Cardiac Output and Stroke Volume Quiz

Cardiac Physiology Background

• Lecture date: 12/11/2023
• Course: BPS 337
• Instructor: Richard T Clements

Cardiac Physiology Refresher

• Cardiac Cycle
• Determinants of Cardiac Output (CO)
• Pressure-Volume (PV) Loops
• Mechanism of Cardiac Contraction/β-AR Modulation
• Cardiac Function and Heart Failure (HF)
• Coronary Circulation and O2 Supply/Demand
• Cardiac Action Potential/β-AR Modulation

Cardiac Cycle

• Aortic valve opens
• Isovolumic contraction
• Ejection
• Isovolumic Relaxation
• Rapid Inflow
• Mitral valve closes
• Mitral valve opens
• Diastasis
• Atrial Systole

Pressure-Volume Loops

• Shows the relationship between left ventricular (LV) pressure and volume during the cardiac cycle.
• Includes key points like End-Diastolic Volume (EDV), End-Systolic Volume (ESV), Stroke Volume (SV), End-Diastolic Pressure (EDPVR), End-Systolic Pressure (ESPVR)

Multiple PV Loops Over Time

• Multiple pressure-volume loops on graph demonstrates cardiac cycle variations over time.

Cardiac Output

• CO = HR * SV
• Factors affecting SV: preload, afterload, contractility
• Determinants of Cardiac Output: afterload, preload, contractility, and heart rate.

Preload

• The pressure that fills the ventricle.

• Increases in preload increase stroke volume (SV) and cardiac output (CO).

• Frank-Starling Mechanism: the more the ventricle wall is stretched, the more force is produced

• Intrinsic properties of cardiac myocytes (stretch, tension) and Ca++ release machinery

• Factors affecting preload: increased venous return, increased venous blood volume, increased venous pressure, decreased venous compliance, atrial inotropy, increased ventricular compliance

Afterload

• Pressure or resistance the heart has to actively work against.
• High blood pressure = high afterload
• Factors Affecting Afterload: blood pressure, vascular resistance, stiffness of the aorta, peripheral circulation
• Increases in afterload decrease SV and CO

Contractility

• Force generated for a given sarcomere/fiber length
• Modified by catecholamines, sympathetic/parasympathetic activity, inotropes, preload, afterload (Anrep Effect), HR (Bowditch Effect)

ESPVR (Ees) and Contractility

• End systolic pressure-volume relationship
• Shows relationship of contractility to cardiac output (CO)

Preload, Afterload, and Contractility

• Interdependent: changes in one affect the others.

Heart Rate

• Increases cause an increase in CO (CO = HR * SV).
• High heart rate = Impaired filling (decreased preload), decreased stroke volume and reduced heart rate.
• High heart rate increases myocardial O2 demand and impairs contractility

Summary: CO and SV

• 4 Determinants (preload, afterload, contractility, and heart rate)
• Frank-Starling Mechanism (heart responds to increased preload with increased ejection and CO)
• ESPVR slope is contractility (Ees). Increased contractility increases CO. Increased afterload decreases CO.
• PV loops useful to determine parameters regarding cardiac physiology

Cardiac Contraction

• All about Ca++
• Cardiac Troponin-Tropomyosin complex inhibits myosin binding to actin.
• Increases in cytosolic Ca++ bind to TnC allowing myosin and actin interaction, triggering contraction.
• Relaxation occurs when Ca++ levels decrease.

Excitation-Contraction (E-C) Coupling

• Action potential causes Ca++ influx = depolarization.
• Further Ca++ release from sarcoplasmic reticulum (SR).
• Ca++ binds to troponin to initiate contraction.
• Ca++ is removed to initiate relaxation.

B1-AR PKA Activation Promotes Ca++ Release

• PKA increases Ca++ release via RyR and external Ca++ channels.
• pPLB inhibits SERCA to increase Ca++ stores.

Summary Cardiac Contraction

• Action potential depolarizes cell and activates PM Ca++ channels
• Increased Ca++ causes Ca++ release from the SR.
• Released Ca++ binds TnC to allow myosin:actin interaction and contraction
• SERCA activates to restore Ca++ to SR and NCX expels Ca++ from the plasma membrane
• Cell repolarizes.
• B-AR activation causes PKA to increase RyR and SERCA activity. Increased intracellular Ca++ increases contractility

Ejection Fraction and Heart Failure (HF)

• Amount of blood ejected from the heart (stroke volume) divided by the amount in the heart at diastole (EDV) expressed as a percentage.
• EF = SV/EDV*100
• If SV is down, CO is down

Heart Failure with Reduced Ejection Fraction (HFrEF)

• Reduced contractility, causing decreased stroke volume (SV), and ejection fraction (EF).
• Increased End-Diastolic Volume (EDV)

Heart Failure with Preserved Ejection Fraction (HFpEF)

• Impaired relaxation or stiffness of the ventricles.
• Preserved Ejection Fraction (EF), but diastolic dysfunction
• Increased End-Diastolic Volume Pressure (LVEDP)

Causes of HFrEF

• Structural abnormalities, Previous MI (myocardial infarction), Coronary artery disease, Diabetes, Metabolic syndrome, Lipids, Inflammation, O2 disruptions, etc.

Causes of HFpEF

• Not entirely clear mechanism, but factors like obesity, hypertension, CAD, diabetes, etc., are implicated.

Fibrosis and Cardiac Remodeling

• Fibrosis and ECM deposition are major components of cardiac remodeling (in addition to hypertrophy).
• Deposition of ECM molecules promotes fibrosis. Fibrotic hearts are stiffer and less elastic, impairing contractile function.

Coronary Circulation and Blood Flow

• Highest oxygen demand in the body.
• Coronary A-VO2 difference is the highest of any circulation (10-13 ml/100ml).
• Coronary venous blood is VERY dark.
• Flow changes dramatically due to metabolic demand (autoregulation and reactive hyperemia)
• Flow is reduced during systole due to heart muscle contraction and increased coronary resistance. Majority of flow is during diastole.

Myocardial Energy Demand

• Balance of myocardial O2 supply and O2 demand.
• Factors affecting supply: heart rate, oxygen content of blood, coronary perusion.
• Factors affecting demand: heart rate, contractility, afterload, preload.
• Oxygen consumption/demand is all electron transport in mitochondria.

O2 Supply

• Coronary circulation subject to vasoconstriction & vasodilation (same as peripheral circulation).
• Vasodilation enhances coronary flow & O2 supply, vasoconstriction reduces.
• Atherosclerosis impairs normal vasoregulation & reducing coronary flow.
• Coronary flow is determined by pressure (MAP) and resistance (R).

Molecular Basis of Smooth Muscle Contraction

• Agonists activate receptors, leading to plasma membrane Ca++ channel opening.
• Depolarization of smooth muscle with or without signaling causes Ca++ release from intracellular stores (via IP3 receptor).
• Ca++ activates MLCK & phosphorylates MLC.
• MLC phosphorylation causes myosin activation & contraction.

Molecular Basis of VSMC Dilation

• In endothelial cells: receptor activated pathways activate nitric oxide synthase (eNOS) releases NO.
• NO (nitric oxide) diffuses to VSMC activating soluble guanylyl cyclase (SGC) converting GTP to cyclic GMP (cGMP).
• SGC & cGMP cause a coordinated response to limit VSMC contraction
• Decrease Ca++ influx/release
• Decrease MLC phosphorylation
• Increase K+ efflux
• PKA activation inhibits PKG which limits MLC phosphorylation

PKA and smooth muscle dilation

• PKA has opposite effect on smooth muscle than on the heart.
• PKA inhibits MLCK and activates MLCP to reduce contraction.

Summary of VSMC Signaling

• Vessels dilate/constrict dramatically changing flow.
• Signalling mechanism of vessel contraction/dilation (signaling pathways & factors).
• Mechanisms of dilation (Nitric oxide, cGMP, PKG).

Summary Coronary Circulation

• Coronary circulation provides O2 to the heart.
• Factors that increase CO increase cardiac O2 demand (preload, afterload).
• O2 supply in the coronary circulation can be modified by vasodilation and impaired contraction.

Arrhythmia: Propagation of the Action Potential

• SA nodal cells in atria initiate contraction.
• Impulse travels through atria (P-wave).
• Impulse travels from atria to ventricle (via AV node) (PR interval)
• Conduction through Purkinjie system to ventricle .
• Ventricular cardiomyocytes spread the action potential (QRS).
• Cardiomyocytes repolarize (T wave)

Action Potential and Ca++ Cycling

Membrane Potential and Ionic Gradients

• Resting membrane potential determined by differences in ion concentrations inside and outside the cell.
• Large amounts of Na+ outside, K+ inside. Opening of ion channels cause rapid influx/efflux. Action potential changes dependent of these gradients.

SA/AV Node Action Potentials

• Na+ channel influx (funny current), Phase 4
• Depolarization opens Ca++ channels, Phase 0
• K+ channels open, causing efflux, Phase 3

Sympathetic Stimulation of Heart Rate

• Activation of β1 receptors increases Na+ current (funny current).
• Increased positive charge allows Ca++ channels to open, increasing heart rate.
• Parasympathetic stimulation decreases funny currents.

ANS Effects Heart Rate

• Increasing sympathetic stimulation or B-AR activation increases Na+ current (phase 4).
• SA nodal cells reach threshold and Ca++ channels open earlier to increase heart rate. Vagal stimulation and Beta blockers have opposite effects on SNS.

Cardiomyocyte Action Potential

• Na+ channels open due to depolarization of neighboring cells.
• K+ channels open (efflux) to repolarize the cell.
• Ca++ channels open to assist with contraction.

SA/AV Node and Ventricular action potentials

• SA and AV node and ventricular action potentials differ greatly.

Action Potential Ion Currents

• Different proteins and channels contribute to phase based action potential depolarization & repolarization (0,1,2,3,4).
• Disturbances can cause cardiac arrhythmia

ECG Signal

ECG Refresher of Intervals and Waves

• ECG measures electrical activity in the heart.
• Different waves (P, QRS, T) & intervals (PR, QRS, ST, QT) represent different stages of cardiac cycle.

Action Potential/ECG Summary

• Na+ high outside, K+ high inside.
• Na channels open, positive charge inside
• K+ and Ca++ channels balance & repolarize.
• SA and AV node action potential propagation differ from cardiomyocytes.

Summary: Things to Know This Lecture

• Cardiac contraction mechanism
• B-AR modulation of contractility
• Vascular contraction mechanism
• How A1-AR & other contractile agonists modulate contraction
• Vascular dilation mechanism.
• How Beta adrenergic agents increase HR.
• SA/AV node modulation of cardiac action potential
• PKA dependent modification of Na channels
• Determinants of cardiac output
• Do NOT worry about HF, PV loops, & O2 supply/demand for this test.