2. Veins Reservoir function 60% blood in veins Specific reservoirs in spleen, liver, skin, lungs and heart! Effect of gravity Venous pump Valves (varicose veins) Abdominal pump Thorax pump Central venous pressure (CVP) – Right Atrial Pressure Ability of the heart to pump Venous return Values: normal is 0 mmHg Increased (straining, heart failure, massive transfusion) Decreased (extraordinary heart contractions, haemorrhage)

3. Veins Measuring CVP Noninvasive: Height to which external jugular veins are distended when the subject lies in recumbent position Vertical distance b/w rt. atrium and the place the vein collapses (the place where the pressure =0) =venous pressure (in mm of Hg) Invasive: Inserting a catheter into the thoracic great veins Direct pressure reading

4. Microcirculation Capillaries Arterial end Venous end Filtration across capillaries: Starling Forces Capillary pressure (Pc) Interstitial fluid pressure (Pif) Plasma colloid osmotic pressure (πp) Interstitial colloid osmotic pressure (πif) NFP = Pc – Pif – πp + πif Filtration = NFP x Kf Where, Kf is Capillary filtration coefficient

5. Starling’s Forces

6. Edema Accumulation of interstitial fluid in abnormally large amounts Causes: Increased filtration pressure Arteriolar dilation Venular constriction Increased venous pressure (heart failure, incompetent valves, venous obstruction, increased total ECF volume, effect of gravity, etc) Decreased osmotic pressure gradient across capillary Decreased plasma protein level Severe liver failure, Protein malnutrition, Nephrotic syndrome Accumulation of osmotically active substances in interstitial space

7. Edema Increased capillary permeability Substance P Histamine and related substances Kinins, etc Inadequate lymph flow (lymphedema) Elephantiasis (In filariasis, parasitic worms migrate into lymphatics & obstruct them)

8. Lymphatics Normal 24-h lymph flow is 2 - 4 L Lymphatic vessels divided into 2 types: Initial lymphatics Lack valves Lack smooth muscle Found in regions such as intestine or skeletal muscle Fluid enters thru loose junctions Drain into collecting lymphatics Collecting lymphatics

9. Lymphatics Return of filtered proteins Very important fn amount of protein returned in 1 day = 25–50% of the total circulating plasma protein Transport of absorbed long-chain fatty acids and cholesterol from the intestine

10. Local Control of Blood Flow Why control blood flow? Blood flow is variable between one organ and another, Depends on overall demands of each organ system These inter-organ differences in blood flow are the result of differences in vascular resistance

11. Local Control of Blood Flow:Mechanisms Local: Matching blood flow to metabolic needs Exerted through direct action of local metabolites on arteriolar resistance Acute: rapid changes in local vasoconstriction/ dilation of arterioles, metarterioles, precap-sphincters Long-term: slow, controlled (days, weeks & months) – increase in physical size, number Nervous / Hormonal: SNS Histamine, bradykinin, & prostaglandins

12. Acute Mechanisms Autoregulation Reactive hyperemia Active hyperemia

13. Acute Mechanisms:Autoregulation Maintenance of constant blood flow to an organ in the face of changing arterial pressure Kidneys, brain, heart, & skeletal muscle + others exhibit autoregulation

14. Acute Mechanisms:Active hyperemia Blood flow to an organ is proportional to its metabolic activity Example: Metabolic activity in skeletal muscle increases as a result of strenuous exercise Blood flow to muscle will increase proportionately to meet the increased metabolic demand

15. Acute Mechanisms:Reactive hyperemia Increase in blood flow in response to or reacting to a prior period of decreased blood flow Example: Arterial occlusion to an organ occurs During the occlusion, an O2 debt is accumulated Longer the period of occlusion, the greater the O2 debt Greater the subsequent increase in blood flow above the preocclusion levels. The increase in blood flow continues until the O2 debt is "repaid."

16. Explanation Myogenic hypothesis Explains autoregulation Not active or reactive hyperemia If arterial pressure - suddenly increased - arterioles are stretched - vascular smooth muscle - contracts in response to this stretch* Metabolic hypothesis O2 demand theory Vasodilator theory CO2, H+, K+ lactate, and adenosine

17. Long-term Mechanisms for Blood Flow Control Vascularity changed – acc. to metabolic profile Role of oxygen Role of vascular endothelial growth factors VEGF Fibroblast growth factor Angiogenin Vascularity is determined by max. tissue need (not average) Collateral circulation

18. Humoral control of Blood Flow Vasocontrictor agents (NE, epinephrine, Angiotensin-II) Vasodilatory agents (bradykinin, histamine) Ions & other agents Increase in Ca++: vasoconstriction Increase in K+: vasodilation Increase in Mg++: powerful vasodialtion Increase in H+: vasodilation Acetate and citrate: vasodilation Increase in CO2: vasodilation

19. ARTERIAL BLOOD PRESSURE CONTROL

20. General The ‘large water tower’ example MAP is maintained – hence tissues can ‘tap into’ the general blood flow CVS needs to maintain just MAP ! Nervous and hormonal factors play major roles Timeline: Acute Intermediate Long term

21. CNS areas controlling BP

27. Baroreceptor Reflex

28. Baroreceptor Features: Sensitivity Carotid sinus baroR are not stimulated at all by pressures between 0 and 50 to 60 mm Hg Above these levels, they respond rapidly and reach a maximum at ~180 mm Hg Around 100 mmHg – very sensitive Responses of the aortic baroR – similar But they operate about 30 mm Hg higher

29. Baroreceptor Features: Speed Respond extremely rapidly to BP changes Increases in the fraction of a second during each systole Decreases again during diastole BaroRs respond much more to rapidly changing pressure than to a stationary pressure

30. Baroreceptor Features: Posture Standing – BP in head and upper body falls Marked reduction may cause cause loss of consciousness. Normally, Falling BP at the baroreceptors elicits – BaroR reflex Resulting in strong sympathetic discharge Maintenance of BP!

31. Baroreceptor Features: Buffer Control BaroR reflex is a pressure buffer system

32. Baroreceptor Features: Accomodation Role in long-term regulation of BP ‘Resets’ in 1-2 days to ‘new’ pressure

34. Baroreceptors are more sensitive to pulsatile pressure than to constant pressure* Especially at lower pressures

35. CNS Ischemic Response Cerebral ischemia Vasoconstrictor & cardioaccelerator neurons in the vasomotor center b/c strongly excited Accumulating local concentration of CO2 Causes strong neuronal +++ This BP elevation in response to cerebral ischemia is known as the CNS ischemic response* Emergency pressure control system only Kicks in only when BP falls 60 mm Hg and below Cushing’s reaction

36. Intermediate Control Mechanisms Fluid shift Stress relaxation Renin-angiotensin vasoconstrictor mechanism Biogenic amines Vasoconstrictors (Epinephrine via α1, Serotonin etc) Vasodilators (Epinephrine via β2, Histamine, ANP etc)

37. Long-term BP Control Mechanism Pressure natriuresis Pressure diuresis Renin-Angiotensin-Aldosterone

38. Long-term BP Control Mechanism

39. Cardiac Output Quantity of blood pumped into the aorta each minute by the left ventricle Normal values: 5.6 L/min (males), 4.9 L/min (females) Cardiac index: C.O./min/m2 Average: 3.2 L (@ rest) Maximum value @ age 10 – then decreases

40. Cardiac Output

41. Cardiac Output Mean circulatory filling pressure

42. CO Regulation: Conceptual Overview Cardiac Heart rate Contractibility Coupling factors* Preload Afterload Ancillary factors All factors affecting venous return

43. CO Regulation: DetailedCO = SV x HR Stroke Volume SV = EDV – ESV = 120 – 50 = 70 ml EDV Preload (Myocardial fiber length) Affected by VR Filling time of diastole Rapid HR – diastole time decreases – EDV decreases Atrial contraction Inadequate contraction affects EDV Ventricular distensibility if decreases – EDV decreases ESV Afterload (Aortic pressure – arterial BP) Affects myocardial fiber shortening ability Contractility SNS (NE via β1) Heart Rate HR and SV are inversely proportional ANS

44. CO Regulation: Another angle

45. Conditions affecting CO No change Sleep Moderate changes in temperature Increased Anxiety/Excitement Exercise Increased temperature Pregnancy Epinephrine/histamine Anemia & hyperthyroidism Decreased Sitting/standing Rapid arrhythmias Heart disease

46. Mean Circulatory Filling Pressure With heart stopped – after pressure equilibrates – pressure throughout CVS – MCFP MSFP Vs MCFP* Factors affecting: BV (more raises MCFP) Sympathetic +++ (raises MCFP) Directly proportional to VR

47. Venous Return VR = MSFP* – Rt. Atrial Pressure / Resistance in venous return VR = 7 – 0/1.4 = 5 litres VR is affected by: Blood volume Skeletal muscle contraction Venous valves Thoracoabdominal pump Myocardial contractibility

48. Coupling of Cardiac & Vascular Function Characteristics of arteries and veins (vascular compliance, BV & vascular resistance) affect heart fn & its other variables However, it is also true that performance of the heart influences volumes and pressures within the vasculature So vasculature affects heart & vice versa Equilibrium must exist between cardiac and vascular function

49. Changes in Arterial Compliance Change Cardiac Work One of the more important consequences of the elastic nature of large arteries is that it reduces cardiac work* Increased arterial compliance (increase in arterial elasticity / afterload reduction) Reduces cardiac work Decreased compliance Increases cardiac work Myocardial O2 demand will be increased by any factor that reduces arterial compliance**

50. Relationship b/w Venous filling P. & CO : Tricky!* CVP - key determinant of filling of the right heart - key determinant of cardiac output Starling's Law However! Increased cardiac output into the arterial segment should result in ‘depletion’ in venous pressure & volume Q(1) How are values of cardiac output above or below the resting level ever achieved or maintained, Q(2) What determines the resting equilibrium between cardiac output and central venous pressure?

51. Cardiac & Vascular fn Curves Cardiac fn Curve plots CO as a function of CVP An extension of Starling's law Position and slope depends on ‘cardiac’ factors Vascular fn Curve shows how CVP changes as a function of VR Position and slope depends on ‘vascular’ factors (BV,SVR,compliance)

52. Cardiac & Vascular fn Curves Combining the curves provides a useful tool for predicting the changes in CO That will occur when various CVS parameters are altered CO can be altered by: Changes in the cardiac function curve By changes in the vascular function curve By simultaneous changes in both curves

53. Inotropic agents alter cardiac fn curve Vice versa CO is increased and CVP is decreased

54. Changes in BV* alter MSP : alter vascular fn curve CO is increased and CVP is increased Vice versa

55. Changes in TPR alter both curves Cardiac fn curve shifts downward (increased afterload) Counterclockwise rotation of vascular fn curve Vice versa

56. CO Measurement Principle of mass balance Introducing a known conc. of a dye (A) into an unknown volume of a fluid (V) By calculating conc. of dye in fluid (C) along with A – V can be calculated via: C1V1=C2V2 A=CxV C=A/V

57. CO Measurement Indicator dilution method Known amount of indicator (Indocyanine green – Cardiogreen) injected into venous circulation (A) Blood sampled serially from distal artery Concentration of dye (C) in serial samples: Rises Peaks Declines C is then averaged between T1 (time of appearance of dye in blood) and T2 (time of appearance of dye in blood) - Cave

58. CO Measurement Thermodilution method Variation of indicator dilution method More used in clinical practice Swan-Ganz catheter placed via vein – threaded to the pulmonary artery Catheter releases ice-cold saline into right heart via a side port Saline changes temperature of the blood coming in contact with it – reflected by CO – to be measured by thermistor on catheter tip (placed downstream into pulmonary artery) Equations similar to indicator dilution technique employed here

59. CO Measurement Fick’s principle – principle of mass balance taking into account oxygen entry/exit 1 liter blood can take 40 ml O2 How many 1-liter ‘units’ will it take to carry 200 ml in a min? – 5 L This much needs to supplied by heart – CO!

60. Energetics of Cardiac Function Oxidative phosphorylation of either carbohydrates or fatty acids Steady supply of O2 required (via coronary blood flow) Cardiac energy consumption = cardiac O2 consumption Work done by heart External: ejection of blood from the ventricles (Volume work) Internal: stretching elastic tissue, overcoming internal viscosity, rearranging muscular architecture of heart as it contracts (Pressure work)

61. “Pressure Work” Vs “Volume Work” Ventricles have to do external & internal work: If the external work of the heart is raised by increasing SV, but not MAP, the O2 consumption of heart increases very little Alternatively, if MAP is increased, O2 consumption/beat goes up much more Pressure work by the heart is far more expensive in terms of O2 consumption than volume work In other words, an increase in afterload causes greater increase in cardiac O2 consumption than does an increase in preload

62. “Pressure Work” Vs “Volume Work” Which one would produce angina due to less O2 delivery to myocardium? Aortic stenosis or Aortic regurgitation

63. “Pressure Work” Vs “Volume Work” Increase in O2 consumption produced by increased SV (when myocardial fibers are stretched) – preload increase An example of operation of law of Laplace More the stretch – bigger the radium – more the tension developed – more the O2 consumption In comparison, SNS induced increase in cardiac performance Via intracellular Ca++ manipulation – not so much to do with radius – less O2 consumption