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USMLE REVIEW: CARDIOVASCULAR PHYSIOLOGY

April Apperson, UCSD SOM Tutorial

I.

The cardiovascular system provides transcapillary exchange of O2 and nutrients into working tissues, while removing CO2 and cellular wastes. C.O. is regulated to change with V02 & VCO2 so blood flow can be proportional to tissue metabolism C.O. is regulated by modifying venous function (returning blood to the heart) and pump (heart function. A. At steady state (averaged over 30 beats or 30 seconds), blood flow through the pulmonary and systemic circulations are equal because these circulations are in series: 1. Cardiac output (C.O. aorta to arteries to tissues) = systemic venous return (V.R. venous blood in tissues to right atrium, RA) = pulmonary blood flow (PuBF pulmonary artery to capillaries to pulmonary venous return back to left atrium (LA) = 2. Factors determining circulatory flows and pressures are best recalled as equations: a. Flow = (P1 P2)/R describes the effects of changes in pressure or resistance on flow may also be used to predict the effect of increased flow on the pressure difference does not indicate factors that change resistance (those are separate). flows are driven by pressure gradients between two mean pressures: vascular & atrial. b. flow = (volume/beat)(HR) because a circulatory flow begin and end at the heart. 3. At steady state (averaged over 30 seconds), all circulatory flows are equal, so: = HR(RV stroke volume) || HR(LV stroke volume) || HR(RV filling volume) = = = V02/(C a02 C v02) || Pulmonary blood flow || Cardiac output || Systemic venous return = = = (PuAPr LAPr)/PuVR || (AoPr RAPr)/SVR || (MCFP RAPr)/RVEINS =

a.. PuBF = VO2/(CaO2 CvO2) since it can be measured by the rate of O2 uptake from the lungs, which = rate of O2 removal by the tissues. b. Stroke volume (SV) = [volume at end diastole (maximum) volume at end systole (minimum)]: SV = EDV - ESV Ejection fraction (EF) = (volume ejected)/(beginning volume): EF = SV/EDV

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B. Vascular compliance and resistance and their response to smooth muscle constriction determines much of cardiovascular pressures and flows. 1. Compliance (stretchability, very similar to capacity) (volume)/(Pin - Pout) and affects pressure. 2. Resistance decreases pressure of a flowing liquid, or may retard flow, but has no effect without flow. 3. The resting compliance and resistance of different systemic vessels depends on their physical structure and number. Systemic Vessel Arteries Small arteries & arterioles Veins At rest Compliance Moderate to low hold 10% blood volume at high pressure Insignificant and cant decrease Resistance Very low High - accounts for 75% of SVR Very low Effect of constricting smooth muscle Decreases C with no change in resistance increases arterial pressure at same volume Increases R with no change in C slows blood loss from arteries between ejections, increasing arterial blood volume and arterial pressure Decreases C with no change in resistance increases MCFP and moves venous volume back to heart (if pump can accommodate increased flow)

High - hold 75% of blood volume at low pressure; small changes in blood volume dont change MCFP significantly

B. Circulatory pressures and how they change 1. Mean arterial pressure (arterial blood volume)/Carteries) + Pout, but Pout can be ignored a. Arterial blood volume is modified during systole by C.O. and during diastole by how quickly the blood flow across arteriolar resistance into veins = SVR, so MAP (C.O.)(SVR). a. SVR is regulated primarily by SNS through 1 receptors: SNS will SVR. High SVR also increases pressure drop to capillaries, decreasing capillary pressure; the reverse is also true. SVR affects arterial diastolic pressure directly, and arterial systolic pressure indirectly. b. In a normal heart, aortic (arterial) systolic pressure peak left ventricular pressure, so ventricular systole also affects aortic systolic pressure. 2. Venous pressure at the beginning of the large veins is the pressure that drives venous return to the heart; venous pressure is more dependent on venous compliance than on venous resistance. a. Mean circulatory pressure (MFCP) (systemic venous volume)/(CVEIN) + POUT. b. Blood volume changes change venous volume and MCFP and changes V.R. ( C.O.) with a normal heart. c. CVEIN is by SNS tone, which MCFP; the reverse is also true. d. Dynamic exercise causes rhythmic skeletal muscle pumping that POUT for veins, which C.O. 3. Capillary pressure (PC) (capillary volume)/CCAPILLARY but CCAPILLARY is not regulated. a. SVR will PC, while venous pressure or blood volume will PC. b. PC is important in transcapillary filtration (see below).

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D. At a constant flow, vascular resistance determines the pressure drop across each region of vasculature.

The thick line depicts the mean pressure in the blood vessels, while the shaded region indicates the presence of pressure pulses. The arterial pressure pulses are damped out in the smaller arteries and arterioles.

E. Resistance (R) is a combined property of the tube and the fluid that decreases the energy ( fluid pressure during laminar, non-turbulant, flow) of the flowing fluid. 1. Resistance has no effect in the absence of flow. 2. During laminar flow, resistance (R ) [(fluid viscosity ()) (tube length)] [(# of parallel tubes)(tube diameter)4] 3. In a single vessel or across a heart valve, resistances affects pressure drop during flow: An arterial stenosis decreases the perfusion pressure past the stenosis. A heart valve stenosis increases the pressure drop across the valve when it is open. II. Cardiac function, when combined with venous and arterial function, determines cardiac output and arterial pressure. A. Cardiac muscle function is initiated by action potentials (AP) spreading through the specialized cardiac cells of the conduction system and the working atrial and ventricular muscle. Sino-atrial and atrio-ventricular nodes (SAN, AVN) conduct slow action potentials as shown to the left Working atrial and ventricular muscle and His-Purkinje conduction fibers (when not acting as pacemakers) conduct fast action potentials as shown on the next page.

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Conduction velocity is proportional to phase 0 slope and amplitude (so slow fibers have slow AP). Ca++ entering working atrial and ventricular muscle during phase 2 = trigger Ca++ to initiate contraction. Phase 3 slope in all cells determines action potential duration (APD; of least interest of these effects). Phase 4 slope in the pacemaker cells (usually the SAN) determines firing rate, and so heart rate.

2. Spontaneous firing rate of sino-atrial node (SAN) pacemaker cells = heart rate. a. SAN depolarization occurs prior to the P wave on the ECG, but does not cause deflection. b. Intrinsic SAN firing rate 100/minute; PSNS ( ) and SNS (1 ) modify phase 4 slope to change rate. resting heart rate is reduced by PSNS tone. heart rate > 100/minute is due to SNS tone. 3. Depolarization (phase 0s of APs) spread across the right atrial muscle then the left atrial muscle. a. This creates P wave on ECG (see below right) b. Ca++ entry during phase 2 of atrial action potentials initiates atrial contraction during PR segment. 4. Depolarization spreads to the ventricles. a. Impulse conduction velocity slows across the atrio-ventricular node (AVN) to allow time for atrial contraction to finish. AVN depolarization does not deflect the ECG but occurs during the PR segment. AVN conduction velocity determines PR interval on the ECG. AVN conduction velocity is decreased by Ca++ blockers that reduce phase 0 of its slow APs. b. The impulse spreads rapidly through the His-Purkinje system into ventricular muscle. His and Purkinje depolarization dont deflect the ECG but occur during the PR segment. The His bundle splits into left and right bundle branches (LBB and RBB), off which Purkinje fibers conduct the impulses to the muscle cells. c. The depolarizations spreading across ventricular muscle creates the QRS complex. Slowing fast Na+ channel function prolongs the QRS, e.g., quinidine (Type I anti-arhythmics), ischemia, chronic depolarization. Purkinje fibers off the LBB depolarize septal muscle first: this vector is right and anterior. Purkinje fibers off the LBB & RBB depolarize the apex and ventricular free walls; this vector is left, inferior and posterior. 5. An ECG measures electrical potentials on the surface of the skin generated when cardiac muscle depolarizes or repolarizes (see next page).

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a. Only the atrial and ventricular muscle are thick enough the generate deflections on the ECG. b. The coordination of an ECG with the spread of APs through the heart is shown below right. 6. In the absence of SAN overdrive suppression, other potential pacemakers can determine heart rate or ventricular rate: AVN pacemakers fire 45-60/minute. His or Purkinje pacemakers fire < 45/minute

C. Left ventricular cardiac cycle: ventricular filling, isovolumetric contraction (IVC), ejection, isovolumetric relaxation (IVR), then ventricular filling begins again. Data chart for drawing Wiggers and PV diagrams from data Timing (for both conditions) Pressure and estimates End diastole, so mitral closes (MC) peak 1st QRS = .3 sec from y-axis LVEDP (mean LAPr or PCWP) Begin ejection, so aortic opens (AO) (no specific times needed for these points - just AoDP draw a smooth LV pressure curve from MC to peak AoSP Peak LV pressure LV pressure and back down to MO and find the AO LVESP = DP + End systole, so aortic closes (AC) and AC points on the LV pressure line) 2/3(SP - DP) Begin filling, so mitral opens (MO) Peak 1st QRS + .4 sec = .7 sec Peak V pressure Peak 2nd QRS = peak 1st QRS + RR interval Event

Volume and calculations LVEDV (SV/EF) LVEDV Not specified LVESV (EDV - SV) LVESV

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1. The cardiac cycle Wiggers diagram correlates ventricular pressures, volumes and the ECG in time Ventricular pressures during filling atrial pressures venous pressure = low. rapid filling (RF) occurs when the LV is still relaxing & provides 75% of total. slow filling adds only a few % of the total filling volume. atrial systole (AS) occurs adds 20% of total filling volume. Isovolumetric contraction occurs from MC to AO. Ventricular ejection into the aorta occurs rapidly until peak LV pressure is reached, then slowly. Isovolumetric relaxation occurs from AC to MO Assumptions: During valve opening or closing, the pressures on the two sides of the valve are equal. Normal heart valves have very low resistance; even with flow, there is little pressure difference. D. The determinants of ventricular muscle function are preload (PL), afterload (AL), and contractility (IS = inotropic state); PL, AL, IS and heart rate (HR) are the determinants of cardiac output (C.O.). 1. Cardiac muscle contraction is initiated by electrical depolarization which initiates Ca++ release. The acto-myosin cross-bridge formation provides the energy available for the contraction. The muscle uses energy (lost as heat) to develop pressure, then uses any remaining energy to shorten the muscle fibers; in the whole heart, pressure continues to rise, then fall during ejection (shortening). Definition Effect on contraction Indices in left ventricle IS Inotropic state = contractility = the dP/dTMAX (@ constant PL) intrinsic contractile state of the muscle Ejection fraction (@ constant AL) provided by Ca++. The sum of IS + PL Slope of ESPVR on PV loop Ca++ release from SR will IS which together determine the contractile available energy & vis acto-myosin crossversa. bridge energy available during PL Preload = wall stress at end-diastole LVEDP mean LAPr (if no contraction. mitral valve stenosis) mean PL determines the muscle and sarcomere PuAWPr (if pulmonary length just prior to contraction. resistance is normal) PL will sarcomere length towards LVEDV Lmax & contractile energy, & vis

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AL AL determines the fraction of available cross-bridge energy needed to develop pressure; any remaining energy shortens the muscle (providing SV = ejection). 2. Contractility is determined by regulation of sarcoplasmic (SR) Ca++ release in myocytes. a. Ch ange SR Ca++ release by: 1) c AMP (1 agonists, caffeine (PDE-I)) will contractility by trigger Ca++ entry, SR Ca++ release and SR Ca++ re-uptake 2) 3Na+/Ca++ exchange activity will SR Ca++ storage after a few beats, which will contractility: Digitalis decreases Na/K ATPase activity. Hyponatremia. Increased HR Ischemia or heart failure will ATP and so contractility; Ca++ channel blockers and many general anesthetics will co ntractility. versa. Afterload (really = total load) = wall stress throughout ejection, which is best estimated as mean wall stress or wall stress at end-systole. AL requires that more of the available energy be used to develop pressure, leaving less for stroke volume; the reverse is also true. LVEDP or LVEDV on PV loops LVESP on PV loop MAP if no aortic stenosis SVR if no change C.O.

b. Increased contractility will peak LV pressure (AoSP), systolic time, and dP/dt. 3. Afterload MAP in a normal heart, and MAP = C.O.SVR. 4. Preload is affected by virtually all interventions: LVEDV = LVESV + (systemic V.R.)/HR. a. AL & IS change LVESV and so changes PL b. Changing HR will change diastolic filling time, which changes PL. c. Changing blood volume (diuretics) or venous compliance (SNS) change MCP and so may change V.R. and preload; vasodilators will decrease MCP, V.R. and PL. The P-V diagram plots ventricular pressures against volume; time is not directly shown, but implied in formation of the pressure-volume loop. Ventricular contraction begins on the EDPVR: The EDPVR starts close to (0,0) then increases slowly and exponentially, always passing through the end-diastolic point (preload). Acute changes do not affect the EDPVR position: Volume-overload hypertrophy shifts it right Pressure-overload hypertrophy shifts it left Ventricular ejection ends on the ESPVR The ESPVR starts around 20 on the y-axis, always passing through the end-systolic point (AC). E. At rest (constant venous return), steady-state changes in afterload and inotropic state are compensated by changes in preload to maintain close to the original stroke volume; preload changes are steady-state. III. Regulation of blood pressure and cardiac output. A. Cardiac output is typically coordinated with metabolic rate (V02, VC02) via the SNS:

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increased SNS will increase cardiac output, and vis versa; blood volume will change cardiac output by changing venous return. 1. Isolated changes in HR, BP and contractility within normal range will not change C.O. significantly; HR > 180 or < 50 bpm, or very high BP or very low contractility will all C.O. 2. SNS will C.O. and SVR, which, together with C.O., will MAP. 3. Changes in blood volume will directly change MCP (pressure at the beginning of the large systemic veins) and so V.R., which changes C.O. (and so will have some effect on MAP). B. One of major reflexes regulating BP and C.O is the high pressure baroreceptor reflex to changes in arterial pressure. 1. Stretch receptors in the carotid sinus and aortic arch carry nerve traffic up CN IX (glossopharyngeal) from the carotid sinus and up CN X (vagus) from the aortic arch to the cardiovascular centers in the brainstem. 2. Increased net nerve traffic to the CNS centers will PSNS to the heart and SNS to the heart and vessels. PSNS will HR within 1 second, as well as CV through the AVN, lengthening the PR interval SNS relaxes veins to MCP, inotropic state, and helps HR; together, these will C.O. SNS will SVR, which, together with C.O., will BP. 3. Response to stretch on arterial baroreceptors (e.g. BP, carotid occlusion) = PSNS & SNS: PSNS will HR within 1 second, as well as CV through the AVN, shortening the PR interval SNS constricts veins to venous return, inotropic state and helps HR; together, these C.O. SNS also constricts arterioles to SVR, which, together with C.O., will BP. C. Exercise will SNS, but muscle work also V.R. by compression and SVR through metabolitemediated vasodilation; therefore: exercise C.O. more and MAP less than an equivalent pure in SNS (e.g. anxiety). Factor V02; VC02 (A-V)02D C.O. HR SV MAP (BP = 120/80) SVR LVEDV Mild exercise (HR up to 100) x4 x 2.5 x1.6 100 = x 1.3 x 1.2 no change 130/75 to 60% no change Moderate exercise (HR 100 140) x 5.6 x 2.9 x2 120 = x1.6 x 1.25 little increase 130/80 to 50% small increase Maximum (HR 170, lactic acidosis) x 11.2 x 3.6 x 3.2 180 = x 2.4 x 1.3 x 1.25 150/80 to 40% small increase

D. Flow, velocity, viscosity and turbulance (1 mL = 1 cm3 ) 1. Mean velocity (cm/sec) = flow (cm3/min)/total cross-sectional area (cm2); v = Q/AT. a. At constant flow, Q = vAT, so high AT causes low velocity and vis versa: AT = (# vessels)(r 2) Within a circulation, flow is constant; AT of capillaries >> veins > arteries, so velocity is highest in arterial flow and lowest in capillary flow.

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In an artery with a moderate stenosis, flow is constant, so velocity across the stenosis > velocity on either side of the stenosis this is the basis for Doppler measurements of flow! b. If flow changes or two flows are compared, v is directly proportional to flow (not inverse to radius) At a branch, the largest diameter branch gets the greatest flow and has the highest velocity. If an arterial stenosis is severe enough to decrease arterial flow, the decrease in flow can be detected by a decrease in velocity in the artery before or after the stenosis (through use of Doppler technology). 2. Viscosity ( ) increases resistance (see above). a. Hematocrit affects viscosity directly, so SVR decreases with severe anemia and increases with severe polycythemia. b. Shear strain rate (mean velocity/diameter) affects viscosity inversely; most capillary and arterial shear strain rates are similar, since velocity and diameter both decrease in capillaries, but decreasing capillary flow can increase viscosity and resistance in that capillary. E. Transcapillary exchange across the capillary wall is determined by transmural pressure gradients and permeability: 1. Flow = Kf[(PC PISF) ( C ISF)] a. Filtration = flow from capillary into ISF; occurs if (PC PISF) > ( C ISF) b. Reabsorption = flow from ISF back into capillary; occurs if ( C ISF) > (P C PISF ) 2. Normally in non-renal capillaries, filtration exceeds reabsorption slightly, creating lymph flow. a. Increasing Kf or PC, or decreasing C will increase net filtration and lymph flow. Kf is determined by capillary characteristics and is by inflammation. PC is by: flow, arteriolar (pre-capillary) resistance, venous (post-capillary) resistance or venous pressure, or volume; the reverse conditions will PC.
C

can be by dehydration; it is by severe liver or kidney disease.

b. Edema occurs when net filtration exceeds the drainage capacity of the lymph system. Worksheet for coronary blood flow April Apperson, UCSD SOM Tutorial

CBF = AoPr RAPr/CVR

CVR = RA + Ra = sum of resistances of large arteries (RA), arterioles (Ra) and capillary & veins (typically these are ignored).

CBF is the same in the artery, the combined arterioles, the combined capillaries, etc.

CPP = coronary perfusion pressure = pressure at the end of the large surface arteries = beginning of the small arteries and arterioles buried within the muscle; this pressure drives flow through the the capillaries for transcapillary exchange. Atherosclerotic stenoses occur in the large arteries.

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CBF =

AoPr RAPr CVR

AoPr CPP RA

CPP RAPr Ra CBF with minimum CVR

CBF changes because CVR changes: 1) CBF must change 1:1 with MV02 because myocardial (A-V)02D is maximal at rest and cant increase. The major determinants of MV02 are HR, contractility and afterload. 2) A vasodilator injected into the coronary arteries increases CBF to maximum with no change in MV02. Changing CPP (between 60 180 mmHg) with no change in MV02 will not change steady-state CBF because of autoregulation. CPP will arteriolar pressure to cause myogenic constriction, & transiently CBF to metabolites and arteriolar resistance; CBF returns to original level. CPP will do the opposite. CPP mean aortic pressure in normal coronary arteries, and changes with MAP; CPP < MAP in the presence of a significant coronary artery stenosis. Abbreviations used in cardiovascular physiology: AL AVN Ca02; Cv02 C.O. DP EDP EDPVR EDV EF ESP ESPVR ESV HR IS ISF IVC

= afterload = wall stress the heart must develop to finish ejection; often estimated from MAP = atrioventricular node = 02 concentration in arterial and mixed venous blood, respectively = cardiac output = L/minute flowing through the system; at steady-state, C.O. = V.R. = PuBF = arterial diastolic pressure; the arterial pressure at the time the aortic valve opens ( LVEDP) = ventricular end-diastolic pressure = pressure at beginning of ventricular contraction (usually at S1 when the mitral and tricuspic valves close), e.g. LVEDP, RVEDP = end-diastolic pressure volume relation = resting curve on a ventricular pressure-volume diagram; the preload (estimated from EDV or EDP) will be a point on this curve. = ventricular end-diastolic volume = volume at end of filling, e.g. LVEDV, RVEDV = ejection fraction = SV/EDV = ventricular end-systolic pressure = pressure at end of ejection (not peak ventricular pressure), e.g. LVESP, RVESP = end-systolic pressure volume relation = upper line on a ventricular pressure-volume diagram; endsystolic pressure will always fall on this line, or peak ventricular pressure if there is no ejection. = ventricular end-systolic volume = volume at end of ejection, e.g. LVESV, RVESV = heart rate = pulse = inotropic state (contractility); proportional to SR calcium released during ventricular contraction = interstitial fluid = fluid surrounding all tissue cells, but outside blood vessels = isovolumetric contraction (between filling and ejection)

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IVR LAPr LVPr MAP MCP = isovolumetric relaxation (between ejection and filling) = mean left atrial pressure = left ventricular pressure, which varies throughout the cardiac cycle = mean arterial blood pressure, can be estimated as MAP DP + 1/3(SP DP) = mean circulatory pressure = venous blood pressure at the beginning of the large systemic veins; MCP provides the driving force for venous return = oncotic pressure = fraction of the osmotic pressure due to the presence of protein; C = capillary oncotic pressure; ISF = ISF oncotic pressure. PL = preload; the ventricular wall stress at end-diastole, and often estimated from EDP or EDV. PuADP = pulmonary artery diastolic pressure = artery pressure when the pulmonic valve opens PuAPr = mean pulmonary artery pressure PuASP = pulmonary artery systolic pressure = peak artery pressure during right ventricular ejection PuBF = pulmonary blood flow; at steady state, V.R. = PuBF = C.O. PuVR = pulmonary vascular resistance = mean right atrial pressure RVEIN = resistance of the systemic veins, which is 1/20 of SVR (0 1) = reflection coefficient of a capillary, which measures retention of protein (see oncotic pressure) S1 = first heart sound, due to closing of the atrio-ventricular valves (mitral and tricuspid) S2 = second heart sound, due to closing of the semi-lunar valves (aortic and pulmonic) S3 = third heart sound, heard immediately after S2 during early rapid filling, can be normal or abnormal S4 = fourth heart sound, heard immediately before S1 during late rapid filling; it is always abnormal SAN = sino-atrial node, the normal pacemaker for the heart SP = systolic blood pressure = highest arterial blood pressure; LVESP, but usually peak LVPr SR = sarcoplasmic reticulum SV = stroke volume (blood volume ejected per beat); LVSV = left ventricular; RVSV = right ventricular SVR = systemic vascular resistance, predomiantly due to systemic small arteries and arterioles LBB = left bundle branch from His bundle in ventricular conduction system RBB = right bundle branch from His bundle in ventricular conduction system V02 = 02 consumption (mL 02/minute) by the tissues V.R. = venous return = flow back from systemic veins to the heart; at steady-state, V.R. = PuBF = C.O.