1. THE AUSTRALIAN NATIONAL UNIVERSITY
Cardiac Output as HR·SV and Introduction to Starling's Law Christian Stricker Associate Professor for Systems Physiology ANUMS/JCSMR - ANU

3. At the end of this lecture students should be able to
Aims
At the end of this lecture students should be able to
estimate CO and EF;
outline how CO is determined by HR;
define the terms preload and afterload;
explain the functional properties of the pump in regard to
contractility,
fibre thickness,
relationship between force production and sarcomere length, and
relationship between shortening velocity and force production;
outline how pre- and afterload affect CO;
discuss how Starling’s law affects CO; and
illustrate how afterload can influence preload.

4. Contents
Measures of cardiac output (stroke volume, heart rate, cardiac index, ejection fraction)
Heart rate and cardiac output
Preload
Contractility (Starling’s law)
Fibre thickness
Afterload
Ventricle size and wall tension
How afterload can affect preload

5. Cardiac Output (CO)
Cardiac output = ejected vol. per time [min-1]. Example: Heart rate (HR) = 70 min-1 (bpm) Stroke volume (SV) = 80 mL
Cardiac index (CI) = CO normalised per unit body surface area (BSA, normally 1.6 m2). Example:
Ejection fraction = ratio of SV to end-diastolic volume (EDV, ~120 ml) in %. Typically > 55%. Example:

6. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Ventricular radius (Laplace’ law)
Systolic pressure (Resistance)

7. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Ventricular radius (Laplace’ law)
Systolic pressure (Resistance)

8. HR, SV and CO HR determined by autonomic innervation:
Corrected from Patton et al., 1989
HR determined by autonomic innervation:
Sympathetic: HR↑
Parasympathetic: HR↓
SV & HR linearly related.
Mechanism: pulse rate↑ → ventricular filling↓.
CO maximal at ~130 bpm; drops with higher HR.
Explanation: above optimal frequency, HR↑ insufficient to compensate for SV↓.

9. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Ventricular radius (Laplace’ law)
Systolic pressure (Resistance)

10. “Preload”
Preload = pressure (or volume) at end of diastole → sets end-diastolic ventricular fibre length.

11. Preload and SV (Frank-Starling)
Patton et al., 1989
O. Frank 1895 (frog heart); E.H. Starling 1914 (dog)
End-diastolic filling pressure (~15 torr) expands ventricle to particular volume: sets cardiac fibre length.
Within a certain limit, SV↑ for larger volumes/pressures.
Put simply: Bigger preload → larger SV (within about a ~2 fold range): homeostatic mechanism.

12. How Preload Determines SV
Patton et al., 1989
Steep relationship between force/pressure production and sarcomere length (see also muscle physiology).
Increased cardiac force translates into increased SV: force ↑ → effective load↓ → shortening vel↑ → ejection↑ → SV↑ (see below).
Homeostatic mechanism to match RV with LV output.
If -1% LV mismatch, within 2 h, total blood volume in pulmonary circulation → pulmonary oedema.

13. Preload Determinant: Compliance
If ventricular filling causes a small change in ventricular pressure, then the ventricle is compliant - otherwise stiff:
Dilated cardiomyopathy
Impaired ventricular muscle relaxation (myocardial hypertrophy, myopathy).
Fibrosis (for example after lots of small local infarcts).
Decreased compliance results in SV↓ (filling↓).

14. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Ventricular radius (Laplace’ law)
Systolic pressure (Resistance)

15. Modulation of Contractility: Ca2+
Contractility depends on
[Ca2+]i reached for EC-coupling: high [Ca2+]i → larger isometric force (Sarnoff & Mitchell, 1961).
Fibre length at beginning of contraction: stretched fibres → larger force.
Sympathetic activity (see earlier – no parasympathetic effect!).
Also dependent on HR and afterload.
Patton et al., 1989

16. Modulation of Contractility: Drugs
NA (diffusely released on myocytes): contractility↑
L-type Ca2+ channels,
Cytosolic Ca2+ concentration,
Store refilling via SERCA/PLB, and
Contractile proteins (troponin 1).
Hormones and drugs
Digitalis, β-adrenomimetics (isoproterenol), glucagon
Anaesthetics, toxins
Disease states:
Alterations in electrolytes, acid-base balance
Coronary artery disease / hypoxia
Myocarditis
Bacterial endotoxaemia
Rhoades & Tanner, 2003

17. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Ventricular radius (Laplace’ law)
Systolic pressure (Resistance)

18. Contractility and Fibre Thickness
Force increases with hypertrophy (athletes).
Mechanism: more contractile proteins (myofilaments) per myocyte produce bigger force.
Changes reversible (can be exploited after infarction).
In hypertrophic cardiomyopathy, changes can lead to force production↓.
Ventricular remodelling is under β-adrenergic control.

19. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Systolic pressure (Resistance)
Ventricular radius / volume (Laplace’ law)

20. “Afterload” Afterload = pressure (or volume) at end of systole.
End-systolic pressure/volume
≠ Psyst
≠ Pdiast
~ average pressure (MAP, see later) against which ventricle must contract to eject blood into aorta (“load” given by total peripheral resistance, TPR).

21. Systolic Pressure & Afterload
Patton et al., 1989
End-systolic pressure at aortic valve closure (>100 torr).
Put simply: Afterload↑ → SV↓ (flow velocity during ejection↓).
Afterload depends on aortic elasticity (later).

22. How Afterload Determines SV
Patton et al., 1989
Shortening velocity – force/afterload - relationship (see muscle).
Afterload↑ decreases shortening velocity of cardiac fibres → smaller SV ejected; i.e. SV↓.

23. Factors Determining CO
Heart rate (HR): Electrical properties
Stroke volume (SV):
Force of contraction: Muscular properties
End-diastolic fibre length (Starling’s law): pre-“stress”, pre-“tension”, preload, compliance
Contractility: force generation of cardiac fibre
Trophic state of cardiac fibre (thick, thin)
“Afterload”: Circulatory properties
Systolic pressure (Resistance)
Ventricular radius / volume (Laplace’ law)

24. Determinants of Afterload
Modified from Schmidt & Thews, 1977
Laplace’ law: T ~ ri (Tension force proportional to radius).
For same afterload and myocardial thickness, a small ventricle/volume requires less tension than a big one; i.e. a large ventricle/volume requires more force to contract.
Clinical implications in dilated heart failure.

25. Pre- and Afterload Interactions
Patton et al., 1989
Shortening velocity of fibre↓ → SV↓ → atrial filling pressure↑: afterload↑ → preload↑.
Important implications in heart failure.

26. Take-Home Messages SV decreases linearly with HR.
CO is determined by SV and HR.
HR can be modulated by sympathetic and parasympathetic influences.
SV can be increased by
preload ↑ (end-diastolic filling pressure - Starling),
contractility ↑ (sympathomimetics, digitalis, etc.),
fibre thickness ↑, and
afterload ↓ (Psyst, ultimately Rperiph).
A large ventricle requires more tension force.
Ultimately, afterload↑ causes preload↑.

27. MCQ
Which of the following statements best describes the increased cardiac output that occurs with increased sympathetic stimulation of the heart?
Decreased heart rate and increased contractility
Decreased diastolic filling time and increased heart rate
Increased contractility and increased heart rate
Decreased ventricular relaxation and increased ejection fraction
Increased ventricular relaxation and decreased ejection fraction

28. That’s it folks…

29. MCQ
Which of the following statements best describes the increased cardiac output that occurs with increased sympathetic stimulation of the heart?
Decreased heart rate and increased contractility
Decreased diastolic filling time and increased heart rate
Increased contractility and increased heart rate
Decreased ventricular relaxation and increased ejection fraction
Increased ventricular relaxation and decreased ejection fraction