대한심장학회 추계학술대회 Oct 12-14, 2017, Walkerhill hotel, Seoul

Preload, , and Cardiac function

Jae Yeong Cho, M.D., Ph.D.

Department of Cardiovascular Medicine, The Center of Chonnam National University Hospital, Gwangju, Republic of Korea

The Heart Center of Chonnam National University Hospital The Heart Center of Chonnam National University Hospital The Korean Society of Cardiology COI Disclosure

Name of the First Author: Jae Yeong Cho

The authors have no financial conflicts of interest to disclose concerning the presentation

KSC 2017 The 61th Annual Scientific Meeting of the Korean Society of Cardiology Cardiac Function The primary function of the heart ►Imparting energy to blood to generate and sustain an arterial sufficient to adequately perfuse organs ►Contracting its muscular walls around a closed chamber to generate sufficient pressure to propel blood from the LV through the AoV, and into the aorta.

The Heart Center of Chonnam National University Hospital Cardiovascular Physiology Concepts 2ed, 2012 Cardiac Function: CO = SV x HR L/min = ml/beat x beats/min ► (SV) : A volume of blood ejected into the aorta each time the LV contracts ►Changes in either SV or HR alter cardiac output

The Heart Center of Chonnam National University Hospital Cardiovascular Physiology Concepts 2ed, 2012 Preload The initial stretching of the cardiac myocytes prior to contraction

► The more they are stretched, the stronger is the contraction that occurs during systole, and the greater is the stroke volume  the Frank-Starling Relationship ► Why should end-diastolic sarcomere length affect strength of contraction? : Old answer - greater availability for actin-myosin cross-bridging : New answer - Length dependent activation of calcium channels

The Heart Center of Chonnam National University Hospital Length – Force relationship

The Heart Center of Chonnam National University Hospital The Length – Tension relationship: Why?(1)

the extent of overlap of the thick and thin filaments in the sarcomere at rest

The Heart Center of Chonnam National University Hospital CV Physiology – a clinical approach, 2011, LWW The Length – Tension relationship: Why?(2)

► A length-dependent change in sensitivity of the myofilaments to calcium ► At short lengths, only a fraction of the potential cross- bridges are apparently activated by a given increase in intracellular calcium ► At longer lengths, more of the cross-bridges become activated, leading to an increase in active tension development The “sensor” responsible for the length-dependent activation of the seems to reside with the troponin C molecule The Heart Center of Chonnam National University Hospital Cardiovascular Physiology 7ed, 2010 The Length – Tension relationship: Why?(3)

► Within several minutes after increasing the resting length of the cardiac muscle, there is an increase in the amount of calcium that is released with excitation, which is coupled to a further increase in force development. ► Stretch-sensitive ion channels in the cell membranes may be responsible for this delayed response.

The important point is that the dependence of active tension development on muscle length is a fundamental property of the cardiac muscle that has extremely powerful effects on heart function.

The Heart Center of Chonnam National University Hospital Cardiovascular Physiology 7ed, 2010 Frank-Starling’s Law

. Volume of blood ejected by the depends on the volume present in the ventricle at the end of diastole . Underlying principle . Length-tension relationship in cardiac muscle fibers . SV & CO correlated directly with EDV . EDV correlates with Venous Return (VR) . CO = VR (FS law ensures this) . Cardiac muscle normally operates only on the ascending limb of the systolic curve

The Heart Center of Chonnam National University Hospital Frank-Starling Curve in Heart Failure

The Heart Center of Chonnam National University Hospital Preload

► The stretch on the sarcomeres just prior to initiation of contraction (systole). ► The more blood there is in the chamber just prior to systole (end-diastole), the more the sarcomeres are stretched.

Pre-contraction length of a sarcomere = preload  dependent on the ventricular EDV  dependent on the ventricular EDP and compliance

The Heart Center of Chonnam National University Hospital Preload is dependent on EDP and compliance

EDV is dependent on the ventricular EDP and compliance

The Heart Center of Chonnam National University Hospital Pressure-Volume Loop

a – ventricular filling

b – isovolumetric contraction

c – ventricular ejection

d – isovolumetric relaxation

ESPVR = end-systolic pressure-volume relationship EDPVR = end-diastolic pressure-volume relationship

The Heart Center of Chonnam National University Hospital Pressure-Volume Loop

The Heart Center of Chonnam National University Hospital Cardiovascular Physiology 7ed, 2010 Effects of increased preload on tension development by an isolated strip of cardiac muscle

Increasing preload : a  b  c

The Heart Center of Chonnam National University Hospital Effects of increased preload on tension development by an isolated strip of cardiac muscle Increasing preload : a  b  c

The maximal active tension in cardiac muscle = A sarcomere length of about 2.2 µm

The Heart Center of Chonnam National University Hospital Effects of increased muscle length (increased preload) on muscle shortening (isotonic contractions)

The Heart Center of Chonnam National University Hospital Frank-Starling mechanism (EDP – SV)

The Heart Center of Chonnam National University Hospital Effect of increasing preload (venous return) on LV P-V loops

The Heart Center of Chonnam National University Hospital Factors determining ventricular preload

► Venous pressure ► Ventricular compliance ► Heart rate ► Atrial contraction ► Inflow resistance ► Outflow resistance ► Ventricular inotropy

The Heart Center of Chonnam National University Hospital Cardiovascular Physiology Concepts 2ed, 2012 Afterload

▶ the "load" that the heart must eject blood against ▶ closely related to the

LaPlace’s Law: wall stress (σ), (P, ventricular pressure; r, ventricular radius; h, wall thickness)

The Heart Center of Chonnam National University Hospital Afterload

► Afterload refers to the forces that oppose ejection of blood out of the chamber. ► Afterload is increased when aortic pressure and systemic vascular resistance are increased, by aortic valve stenosis, and by ventricular dilation. ► When afterload increases, there is an increase in end- systolic volume and a decrease in stroke volume. ► All else being equal, raising afterload decreases SV, and lowering afterload increases SV.

The Heart Center of Chonnam National University Hospital When afterload decreases…

SV

SV

• Vasodilator in Acute HF  decrease in arterial pr.  decrease in LVEDV  More decrease in LVESV  Stroke volume increase

The Heart Center of Chonnam National University Hospital A patient with fulminant myocarditis on ECMO

A B

C D

The Heart Center of Chonnam National University Hospital Increasing afterload & length/velocity

Effects of afterload on myocyte shortening Force – Velocity relationship

The greater the afterload, the slower the velocity of shortening

The Heart Center of Chonnam National University Hospital Overcoming velocity reduction with preload

An increase in preload (a  c) on a cardiac myocyte can help to offset the reduction in velocity that occurs when afterload is increased

The Heart Center of Chonnam National University Hospital Effects of Afterload on Frank-Starling Curves

Reducing ventricular afterload in heart failure patients is an important therapeutic approach to enhance SV

The Heart Center of Chonnam National University Hospital Effects of Afterload on P-V loops

Reducing aortic pressure increases stroke volume and decreases ESV

The Heart Center of Chonnam National University Hospital Afterload

The Heart Center of Chonnam National University Hospital Adv Physiol Educ 2001;25:53-61 Contractility (inotropy)

► Contractility refers to the intrinsic strength of the ventricle, independent of loading conditions. ► All else being equal (i.e. preload and afterload unchanged), raising contractility (i.e. epinephrine release) increases SV, and lowering contractility decreases SV.

The Heart Center of Chonnam National University Hospital Effects of Inotropy on the length-tension relation ship

A length-independent activation of the contractile proteins

The Heart Center of Chonnam National University Hospital Effects of increasing Inotropy on the force-velocity relationship

Increased inotropy increases the velocity of shortening at any given afterload

The Heart Center of Chonnam National University Hospital Effects of Inotropy on P-V loop

• EF = the width / EDV • EF often is used as a clinical index for evaluating the inotropic state of the heart

The Heart Center of Chonnam National University Hospital Factors that increases Inotropy

↑ Sympathetic ↑ Circulating Activation Catecholamines ↑ Ventricular Inotropy ↑ Afterload ↑Heart rate (Anrep Effect) (Bowditch Effect)

• Anrep Effect – unknown mechanism • Bowditch effect – inability of the Na+/K+-ATPase to keep up with the Na+ influx at elevated heart rates  accumulation of intracellular Ca++ d/t Na+-Ca++ exchanger

The Heart Center of Chonnam National University Hospital Interdependence of pre-, afterload, and inotropy

A: Increasing preload (EDV) with and without a secondary increase in afterload (Aortic pressure) B: The effects of increasing afterload with and without a secondary increase in preload C: The effects of increasing inotropy with and without secondary changes in preload and afterload

The Heart Center of Chonnam National University Hospital Preload ↑ Afterload ↑

Inotropy ↑

The Heart Center of Chonnam National University Hospital Take Home Messages

. Increased preload enhances cardiac function (FS law) . Increased afterload decreases cardiac output . Interdependence between preload, afterload, and inotropy should be considered . Treatment of heart failure may be improved by better understanding of basic cardiovascular physiology concepts

The Heart Center of Chonnam National University Hospital Thank you for your attention!!

The Heart Center of Chonnam National University Hospital