MPP2 2025 Lecture 07 Cardiac Output Regulation PDF
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MU-WCOM
Richard Klabunde
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Summary
This document provides lecture notes on the regulation of cardiac output, focusing on preload, afterload, and inotropy. It discusses learning objectives, learning resources, determinants of cardiac output, and clinical conditions. It also explores the mechanism of length-dependent activation and the effects of afterload. There are learning objectives and some multiple choice questions at the end.
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Regulation of Cardiac Output Lecture 07 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Describe how changes in heart rate and stroke volume affect cardiac output 2. Define...
Regulation of Cardiac Output Lecture 07 Richard Klabunde, PhD Professor of Physiology MU-WCOM 1 Learning objectives 1. Describe how changes in heart rate and stroke volume affect cardiac output 2. Define ventricular preload, afterload and inotropy 3. Describe how changes in each of the following affect preload: a. Central venous pressure, and blood volume b. Ventricular compliance c. Atrial inotropy d. Heart rate e. Inflow and outflow resistance f. Afterload g. Ventricular inotropy 4. Describe the mechanisms by which changes in preload alter cardiomyocyte force of contraction 2 Learning objectives cont. 5. List clinical conditions that increase or decrease afterload 6. Describe using Frank-Starling relationships how preload, afterload and inotropy affect stroke volume (SV) 7. Draw ventricular pressure-volume loops depicting how changes in preload, afterload and inotropy affect end-diastolic volume (LVEDV), end-systolic volume (LVESV), SV, and ejection fraction (EF) 8. Describe the receptor and intracellular mechanisms responsible for sympathetic and catecholamine regulation of cardiac muscle excitation-contraction coupling and relaxation 9. Describe using pressure-volume loops the interdependent effects of changes in preload, afterload, and inotropy on LVESV and LVEDV 3 Learning resources Klabunde, Cardiovascular Physiology Concepts, Wolters Kluwer: 3e, Ch 2: 9-17; Ch 4: 71-90 Use within slides Klabunde, cvphysiology.com (use Guided Learning: Cardiac Function) 4 Determinants of cardiac output and stroke volume Intrinsic & Neurohumoral Control CO (mL/min) = SV(mL/beat) x HR (beats/min) EDV – ESV 1° 1° 2° Afterload Preload Inotropy 5 Preload The initial stretching of the cardiomyocyte sarcomere before contraction – related to end-diastolic volume 6 Frank-Starling relationship Increased ventricular filling increases stroke volume The relationship between SV and preload (measured as LVEDP or LVEDV) is called the "Frank- Starling relationship" or "Starling's Law of the heart" Length-dependent activation Klabunde, Cardiovascular Physiology Concepts, 3e 7 Mechanism of length-dependent activation Primary: Changes in TN-C affinity for Ca++ Sarcomere stretching increases Ca++ binding to TN-C, which results in increased muscle active tension during contraction Secondary: Changing actin-myosin filament overlap and therefore the number of active binding sites between actin and myosin Sarcomere stretching from 1.6 to 2.2 μ results in more available binding sites 8 Overview of factors that determine preload Klabunde, Cardiovascular Physiology Concepts, 3e 9 How does ventricular compliance alter sarcomere length? Ventricular compliance (C = ΔV/ΔP; inversely related to wall stiffness) Altered by cardiac remodeling (e.g., chronic dilation or hypertrophy) At a given EDP (green line) ○ ↑ compliance (chronic dilation) → ↑ EDV & ↑ sarcomere length ○ ↓ compliance (hypertrophy) → ↓ EDV & ↓ sarcomere length At a given EDV (orange line) ○ ↑ compliance (chronic dilation) → ↓ EDP ○ ↓ compliance (hypertrophy) → ↑ EDP Klabunde, Cardiovascular Physiology Concepts, 3e 10 Effects of decreased preload on LV pressure development and ejection If HR and inotropy are unchanged (i.e., no reflex compensation), then decreased preload causes: ↓ LVEDP & LVEDV (small ↓ ESV caused by ↓ afterload) ↓ dP/dtmax (maximal rate of isovolumetric pressure development) ↓ LVSPmax (peak systolic pressure) ↓ Vmax (maximal ejection velocity) ↓ SV (EDV – ESV) Corollary: Increased preload has opposite effects 11 Effects of decreased preload on pressure- volume loops Decreased preload (↓EDV) at constant HR and inotropy causes: ↓ SV (small ↓ESV) ↓ SV ⟶ ↓AP (sys & dias) Small ↓ ejection fraction (EF = SV/EDV) Corollary: Increased preload has opposite effects 12 Summary: Decreased ventricular preload (filling) decreases: Rate of ventricular pressure development (dP/dt) Rate of ejection (ejection velocity) Stroke volume Ejection fraction Corollary: Increased ventricular preload (filling) increases the above 13 Afterload Force (tension) required for a cardiomyocyte to shorten against a load. 14 What is ventricular afterload? Afterload is related to the pressure the ventricle must generate to overcome aortic pressure and eject blood into the aorta For individual muscle fibers in the ventricular wall, afterload is related to ventricular wall stress that is required to eject blood P = ventricular pressure r = ventricular radius Assume contracting V = ventricular volume ventricle is a sphere h = ventricular wall thickness 15 Clinical conditions affecting afterload NOTE: ∆V only ~1/4 as effective as ∆P on wall stress (afterload) Hypertension + _ Ventricular + AFTERLOAD Ventricular Dilation Hypertrophy + Outflow Tract Obstruction 16 How does afterload affect the Frank-Starling relationship? At a given preload and inotropy, increased afterload decreases SV by decreasing the velocity of fiber shortening and ejection Decreased afterload increases SV Therefore, there is a family of Starling curves, each reflecting the afterload on the ventricle Klabunde, Cardiovascular Physiology Concepts, 3e 17 Effects of afterload (aortic pressure) on ventricular volume changes at constant preload and inotropy Increased afterload (PAo) increases ESV and decreases SV & EF Conversely, decreased afterload decreases ESV and increases SV & EF Klabunde, Cardiovascular Physiology Concepts, 2e, 2012 18 Summary: Elevated ventricular afterload (primarily aortic pressure) decreases: Ejection velocity and stroke volume (analogous to lifting heavy vs. light weight) Ventricular emptying leading to increased end-systolic volume Ejection fraction 19 Inotropy Intrinsic ability of cardiac muscle to develop force independent of changes in preload 20 How does inotropy affect the Frank-Starling relationship? At a given preload and afterload, increased inotropy: ○ ↑ SV by increasing the force of contraction ○ ↑ velocity of fiber shortening and ejection Conversely, decreased inotropy decreases SV Therefore, there is a family of Starling curves, each reflecting the inotropic state of the myocardium Klabunde, Cardiovascular Physiology Concepts, 3e 21 Effects of inotropy on P-V loops at constant preload and afterload Increased inotropy (increased ESPVR slope) decreases ESV and increases SV ○ Conversely, decreased inotropy (decreased ESPVR slope) increases ESV and decreases SV Increased inotropy increases the ejection fraction (EF = SV/EDV) Conversely, decreased inotropy decreases EF Klabunde, Cardiovascular Physiology Concepts, 3e 22 Regulation of inotropy Sympathetic adrenergic nerves (atria & ventricles) Circulating catecholamines (atria & ventricles) Parasympathetic nerves (atria) Heart rate (Bowditch effect) Afterload (Anrep effect – weak) 23 Cardiac sympathetic mechanisms Sympathetic nerves release NE that binds to ꞵ1 and ꞵ2 adrenoceptors, which are linked to Gs-proteins ↑cAMP activates PK-A that phosphorylates several intracellular sites to increase inotropy and heart rate 24 Intracellular effects of PK-A phosphorylation on inotropy 1. ↑ opening of DHP Ca++ channels 2. ↑ opening of ryanodine Ca++ release channels, which ↑ intracellular Ca++ 3. ↑ TN-C binding affinity for Ca++ 4. TN-I and myosin phosphorylation sites → ↑ myosin ATPase activity 5. ↑ SERCA activity: ↑ inotropy & ↑ Klabunde, Cardiovascular Physiology Concepts, 3e lusitropy (relaxation rate) 25 Summary: Increased ventricular inotropy Increases ejection velocity and stroke volume Augments ventricular emptying and therefore decreases end-systolic volume Increases ejection fraction Permits the heart to maintain its stroke volume when afterload is elevated 26 Interdependent Effects of Preload, Afterload, and Inotropy Klabunde, Cardiovascular Physiology Concepts, 3e 27 Why does preload change in response to changes in afterload or inotropy? For example, ↓ afterload or ↑ inotropy → ↑ muscle shortening velocity and ejection velocity ESV decreases, leading to a secondary decrease in preload (EDV) because there is less residual volume added to the venous return EF increases 28 Summary of effects of preload, afterload & inotropy on Frank-Starling curves ↑ Preload (LVEDP) along a given curve increases SV; ↓ preload decreases SV ↓ Afterload or ↑ inotropy increases SV and decreases preload (curve slope increases); ↑ EF ↑ Afterload or ↓ inotropy decreases SV and increases preload (curve slope decreases); ↓ EF Klabunde, Cardiovascular Physiology Concepts, 3e 29 Effects of HR on pressures and volumes Increased HR (75 → 150 bpm): ○ ↓↓ EDV (due to ↓ filling time) ○ ↑ ESV (due to ↑ afterload) ○ ↓↓ SV (70 → 36 mL) ○ ↓ EF (58 → 39%) ○ ↑ CO (5.25 → 5.40 L/min) ○ ↑ AP Decreased HR (75 → 50 bpm): ○ ↑ EDV (due to ↑ filling time) ○ ↓ ESV (due to ↓ afterload) ○ ↑ SV (70 → 86 mL) ○ ↑ EF (58 → 65%) ○ ↓ CO (5.25 → 4.30 L/min) ○ ↓ AP NOTE: Δ HR → Δ preload and Δ afterload 30 Regulation of atrial function Atria respond to preload, afterload, and inotropic interventions in a manner similar to ventricles ○ Force of atrial contraction increases by length-dependent activation in response to increased atrial volume (preload) caused by increased venous return ○ Sympathetic nerve stimulation and increased circulating catecholamines increase atrial inotropy and therefore atrial force of contraction and ejection ○ Vagal stimulation decreases atrial inotropy, unlike ventricles 31 Summary Ventricular preload is related to the extent of ventricular filling (EDV) and sarcomere length; therefore, factors affecting ventricular volume, venous pressure, and ventricular compliance can alter preload. Increased preload increases the force of contraction and SV (Frank-Starling mechanism; length-dependent activation). Ventricular afterload is related to ventricular wall stress; increased afterload decreases the velocity of fiber shortening during contraction, which decreases the SV. Inotropy is the property of a cardiac myocyte that enables it to alter its tension development independent of changes in preload length. Increased inotropy enhances active tension development by individual muscle fibers and increases ventricular pressure development, ejection velocity, and SV at a given preload and afterload. Preload, afterload, and inotropy are interdependent, meaning that a change in one usually leads to secondary changes in the others. 32 END 33 QUESTIONS 34 Q1: A sudden decrease in venous return to the heart (e.g., when a person stands up) A. Decreases the rate of ventricular pressure development B. Increases ventricular end-diastolic volume and stroke volume C. Decreases ventricular compliance D. Increases ventricular end-systolic volume Q2: How does reducing afterload in heart failure patients lead to an increase in stroke volume? A. Frank-Starling mechanism is activated B. Muscle fiber shortening velocity is increased C. Ventricular end-systolic volume increases D. Inotropy is enhanced by Anrep effect 36 Q3: Why does increasing inotropy lead to a secondary decrease in preload? A. Venous return decreases B. Ventricular emptying increases C. Ventricular compliance increases D. Ventricular end-systolic volume increases 37 Q4: Which of the following is a mechanism by which sympathetic activation of the heart increase inotropy? A. Intracellular cAMP decreases B. Decreased SERCA activity C. Increased calcium binding to TN-I D. Increased release of calcium by sarcoplasmic reticulum 38 Answers to questions Q1: A Decreased venous return reduces ventricular filling (↓EDV), and this decreases active tension development by the cardiomyocytes, which decreases the rate of ventricular pressure development. Q2: B Reducing afterload on the LV increases myocyte shortening velocity (through the force-velocity relationship) and therefore increases SV by decreasing ESV. Q3: B Increasing inotropy increases SV by decreasing ESV, which secondarily results in decreased preload (↓EDV) Q4: D Sympathetic activation stimulates beta-receptors, increases intracellular cAMP, activates PK-A, and enhances SR release of calcium 39