DRUGS USED IN DISORDERS OF THE CARDIOVASCULAR SYSTEM Lecture 5:
Physiologic and Pathophysiologic Function of The Heart Marc Imhotep Cray, M.D.
Photo: Photograph of chordae tendineae attached to papillary muscles of a ventricle. Seeley’s anatomy & physiology. 10th ed. New York, NY: McGraw-Hill 2010
Topics Discussion Outline The physiologic function of the heart can be represented in several ways: Cardiac output as measured using the Fick principle Cardiac Cycle (Wiggers diagram) Pressure– Volume Loops: pressure–volume loops provide a tool for analyzing the cardiac cycle, particularly ventricular function Frank– Starling curves: Effects of Cardiac Output, Total Peripheral Resistance, Contractility, Preload, and Afterload as represented on the Frank– Starling curve Common Valvular Abnormalities 2
Cardiac Output Measurement Cardiac output =volume of blood pumped by each ventricle per minute. (N5L/min) Cardiac output (QT) is regulated by autonomic nerves and hormones through changes in heart rate (HR) or stroke volume (SV) In adults, cardiac output is usually expressed in liters per minute: QT = (SV × HR)/1000 QT = Cardiac output (L/min) SV = Stroke volume (mL/min) HR = Heart rate (beats/min)
CVS Pharmacology Lecture 5
Cardiac output can also be measured clinically in the cardiac catheterization laboratory, using a thermodilution method A cold saline solution of known temperature and volume is injected into the right atrium. The reduction in blood temperature measured downstream in the pulmonary artery is a function of cardiac output.
Example If resting SV is 70 mL and HR is 70 beats/min, then QT = (70 mL × 70 beats/min)/1000 = 4.9L/min Marc Imhotep Cray, M.D.
3
Cardiac Output Measurement The Fick Principle (1) A traditional physiologic method for calculating cardiac output applies the Fick principle, which derives blood flow from variables related to O2 consumption Cardiac output can be calculated by applying the Fick concept to the entire body, relating total body O2 consumption to the difference in O2 content between blood in the systemic arteries and the mixed venous blood sampled from the pulmonary artery or the right ventricle
CVS Pharmacology Lecture 5
Example A person consumes 250 mL of O2 per min. Arterial O2 content is 20 mL of O2 per dL of blood, and the O2 content of mixed venous blood is 15 mL of O2 per dL of blood: QT = 250 (mL/min) ÷ (20 mL/dL − 15 mL/dL) = 50 dL/min QT = 50 dL / min = 5 L / min
QT = VO2 /(CaO2 − CvO2) QT = Cardiac output VO2 = O2 consumption CaO2 = Arterial O2 content CvO2 = Mixed venous O2 content Marc Imhotep Cray, M.D.
4
THE FICK PRINCIPLE (2) The Fick principle for measuring cardiac output is expressed by the following equation: â– The equation is solved as follows: 1. O2 consumption for the whole body is measured. 2. Pulmonary vein [O2] is measured in a peripheral artery. 3. Pulmonary artery [O2] is measured in systemic mixed venous blood
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
For example, a 70-kg man has a resting O2 consumption of 250 mL/min, a peripheral arterial O2 content of 0.20 mL O2/mL of blood, a mixed venous O2 content of 0.15 mL O2/mL of blood, and a heart rate of 72 beats/min. What is his cardiac output? What is his stroke volume?
5
Cardiac Output Measurement
CVS Pharmacology Lecture 5
During early stages of exercise, CO is maintained by↑ HR and ↑ SV
Tao Le T and Bhushan V, Cardiovascular, In First Aid for the USMLE Step 1 2015; pg. 553
Marc Imhotep Cray, M.D.
During late stages of exercise, CO is maintained by↑HR only (SV plateaus) If HR is too high, diastolic filling is incomplete and CO↓(e.g., ventricular tachycardia)
6
Cardiac cycle(1)
CVS Pharmacology Lecture 5
The seven phases of the cardiac cycle are (1) atrial systole; (2) Isovolumetric contraction; (3) rapid ejection; (4) reduced ejection; (5), isovolumetric relaxation; (6) rapid filling; and (7) reduced filling.
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
7
Cardiac cycle (2) Expressed as pressure-volume loop
CVS Pharmacology Lecture 5
Phases-left ventricle: 1) Isovolumetric contraction - period between mitral valve closure and aortic valve opening; period of highest 02 consumption 2) Systolic ejection - period between aortic valve opening and closing 3) Isovolumetric relaxation - period between aortic valve closing and mitral valve opening 4) Rapid filling- period just after mitral valve opening 5) Reduced filling- period just before mitral valve closure Source: Tao Le T and Bhushan V, Cardiovascular, IN First Aid for the USMLE Step 1 2013:556
Marc Imhotep Cray, M.D.
8
Steps in the Cardiac cycle (3)
CVS Pharmacology Lecture 5
1 2 (isovolumetric contraction) On excitation, ventricle contracts and ventricular pressure increases. Mitral valve closes when left ventricular pressure is greater than left atrial pressure. Because all valves are closed, no blood can be ejected from ventricle (isovolumetric). 2 3 (ventricular ejection) Aortic valve opens at point 2 when pressure in the left ventricle exceeds pressure in aorta. Blood is ejected into aorta, and ventricular volume decreases. Volume that is ejected in this phase is stroke volume. Thus, stroke volume can be measured graphically by width of the pressure–volume loop. Volume remaining in the left ventricle at point 3 is ESV. Marc Imhotep Cray, M.D.
9
Steps in the Cardiac Cycle (4)
CVS Pharmacology Lecture 5
3 4 (isovolumetric relaxation) At point 3, the ventricle relaxes. When ventricular pressure decreases to less than aortic pressure, the aortic valve closes. Because all of the valves are closed again, ventricular volume is constant during this phase. 4 1 (ventricular filling) Once left ventricular pressure decreases to less than left atrial pressure, the mitral (AV) valve opens and filling of the ventricle begins. During this phase, ventricular volume increases to about 140 mL (the end-diastolic volume).
Marc Imhotep Cray, M.D.
10
Cardiac output variables
CVS Pharmacology Lecture 5
Stroke Volume is affected by Contractility, Afterload, and Preload ↑ SV when ↑ preload,↓ afterload , or ↑ contractility Contractility (and SV) ↑ with : • Catecholamines (↑ activity of Ca2+ pump in sarcoplasmic reticulum) • ↑ intracellular Ca2+ • ↓extracellular Na+ (↓ activity of Na+/Ca2+ exchanger) • Digitalis ( blocks Na+-K+ pump→ ↑ intracellular Na+ → ↓ Na+/Ca2+ exchanger activity → ↑ intracellular Ca2+) Contractility (and SV) ↓with: • β1-blockade (↓ cAMP) • Heart failure (systolic dysfunction) • Acidosis • Hypoxia /hypercapnea (↓ PO2 / ↓ PCO2) • Non-dihydropyridine Ca2+ Channel blockers
Marc Imhotep Cray, M.D.
11
Preload and afterload
CVS Pharmacology Lecture 5
Preload =ventricular EDV Afterload = mean arterial pressure (proportional to peripheral resistance)
Venodilators (e.g., nitroglycerin) ↓ Preload. Vasodilators (e.g., hydralazine) ↓ Afterload (arterial) Preload ↑ with : • Exercise (slightly) • ↑ blood volume (e.g., overtransfusion) • Excitement (↑ sympathetic activity)
Marc Imhotep Cray, M.D.
12
Ventricular pressure-volume loop (1)
CVS Pharmacology Lecture 5
Generated by plotting ventricular pressure against ventricular volume at many different corresponding points during a single cardiac cycle
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
13
Ventricular pressure-volume loop (2)
CVS Pharmacology Lecture 5
EDPVR, end-diastolic pressurevolume relationship; ESPVR, endsystolic pressure-volume relationship; SV, stroke volume (EDV - ESV)
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
14
Left ventricular pressure and volume (3)
CVS Pharmacology Lecture 5
Correlation between changes in left ventricular pressure (upper panel ) and left ventricular volume (lower panel ) during a single cardiac cycle Landmark events of valve opening and closure and the point where peak systolic blood pressure occurs are noted at points A–E
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture ; McGraw-Hill 2009:144-57
Marc Imhotep Cray, M.D.
15
Pressure-volume loop (4)
CVS Pharmacology Lecture 5
Left ventricular pressure is plotted as a function of left ventricular volume Landmark events of valve opening and closure and the point where peak systolic blood pressure occurs are noted at points A–E
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture McGraw-Hill 2009:144-57
Marc Imhotep Cray, M.D.
16
Effects of increasing venous return on LV pressure-volume loops
CVS Pharmacology Lecture 5
This diagram shows acute response to an increase in venous return. It assumes no cardiac or systemic compensation and that aortic pressure remains unchanged Increased venous return increases end-diastolic volume (EDV) but it normally does not change ESV; therefore, stroke volume (SV) is increased. ESPVR, end-systolic pressure-volume relationship. Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
17
Factors that Increase Ventricular Preload
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
Source: Klabunde RE. Cardiovascular Physiology Concepts 2nd Ed. http://www.cvphysiology.com/textbook.htm 18
Effects of changes in afterload (PAo) LV pressure-volume loops
CVS Pharmacology Lecture 5
ď ą Increased aortic pressure solid red loop) decreases stroke volume (width of loop) and increases end-systolic volume (ESV), whereas ď ą decreased aortic pressure (AO dashed red loop) increases stroke volume and decreases end-systolic volume. Preload and inotropy are held constant in this illustration. Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
19
Effects of increasing inotropy on ventricular pressure–volume loops
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
Increased inotropy shifts the ESPVR up and to the left, thereby increasing stroke volume and decreasing endsystolic volume (ESV). Decreased inotropy shifts the end-diastolic pressure–volume relationship down and to the right, thereby decreasing stroke volume and increasing endsystolic volume. Preload and aortic pressure are held constant in this illustration. 20
Factors that increase inotropy
CVS Pharmacology Lecture 5
Source: Klabunde RE. Cardiovascular Physiology Concepts 2nd Ed. http://www.cvphysiology.com/textbook.htm
Marc Imhotep Cray, M.D.
21
Effects of changes in preload, afterload, and contractility on ventricular pressure–volume loop
Increased afterload results from an increase in aortic pressure, which leads to a decrease in SV. This decreases the width of the loop. Increased contractility Increased contractility leads to the ventricle developing greater tension during systole and increases the SV. Marc Imhotep Cray, M.D.
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Increased preload Increased preload results in an increase in EDV. This increase causes an increase in SV (due to FrankStarling relationship), which is reflected as an increased width of the loop.
CVS Pharmacology Lecture 5
22
Changes in t ventricular pressure–volume loop “Describe each”
CVS Pharmacology Lecture 5
Source: Costanz LS. Cardiovascular Physiology IN BRS Physiology 5th ed. LLW, 2012
Marc Imhotep Cray, M.D.
23
Interdependent effects of changes in preload, afterload, and inotropy on left ventricular pressure-volume loops (1)
CVS Pharmacology Lecture 5
A shows effects of increasing preload (end-diastolic volume) with and without a secondary increase in afterload (aortic pressure)
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
24
Interdependent effects of changes in preload, afterload, and inotropy on left ventricular pressure-volume loops (2)
CVS Pharmacology Lecture 5
B shows the effects of increasing afterload with and without a secondary increase in preload.
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
25
Interdependent effects of changes in preload, afterload, and inotropy on left ventricular pressure-volume loops (3)
CVS Pharmacology Lecture 5
C shows effects of increasing inotropy with and without secondary changes in preload and afterload.
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
26
CVS Pharmacology Lecture 5
Starling curve
Source: Tao Le T and Bhushan V, Cardiovascular, IN First Aid for the USMLE Step 1 2013:554
Force of contraction is proportional to end diastolic length of cardiac muscle fiber (preload) ↑ contractility with sympathetic stimulation, catecholamines, digoxin ↓contractility with loss of myocardium (MI) , β-blockers, calcium channel blockers EF↓ in systolic heart failure
Marc Imhotep Cray, M.D.
27
Wiggers diagram, a correlation of electrical and mechanical events during cardiac cycle
CVS Pharmacology Lecture 5
Kibble JD and Halsey CR, CV Physiology, IN Medical Physiology The Big Picture M-H 2009
Marc Imhotep Cray, M.D.
Note the phonocardiogram records heart sounds
28
Summary of normal pressures within cardiac chambers and great vessels
CVS Pharmacology Lecture 5
ď ą The higher of the two pressure values (expressed in mm Hg) in the right ventricle (RV), left ventricle (LV), pulmonary artery (PA), and aorta (Ao) represent the normal peak pressures during ejection (systolic pressure)
Source: Klabunde RE. Cardiovascular Physiology Concepts 2nd Ed., LLW 2012 http://www.cvphysiology.com/textbook.htm
Marc Imhotep Cray, M.D.
Whereas ď ą The lower pressure values represent normal end of diastole pressure (ventricles) or the lowest pressure (diastolic pressure) found in the PA and Ao. Pressures in the right atrium (RA) and left atrium (LA) represent average values during the cardiac cycle 29
Normal Heart Sounds & Common Valvular Abnormalities
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture McGraw路Hill 2009:144-57
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
A. First (S1) and second (S2) heart sounds. B. Physiologic splitting of S2. S1 is caused by the closure of the atrioventricular valves; S2 is caused by the closure of the semilunar valves. Physiologic splitting mainly results from the delayed closure of the pulmonic valve on inspiration. M1, mitral valve closure; T1, tricuspid valve closure; A2, aortic valve closure; P2, pulmonic valve closure. Also see: Audio-HEART and LUNG Auscultation Sounds mp3s 30
Aortic Stenosis
CVS Pharmacology Lecture 5
Systolic murmur of aortic stenosis A. Paradoxical splitting of the second (S2) heart sound occurs because the aortic valve (A2) closes later than the pulmonic valve (P2) due to prolonged left ventricular systole B. Pressure gradient across the narrowed aortic valve
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture; McGraw-Hill 2009:144-57
Marc Imhotep Cray, M.D.
Paradoxical splitting of S2 occurs when closure of the aortic valve is delayed, causing P2 to occur first, followed by A2. The most notable causes are aortic stenosis (which prolongs left ventricular systole) and left bundle branch block (which delays the onset of left ventricular contraction) 31
Aortic Stenosis pressure-volume loop
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
In aortic stenosis (red loop in figure) Left ventricular emptying is impaired because of high outflow resistance caused by a reduction in the valve orifice area when it opens. This high outflow resistance causes a large pressure gradient to occur across the aortic valve during ejection, such that the peak systolic pressure within the ventricle is greatly increased. This leads to an increase in ventricular afterload, a decrease in stroke volume, and an increase in end-systolic volume. Stroke volume (width of pressure-volume loop) decreases because the velocity of fiber shortening is decreased by the increased afterload (see force-velocity relationship). Because end-systolic volume is elevated, the excess residual volume added to the incoming venous return causes the end-diastolic volume to increase. This increases preload and activates the Frank-Starling mechanism to increase the force of contraction to help the ventricle overcome, in part, the increased outflow resistance. 32
CVS Pharmacology Lecture 5
Mitral Insufficiency
Systolic murmur of mitral insufficiency A. The early aortic valve (A2) sound indicates the shortened systole due to retrograde blood flow into the left atrium B. The large atrial v wave due to regurgitation of blood from the left ventricle into the left atrium during systole
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture; McGraw-Hill 2009:144-57
Marc Imhotep Cray, M.D.
33
Mitral Insufficiency pressure-volume loop
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
mitral valve regurgitation (red pressure-volume loop in figure) As the left ventricle contracts, blood is not only ejected into the aorta but also back up into the left atrium. This causes left atrial volume and pressure to increase during ventricular systole. During ventricular diastolic filling, the elevated pressure within the left atrium is transmitted to the left ventricle during filling so that left ventricular EDV (and pressure) increases. This would cause wall stress (afterload) to increase if it were not for the reduced outflow resistance because of mitral regurgitation that tends to decrease afterload during ejection because of reduced pressure development by the ventricle. The net effect of these changes is that the width of the pressure-volume loop is increased (i.e., SV is increased); however, ejection into the aorta (forward flow) is reduced. The increased ventricular "stroke volume" (measured as the EDV minus the ESV) in this case includes the volume of blood ejected into the aorta as well as the volume ejected back into the left atrium. 34
Aortic Insufficiency
CVS Pharmacology Lecture 5
Diastolic murmur of aortic insufficiency. A. Sound intensity of the murmur decreases during diastole as a function of aortic blood pressure. S1 is the first heart sound; A2 indicates timing of the closure of the aortic valve. B. Pathologic runoff of blood from the aorta into the left ventricle decreases aortic diastolic blood pressure and increases left ventricular filling, increasing stroke volume and systolic blood pressure. Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture McGraw-Hill 2009:144-57
Marc Imhotep Cray, M.D.
35
Aortic regurgitation pressure-volume loop
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
As long as ventricle is not in failure, end-systolic volume may only be increased a small amount (as shown in figure) due to the increased afterload (ventricular wall stress). If the ventricle goes into systolic failure, then endsystolic volume will increase by a large amount and the peak systolic pressure and stroke volume (net forward flow into aorta) will fall. Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
In aortic valve regurgitation (red loop in figure) Aortic valve does not close completely at end of systolic ejection. As the ventricle relaxes during diastole, blood flows from the aorta back into the ventricle so the ventricle immediately begins to fill from the aorta. Once the mitral valve opens, filling occurs from the left atrium; however, blood continues to flow from the aorta into the ventricle throughout diastole because aortic pressure is higher than ventricular pressure during diastole. This greatly enhances ventricular filling so that end-diastolic volume is increased as shown. The increased end-diastolic volume (increased preload) activates the Frank-Starling mechanism to increase the force of contraction, ventricular peak (systolic) pressure, and stroke volume (as shown by the increased width of the pressure-volume loop). 36
CVS Pharmacology Lecture 5
Mitral Stenosis
Diastolic murmur of mitral stenosis A. An opening snap (OS) is a unique sound that is characteristic of mitral stenosis. The sound produced by obstructed flow through the mitral valve is described as a presystolic murmur (PSM). Obstructed ventricular filling may delay closure of the mitral valve (M1) relative to closure of the tricuspid valve (T 1). B. Obstruction of the mitral valve causes a sustained increase in left atrial pressure.
Kibble JD and Halsey CR, CV Physiology, In Medical Physiology The Big Picture McGraw路Hill 2009:144-57
Marc Imhotep Cray, M.D.
37
Mitral stenosis pressure-volume loop
CVS Pharmacology Lecture 5
Mitral stenosis (red pressure-volume loop in figure) Impairs left ventricular filling so that there is a decrease in enddiastolic volume (preload) This leads to a decrease in stroke volume by the Frank-Starling mechanism and a fall in cardiac output and aortic pressure.
Source: Klabunde, RE, Ventricular Pressure-Volume Relationship
This reduction in afterload (particularly aortic diastolic pressure) enables the end-systolic volume to decrease slightly, but not enough to overcome the decline in end-diastolic volume. Therefore, because end-diastolic volume decreases more than end-systolic volume decreases, the stroke volume (shown as the width of the loop) decreases
Marc Imhotep Cray, M.D.
38
CV Physiology Concepts Schematic From IVMS Function of the Heart illustrations and Equations Notes
Click for enlarged view Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
THE END
Marc Imhotep Cray, M.D.
CVS Pharmacology Lecture 5
40
Further study (SDL):
CVS Pharmacology Lecture 5
Online resource center: Medical Pharmacology Cloud Folder
Lectures/discussions to follow: 2. 3. 4. 5. 6. 7.
Hypercholesterolemia and Atherosclerosis Angina Heart Failure Arrhythmias Hypertension Peripheral Vascular Disease
Suggested reading: Costanzo LS, Cardiovascular Physiology. In Physiology: with STUDENT CONSULT Online Access, 5e; Saunders 2013:189-95 Klabunde RE, Ch. 4-Cardiac Function and Ch. 5-Vascular Function. In Cardiovascular Physiology Concepts,2e; LLW 2011:60-120
Tao Le T and Bhushan V, Cardiovascular, In First Aid for the USMLE Step 1 2015; McGraw-Hill 2013:254-57
Marc Imhotep Cray, M.D.
41