6: Regulation of Cardiac Output

Cardiac Output Regulation

• Cardiac output (CO) is the amount of blood pumped by the heart per minute.
• CO = Stroke Volume (SV) × Heart Rate (HR)
• Stroke volume (SV) is the volume of blood pumped per beat.
• HR is the number of beats per minute.

Learning Objectives

• Describe how heart rate and stroke volume affect cardiac output.
• Define ventricular preload, afterload, and inotropy.
• Describe how changes in preload are affected by:
  • Central venous pressure
  • Blood volume
  • Ventricular compliance
  • Atrial inotropy
  • Heart rate
  • Inflow and outflow resistance
  • Afterload
  • Ventricular inotropy
• Describe mechanisms by which preload changes alter cardiomyocyte force of contraction.
• List clinical conditions that increase or decrease afterload.
• Describe the Frank-Starling relationships and how preload, afterload, and inotropy affect stroke volume.
• Draw ventricular pressure-volume loops depicting changes in preload, afterload, and inotropy, affecting end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (SV), and ejection fraction (EF).
• Describe receptor and intracellular mechanisms responsible for sympathetic and catecholamine regulation of cardiac muscle excitation-contraction coupling and relaxation.
• Describe the interdependent effects of preload, afterload, and inotropy on LVEDV and LVESV using pressure-volume loops.

Preload

• Preload is the initial stretching of the cardiomyocyte sarcomere before contraction, related to end-diastolic volume.
• Increased ventricular filling increases stroke volume.
• The relationship between stroke volume (SV) and preload (measured as LVEDP or LVEDV) is called the Frank-Starling relationship or Starling's Law of the heart.
• This relationship is length-dependent activation.

Frank-Starling Relationship

• Increased ventricular filling increases stroke volume.
• The relationship between SV and preload (LVEDP or LVEDV) is called the Frank-Starling relationship or Starling's Law of the heart.
• Length-dependent activation

Mechanism of Length-Dependent Activation

• Primary:
  • Changes in TN-C affinity for Ca²⁺
  • Sarcomere stretching increases Ca²⁺ binding to TN-C, increasing muscle active tension during contraction.
• Secondary:
  • Changing actin-myosin filament overlap and active binding sites between actin and myosin.
  • Sarcomere stretching (1.6 to 2.2 μm) creates more available binding sites.

Overview of Factors Determining Preload

• Factors affecting preload include:
  • Atrial inotropy
  • Outflow resistance and afterload
  • Heart rate
  • Ventricular compliance
  • Venous pressure
  • Venous compliance
  • Total blood volume
  • Venous return

How Ventricular Compliance Alters Sarcomere Length

• Ventricular compliance (C = AV/∆P), inversely related to wall stiffness.
• Altered by cardiac remodeling (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 ↑.

Afterload

• Afterload is the force (tension) required for a cardiomyocyte to shorten against a load.
• Afterload is related to the pressure the ventricle must generate to overcome aortic pressure and eject blood.

Clinical Conditions Affecting Afterload

• Hypertension
• Ventricular dilation
• Outflow tract obstruction
• Ventricular hypertrophy

How Afterload Affects Frank-Starling Relationship

• At a given preload and inotropy, increased afterload decreases stroke volume (SV) by decreasing the velocity of fiber shortening and ejection.
• Conversely, decreased afterload increases SV.
• A family of Starling curves, each reflecting the afterload on the ventricle.

Effects of Afterload

• Increased afterload (aortic pressure) decreases stroke volume (SV) and ejection fraction (EF) by increasing end-systolic volume (ESV).
• Conversely, decreased afterload decreases end-systolic volume (ESV) and increases SV and EF.

Elevated Ventricular Afterload

• Elevated ventricular afterload (primarily aortic pressure) decreases ejection velocity, stroke volume, and ejection fraction.
• Ventricular emptying leads to increased end-systolic volume.

Inotropy

• Inotropy is the intrinsic ability of cardiac muscle to develop force independent of changes in preload.

How Inotropy Affects Frank-Starling Relationship

• At a given preload and afterload, increased inotropy increases stroke volume.
• This is because increased inotropy increases the force of contraction and the velocity of fiber shortening and ejection.
• Conversely, decreased inotropy decreases stroke volume.
• A family of Starling curves reflects the inotropic state of the myocardium.

Effects of Inotropy on P-V Loops

• Increased inotropy decreases end-systolic volume (ESV) and increases stroke volume (SV).
• Increases the ejection fraction (EF).
• Conversely, decreased inotropy increases ESV and decreases SV.
• Decreases the ejection fraction (EF).

Regulation of Inotropy

• Factors include:
  • Sympathetic adrenergic nerves
  • Circulating catecholamines
  • Parasympathetic nerves (atria)
  • Heart rate
  • Afterload

Cardiac Sympathetic Mechanisms

• Sympathetic nerves release norepinephrine (NE) that binds to β₁ and β₂ adrenoceptors (linked to Gs proteins).
• ↑cAMP activates PK-A, phosphorylating intracellular sites to increase inotropy and heart rate.

Intracellular Effects of PK-A Phosphorylation

• ↑ opening of DHP Ca²⁺ channels
• ↑ opening of ryanodine Ca²⁺ release channels
• ↑ TN-C binding affinity for Ca²⁺
• TN-I and myosin phosphorylation sites →↑ myosin ATPase activity.
• ↑ SERCA activity. ↑ inotropy and lusitropy (relaxation rate.)

Increased Ventricular Inotropy

• Increased ventricular inotropy increases ejection velocity and stroke volume.
• Augments ventricular emptying, decreasing end-systolic volume.
• Increases ejection fraction.
• Permits the heart to maintain its stroke volume when afterload is elevated.

Interdependent Effects of Preload, Afterload, and Inotropy

• Preload, afterload, and inotropy are interdependent changes in one usually result in secondary changes in others.

Why Does Preload Change in Response to Changes in Afterload or Inotropy?

• Changes in afterload or inotropy alter muscle shortening velocity and ejection velocity.
• ESV decreases secondary to the decreased preload.
• EF increases.

Summary of Effects of Preload, Afterload, and Inotropy on Frank-Starling Curves

• Increased preload increases stroke volume along the curve.
• Decreased preload decreases stroke volume along the curve.
• Increased afterload or decreased inotropy decrease stroke volume and increase preload.
• Decreased afterload or increased inotropy increase stroke volume and decrease preload.

Effects of HR on Pressures and Volumes

• Increased HR (75→150 bpm): ↓ EDV, ↑ ESV, ↓ SV, ↓ EF, ↑ CO.
• Decreased HR (75→50 bpm): ↑ EDV, ↓ ESV, ↑ SV, ↑ EF, ↓ CO.

Regulation of Atrial Function

• Atria respond to preload, afterload, and inotropic interventions similarly to ventricles, but vagal stimulation decreases atrial inotropy unlike ventricles.

Summary

• Ventricular preload is related to ventricular filling (EDV) and sarcomere length.
• Increased preload increases contractile force and SV through the Frank-Starling mechanism.
• Ventricular afterload is related to ventricular wall stress; higher afterload decreases SV.
• Inotropy is myocyte's ability to develop tension independent of preload, influencing SV.
• Preload, afterload, and inotropy are interconnected, and changes in any would cause secondary changes in the others.

Q1: A Sudden Decrease in Venous Return

• Decreases ventricular compliance.

Q2: Reducing Afterload in Heart Failure

• Muscle fiber shortening velocity is increased.

Q3: Increasing Inotropy

• Ventricular emptying increases.

Q4: Sympathetic Activation of Heart

• Increased release of calcium by sarcoplasmic reticulum.

Answers (Referencing Previous Sections)

• Q1 Answer A
• Q2 Answer B
• Q3 Answer B
• Q4 Answer D