Blood Circulation and Hemoglobin Binding Curves

1. How do we move blood and its contents throughout the body? Jan 31 and Feb2 Examine hemoglobin binding curves for Test #2! Today’s Goals (CH19): What are the major features of our pump called the heart? • How is the circulation divided into two loops with different pressure and degrees of hemoglobin oxygenation? • What are the characteristics of a single cardiac myocyte? • What are the three layers of the heart? • How do the cardiac valves determine the direction of blood flow in the heart? • How dependent is the heart upon oxygen supplies? • How does blood reach the different regions of the heart? • FIVE STEP cardiac cycle

2. Monday is Lecture Test #1 (Ch17 and 18): Let the notes be your guide to what is on a test, book is required to support what you see in the notes. A=+90% B=+80% C=+70% D=+60% F=-60% History: 2015 Q1-15.8/T1-38.7 2016 Q1 14.8/T1-39.6 2017 Q1 16.2/T1-37.2 Most persons find that studying for AP 212 is different from AP 211 • Most persons find AP 212 requires less memorization and more application • Most persons find that each hour of lecture requires 2-3 hours of study time put in as you go (not just before the test) to be in ballpark for a “B” or better. • If your study methods worked, use them again. • If they did not, reassess and try something else. • Essay Hint #1: remember to answer only the question being asked. • Essay Hint #2: be able to use specific details when you answer a general question.

3. Hemoglobin consists of 4 protein subunits (globins) and each globin has a heme at its center. Each heme holds a single Fe++ and can hold a single O2 molecule (4 O2 /hemoglobin).There are about 380,000,000 hemoglobins in each erythrocyte!Each erythrocyte can carry up to about 4X380,000,000 oxygens!

4. Hemoglobin has 4 globins, 4 hemes, 4 Fe++, and binds up to a maximum of 4 O2 (or No O2 at all) The protein subunits are called “globins” Two can be “alpha” in adult or fetus Two can be “beta” in adult that appear just before birth Two can be “gamma” in fetus: lost right around birth The “HEME” is a ring like structure that has Fe++ in the center. Oxygen is attracted to the Fe++ that binds it temporarily and releases it later where needed. Attachment and release is determined by concentration gradients (What are gradients in LUNG or HEART?) Oxygen tends to fall of the heme if there is little oxygen around the heme….so oxygen is then supplied to tissues. Oxygen binds to the heme when there is plenty of oxygen available and none is attached to the heme…this condition occurs when erythrocytes are in the capillaries that line the alveoli of the lung.

5. “Cooperativity” describes how the four globins of hemoglobin interact with each other and oxygen. When all 4 hemes are without oxygen (empty) affinity is low, but gradient is high. The binding of oxygen to any one heme affects the remaining three and makes them more likely to bind oxygen. When another oxygen binds, it makes the remaining two even more likely to bind oxygen. Binding of a third oxygen tremendously increases the affinity of the last empty heme to find and oxygen. Assuming an oxygen can bind the heme, the hemoglobin is now filled (100% saturated) with oxygen. INVERSE: When any single heme in the hemoglobin looses an oxygen, the other three are more likely to lose an oxygen, etc… Net Result? Hemes want to be completely filled with oxygen or completely empty! This gives the binding curve a “sigmoid” shape. This is HUGELY important physiologically!

6. Myoglobin in muscle has one heme and globin (No Cooperativity).Hemoglobin in a erythrocyte has four hemes and globins.Why do the oxygen binding characteristics of these two proteins look so different? Hyperbolic vs. Sigmoid Curve Oxygen is bound to almost 100% of available Hb-hemes in the lung. 1) Oxygen is removed from the hemoglobin 2) Percent saturation reduced (oxygen used). Hb has “Cooperativity”--------- Mb has NO “Cooperativity”!

7. Why would you want fetal hemoglobin (2 gamma subunits) to bind oxygen much more tightly than adult hemoglobin? Is there more oxygen in the blood of the fetus or the mother? Like all molecules oxygen can only diffuse down concentration gradients in the body. DANGER! Carbon monoxide has an extremely high affinity for Hb (Hb-CO), so oxygen cannot bind Hb in the lung!

8. The Bohr Effect is amazing! Acids accumulate ( ↓pH) in metabolically active tissues! This is a signal that oxygen needs have increased in the tissue! If oxygen needs increase, oxygen delivery needs to increase! HOW IS THIS DONE? Protons (H+ or acids) are a signal that cause the hemoglobins to DUMP their oxygen in acidic tissues that should also be hypoxic! The Bohr Effect says that as conditions become more acidic (even slightly) the hemoglobin is more likely to release its oxygen. The reverse can also occur…..remember hyperventilating as a kid? This causes your blood pH to become alkaline and you pass out because you have plenty of oxygen in the blood, you cannot remove the oxygen from your hemoglobin properly in your brain!

9. Test #2: What are some common plasma/blood electrolyte imbalances and the terminologies used to describe them? • Ion----[Plasma]---[ICF]----Deficiency Term-------Excess Term • ↓↓ ↓↓ • Na+--142-----------10------Hyponatremia---------Hypernatremia • K+----5--------------141----Hypokalemia----------Hyperkalemia • Ca++-5-------------<1------Hyopocalcemia--------Hypercalcemia • Cl-----103-----------4--------Hypochloremia--------Hyperchloremia • PO4---4-------------75-------Hyperphosphatemia-Hypophosphatemia • The plasma levels are often evaluated in a panel test:

10. Test #2: Lipoproteins are large particles in the plasma that are specialized for carrying non-water soluble lipids. These are also VERY important items for this unit on cardiac function. • Chylomicron: largest and synthesized by intestine Carry_____________from the _______to the ______________ • Very Low Density Lipoprotein: VLDL: Big and synthesized by liver Carry______________from the _______to the ______________ • Low Density Lipoprotein: LDL: VLDL-left over! Carry______________from the _______to the ______________ • High Density Lipoprotein: HDL: smallest and synthesized by liver Carry______________from the _______to the ______________ • HDL is called “Good Cholesterol” and LDL is called “Bad Cholesterol” • Plasma cholesterol and coronary heart disease/stroke risk: • Dietary influence: • Genetic Influence: • Why do we often die of a heart attack a few hours after a fatty Christmas dinner? Look and see!

11. REVIEW: BLOOD CELLS HAVE AN ANTIGENIC PROPERTY CALLED BLOOD TYPE. • Agglutinogens: Polysaccharides on outside of RBC (antigens) • Agglutinins: Plasma antibodies that seek non-native agglutinogens in your blood • Agglutination/hemolysis: This occurs when your antibodies observe foreign antigens (foreign erythrocytes) in your blood and bind to these cells. Antibodies bound to foreign cells then bind other bound foreign cells and create clumps that clog capillaries and lead to cellular hemolysis, possible death from a bad transfusion. • Blood Banking/ABO designation refers to antiGENS found on your RBCs, so your blood destroys RBCs with other antigens. • Type-O Type-A Type-B Type-AB • Transfusions- Blood or Plasma? • Plasma transfusions:Long shelf-life but fewer risks/benefits! • IgG proteins and Rhesus designations- Rh+ or Rh- Hemolytic Disease of the Newborn (HDN)/Erythroblastosis fetalis First fetus gets off free! Following fetuses at risk of maternal Abs! HDN: Fetal lysis, Bilirubin, Liver function, and UV-phototherapy

12. Universal Donor is Type-O Negative has anti-A, B Rh antibodies and they can develop immune reactions to blood A, B or Rh. Universal Recipient has Type AB positive has antigens on their erythrocytes and has NO antibodies for A, B, or Rh, if they did they would destroy their own blood. They are the universal recipient Rh problems: second Rh+ fetus in an Rh- mother (first is usually ok because mother is not exposed to enough fetal blood (Rh+) to created antibodies to fetal Rh+ until parturition occurs (birth). Second birth is problematic because her body needs far less Rh+ to create a response form memory lymphocytes.

13. One more review: The shift in the oxygen binding curve to the right means less oxygen will be attached to the hemoglobins in an acidic region! So oxygen leaves the hemoglobin and can be delivered to where it is needed most! ↑Carbon dioxide and ↑Temperature have similar effects.

14. Lets Talk about your HEART!WHAT ARE THE PRIMARY ANATOMICAL FEATURES OF OUR HEART? Key Features: • 4 chambers • Base (Top) vs. Apex (Bottom) • Sides: Anterior vs. Posterior vs. L/R Lateral • Location in pericardial sac and thoracic cavity • Cycles of Activity: Systole vs. Diastole • In Lab: Remember to identify the anterior surface by looking for the more prominent anterior interventricular sulcus (posterior sulcus is less prominent), then you also know left vs. right, anterior/posterior.

15. 2 Pressure loops: Low mmHg vs. High mmHg 2 Anatomical loops: Pulmonary vs. Systemic 2 Oxygenation loops: Oxygenated vs Deoxygenated Blood/body colors: Bright red vs Cyanotic Blood Volumes in 2 circuits: Resistance vs. Capacitance What is the expense of pressure? WORK!!! Why is blood flow in the body divided into two very different loops?

16. WHAT ANATOMICAL CHARACTERISTICS OF CARDIAC MYOCYTES MAKE THEM UNIQUE? • Why do these cells function the way they do? • Intercalated discs • Striations • Mitochondria • Gap junctions • Why is the cardiac cell very different from smooth muscle or skeletal muscle cells?

18. WHAT IS THE SIGNIFICANCE OF HAVING THE WALL OF THE HEART DIVIDED INTO THREE DISTINCT LAYERS? 1) Endocardium: prevent clotting/infection 2) Myocardium: force generation 3) Epicardium: parietal vs. visceral Ischemia: local hypoxia/injury Infarct: cell death Post Infarct: tissues consist mostly of non-contractile collagen deposited by fibroblasts (Scar Tissue)! What keeps the heart from smashing/bruising itself to pieces? • Fat: • Fluid: • What protects the heart from the outside?

19. If excess fluids accumulate in the pericardial cavity and put pressure on the heart, it cannot be filled with venous return.

20. HOW DO THE HEART VALVES ENSURE ONE-WAY FLOW OF BLOOD? WHY IS THIS CRITICAL? Blood flow through valves requires a pressure gradient. Two sets of Atrioventricular valves: Right AV vs. Left AV Tricuspid vs. Bicuspid (mitral) Two sets of Semilunar valves: Pulmonic vs. Aortic DISEASE: Valvular stenosis vs. Mitral valve prolapse Streptococcal infection in childhood? Why at the valves? Thrombosis formation: Why at the valves? Why does cardiac work increase dramatically when the valves of the heart fail?

21. Can you name all the structures of the heart that blood would move across in moving from the vena cava to the aorta? Can you also describe the degree of oxygenation at these points? BASE LT AV Valve RIGHT AV Valve APEX

22. WHY IS CIRCULATION THROUGH THE HEART SO VERY COSTLY FOR THE BODY? THE STATISTICS: 1) About 5% of CARDIAC OUTPUT goes right back into heart. The more blood you pump out, the more energy you USE! 2) Your heart USES about 10% of the oxygen consumed by the body! (This is called a HIGH Oxygen extraction ratio) 3) The cardiac tissues mostly desaturate (remove oxygen from) the hemoglobin in the blood that passes thorough it! Does this leave much oxygen in reserve? How do you supply more oxygen? 4) Cardiac metabolism is mostly aerobic (mitochondria), why? 5) Anaerobic Metabolism in the heart is mostly a back-up and works largely via lactic acid and lactate dehydrogenase (LDH) Blood and O2 are only pumped to cardiac cells during diastole (cardiac period of rest or quiescence). Your heart never “rests” longer than about 0.5-0.75 second! VIP: What happens to the time available for blood flow into the heart when it spends more time contracted, as happens when the heart beats very rapidly (tachycardia)?

23. WHAT ARE THE PRIMARY VESSELS SUPPLYING BLOOD TO THE HEART? Two Major Coronary Arteries Supply the Heart! • Left Coronary Artery (the “Widow Maker”?)splits in 2 Left Anterior Descending Circumflex Artery -Left Marginal Artery branches off circumflex • Right Coronary Artery • Marginal Branch of RCA • Posterior Descending Interventricular Artery (usually off RCA) How do you predict the risk of a heart attack in any one part of the heart? 5) Does the region receive blood flow from a single artery? 4) Does the region receive blood from 2 or more arteries 3) Is the ventricular wall thick of thin? 2) Are coronary arteries occluded by a thrombosis/plaque? #1) Most important question: HOW MUCH WORK IS THE HEART DOING? Heart Attack (Infarct) is relatively rare in the atria because of their low work load!

24. (In the figure, dotted line means posterior aspect of heart).

25. An obstruction (thrombosis) of an artery can prevent oxygen delivery to dependent tissues! Some regions of cardiac tissue can be perfused with blood from two or three coronary arteries! (“collateral flow”) • i.e. Apex (bottom): infarct here is rare because these tissues are perfused with blood originating from the LAD and right posterior descending! • i.e. Left lateral aspect of left ventricle: only gets perfussion form one artery: circumflex! HIGH RISK for thrombosis! Why do more anastomoses/collateral flow improve your chances for heart attack survival? Venous drainage during diastole occurs via the great cardiac veins, with some blood entering coronary sinus. • Fetal Adaptations: Ductus arteriosus and Foramen ovale • What purpose do these fetal structures provide?

26. Your heart pumps blood using a five step Cardiac Cycle: • Remember the two equal cycles: Pulmonary AND Systemic 1) Diastolic Filling of Atria and Ventricles (V. Diastole) • Semilunars are closed and AV valves are open! 2) Atrial Systole (VIP: occurs towards the end of V. Diastole) • Ventricles are primed with atrial blood (“topped off”) • Semilunar valves closed 3) Isovolumetric Ventricular Contraction (V. Systole) • Semilunar valves remain closed, AV valve flaps are close by back flow of blood into atria when the ventricular pressure begins to increase. • Pressure is generated until Ventricular mmHg > Arterial mmHg

27. 4) Ventricular Ejection (V. Systole) When Vent P > Arterial P, semilunars open and blood can exit the ventricle Volume of blood ejected from ventricle is dependent on magnitude of pressure gradient Semilunar valves must open before ejection can begin! 5) Isovolumetric Ventricular Relaxation (V. Diastole) End of contraction, semilunars close when VentP< Arterial P AV valves open and diastolic filling begins next cycle Remember the two ventricles BOTH do these activities at about same time with the same volumes at two different pressures! While “Atrial” Systole does occur, it is not as clinically important because the atria only do about 5% of the work done by the ventricles, so they just don’t use as much ATP or need as much oxygen.

28. Remember that the AV and semilular valves close to prevent flow of blood from high to low pressure back into the atria or ventricles!