation of the heart ( heart will not be able to fully expand ) , and thus the circulating blood volume will be decreased (obstructive shock) . This is a life threatening situation which has to be urgently cured by  pericardiocentesis . 

Chambers of the heart : 

Heart has four chambers : two atria and two ventricles . The two right and left atria are separated from the two ventricles by the fibrous skeleton , which involves the right ( tricuspid ) and left ( bicuspid ) valves. Right and left atria are separated from each other by the interatrial  septum .
The two ventricles are separated by the interventricular septum.Interventricular septum is muscular in its lower thick part and fibrous in its upper thin part.
The two atria holds the blood returning from the veins and empty it only in a given right moment into the ventricles. Ventricles pump the blood into the arteries . 

Heart valves : 

There are four valves in the heart : Two atrioventricular valves and two semi-lunar valves:
1. Atrioventricular ( AV ) valves: These valves are found between the atria and ventricles , depending on the number of  the leaflets , the right atrioventricular valve is also called tricuspid valve (has three leaflets ) , while the left one is called bicuspid valve (has two leaflets ) . The shape of the bicuspid valve is similar to the mitre of bishop , so it is also called the mitral valve.
The leaflets of the valves are attached to fibrous threads (composed of collagen fibers ) , known as chordae tendineae , which from their side are attached to papillary muscles in the ventricles. These valves prevent backward flow of blood from ventricles during the systole. 

2. Semi-lunar valves : 

These valves are located on the base of the arteries ( aorta and pulmonary artery ) . They prevent the backward flow of blood from the arteries into ventricles.
The structure of the semilunar valves is quite different from that of the AV valves , as they have crescent-shaped cusps that do not have chorda tendinea , instead these cusps are like pockets which are filled of blood when it returns to the ventricles from the lumen of arteries during the diastole  , so they get closed and prevent the backward flow of blood.

HEART DISORDERS

1. Pump failure => Alters pressure (flow) =>alters oxygen carrying capacity.
   1. Renin release (Juxtaglomerular cells) Kidney
   2. Converts Angiotensinogen => Angiotensin I
   3. In lungs Angiotensin I Converted => Angiotensin II
   4. Angiotensin II = powerful vasoconstrictor (raises pressure, increases afterload)
      1. stimulates thirst
      2. stimulates adrenal cortex to release Aldosterone
         (Sodium retention, potassium loss)
      3. stimulates kidney directly to reabsorb Sodium
      4. releases ADH from Posterior Pituitary
2. Myocardial Infarction

    

   1. Myocardial Cells die from lack of Oxygen
   2. Adjacent vessels (collateral) dilate to compensate
   3. Intracellular Enzymes leak from dying cells (Necrosis)
      1. Creatine Kinase CK (Creatine Phosphokinase) 3 forms
         1. One isoenzyme = exclusively Heart (MB)
         2. CK-MB blood levels found 2-5 hrs, peak in 24 hrs
         3. Lactic Dehydrogenase found 6-10 hours after. points less clearly to infarction
      2. Serum glutamic oxaloacetic transaminase (SGOT)
         1. Found 6 hrs after infarction, peaks 24-48 hrs at 2 to 15 times normal,
         2. SGOT returns to normal after 3-4 days
   4. Myocardium weakens = Decreased CO & SV (severe - death)
   5. Infarct heal by fibrous repair
   6. Hypertrophy of undamaged myocardial cells
      1. Increased contractility to restore normal CO
      2. Improved by exercise program
   7. Prognosis
      1. 10% uncomplicated recovery
      2. 20% Suddenly fatal
      3. Rest MI not fatal immediately, 15% will die from related causes
3. Congenital heart disease (Affect oxygenation of blood)
   1. Septal defects
   2. Ductus arteriosus
   3. Valvular heart disease
      1. Stenosis = cusps, fibrotic & thickened, Sometimes fused, can not open
      2. Regurgitation = cusps, retracted, Do not close, blood moves backwards

Characteristics of Facilitated Diffusion & Active Transport - both require the use of carriers that are specific to particular substances (that is, each type of carrier can 'carry' one type of substance) and both can exhibit saturation (movement across a membrane is limited by number of carriers & the speed with which they move materials

Hypoxia

• Hypoxia is tissue oxygen deficiency
• Brain is the most sensitive tissue to hypoxia: complete lack of oxygen can cause unconsciousness in 15 sec and irreversible damage within 2 min.
• Oxygen delivery and use can be interrupted at several sites

• Causes:
  • Hypoxic: high altitude, pulmonary edema, hypoventilation, emphysema, collapsed lung
  • Anemic: iron deficiency, hemoglobin mutations, carbon monoxide poisoning
  • Ischemic: shock, heart failure, embolism
  • Histotoxic: cyanide poisoning (inhibits mitochondria)

• Carbon monoxide (CO) poisoning:
  • CO binds to the same heme Fe atoms that O₂ binds to
  • CO displaces oxygen from hemoglobin because it has a 200X greater affinity for hemoglobin.
  • Treatment for CO poisoning: move victim to fresh air. Breathing pure O₂ can give faster removal of CO

• Cyanide poisoning:
  • Cyanide inhibits the cytochrome oxidase enzyme of mitochondria
  • Two step treatment for cyanide poisoning:
    • 1) Give nitrites
      • Nitrites convert some hemoglobin to methemoglobin. Methemoglobin pulls cyanide away from mitochondria.
    • 2) Give thiosulfate.
      • Thiosulfate converts the cyanide to less poisonous thiocyanate.