Cardiac Output and Volumes

Cardiac Output

• Cardiac output is the product of stroke volume and heart rate
• Cardiac output is calculated as 5040 ml/min, with a stroke volume of 70 ml and a heart rate of 72 min-1 (beats per minute)
• Cardiac output is the blood flow delivered by the left ventricle into systemic circulation
• 5 liters per minute, the blood flow delivered by the right ventricle into the pulmonary circulation is equal to cardiac output

Cardiac Index

• Resting cardiac output correlates to the size of the body, mainly the body surface
• Cardiac index is a normalized value for cardiac output (CO) based on body surface area (BSA)
• Cardiac Index = CO/BSA
• Typical cardiac index range is 2.5 – 3.5 L/min/m2

Systolic and Diastolic Volumes

• Systolic Volume and End-Diastolic Volume are key measurements of Cardiac Function

End-Diastolic Volume

• EDV is the volume of blood in the right and/or left ventricle at the end of load, also known as filling in diastole.
• Greater EDV causes greater distension of the ventricle and establishes preload.
• Preload is the lengths of the sarcomeres in cardiac muscle before contraction (systole).
• Typical EDV value is 120 ml
• Normal EDV range is 65–240 ml

Determinants of EDV

• Venous return influences EDV
• Venous compliance - increased compliance increases capacitance of veins, decreasing venous return and EDV
• Extracellular Fluid volume (blood volume) increases EDV
• Filling time affects EDV

Stroke Volume

• SV is the volume of blood pumped from one ventricle of the heart with each beat
• Stroke volume is calculated using measurements of ventricle volumes from an echocardiogram, subtracting ESV from EDV
• Stroke volume applies to each of the two ventricles; however, it typically refers to the left ventricle
• Generally, the stroke volumes for each ventricle are equal
• Stroke volume is an important determinant of cardiac output
• Stroke volume itself correlates to cardiac function
• Typical stroke volume value is 70 ml
• Normal stroke volume range is 55 –100 ml

Determinants of Stroke Volume

• Heart size (comparing males versus females)
• Preload corresponds to end-diastolic volume; a reduced heart rate prolongs ventricular filling
• Afterload corresponds to the aortic pressure during systole
• Duration of contraction depends on calcium and potassium channels
• Contractility represents the ability of the heart to eject a stroke volume at a given afterload and preload, involving cardiac glycosides, catecholamines, prostaglandins, and phosphodiesterase inhibitors

End-Systolic Volume

• ESV is the volume of blood in the right and/or left ventricle at the end of ejection, also known as systole
• ESV is affected by afterload and the contractility of the heart
• Typical ESV value is 50 ml
• Normal ESV range is 16 - 140 ml

Ejection Fraction

• Ejection fraction corresponds to the fraction of the end-diastolic volume ejected in each stroke volume
• Ejection fraction is the stroke volume divided by the end-diastolic volume
• 70/120 is approximately 58%
• Ejection fraction is directly related to contractility

Determination of Cardiac Output: Fick Principle

• Fick's principle uses Fick's law of diffusion
• Variables to be measured in Fick's original method include:
  • Oxygen consumption in ml/min (VO2)
  • Oxygen concentration of blood taken from the pulmonary artery (deoxygenated blood; Cv)
  • Oxygen concentration of blood in a peripheral artery (oxygenated blood; Ca)

Fick's Equation

• VO2 = (CO x Ca) – (CO x Cv)
• VO2 = oxygen consumption measured in ml/min
• CO = cardiac output measured in l/min
• Ca = oxygen concentration of arterial blood in ml/l
• Cv = oxygen concentration of mixed venous blood in ml/l
• VO2 = CO x (Ca - Cv)
• CO = VO2/(Ca - Cv)
• (Ca – Cv) = arteriovenous oxygen difference

Determination of Cardiac Output: Indicator Dilution Method

• The output of the heart is equal to the amount of indicator injected divided by its average concentration in the arterial blood after a single circulation through the heart

Determination of Cardiac Output: Pulmonary Artery Thermodilution

• Pulmonary artery thermodilution is a modification of the indicator dilution method
• The indicator diluted is cooled or heated fluid
• Pulmonary artery catheter known as Swan-Ganz
• Cold fluid injected into the RA while temperature is measured at known distance away (6–10 cm) with temperature sensor
• Cardiac output is calculated from measured time/temperature curve, or the "thermodilution curve"
• High CO registers temperature change rapidly, directly proportional to the cardiac output

Regulation of Cardiac Output

• Cardiac output is regulated via the control of heart rate & stroke volume -Regulation of cardiac chronotropy corresponds to the control of the heart rate -Regulation of the cardiac contractility/inotropy corresponds to the control of stroke volume

Regulation of Heart Rate: Chronotropic Effects

• Chronotropic effects produce changes in heart rate
  • Positive chronotropic effect leads to increase in the rate of Spontaneous Diastolic Depolarization (SDD)
  • Increase in heart rate reduces duration of cardiac cycle, reducing diastole relatively more than systole
  • Critical value of HR = 180/min
  • Negative chronotropic effects decreases the SDD rate and shifts the MDP

Regulation of Heart Rate: Positive Chronotropic Effect

• Positive chronotropic effect speeds up SDD
• Sympathetic stimulation, noradrenaline release, and β1 receptors
• Adrenaline from adrenal medulla involving β1 receptors
• Phosphodiesterase inhibitors, such as methylxanthines or caffeine-decreased cAMP degradation and increased heart rate
• Increased body temperature

Noradrenaline & β1-adrenergic receptors in Heart Rate Regulation

• Noradrenaline → β1-adrenergic receptors → Gs protein → adenylate cyclase activation
• cAMP activates cAMP-dependent protein kinase (PKA) →
• (1) ICaL phosphorylation → depolarization faster
• (2) IK current stimulation → repolarization faster and hyperpolarization leads to more negative value of MDP
• If opens → faster SDD, faster AP depolarization (ICaL phosphorylation) contributing to shorter SDD and AP

Regulation of Heart Rate: Negative Chronotropic Effects

• Negative chronotropic effects slow SDD and shift Minimum Diastolic Potential (MDP)
• Parasympathetic stimulation - IK(Ach) and M receptors coupled to Gi protein
• Decreased body temperature

Acetylcholine & Heart Rate Regulation

• Acetylcholine → (1) M cholinergic receptor → Gi protein → adenylate cyclase inhibition
• Decreased ICaL phosphorylation → slower SDD and AP depolarization
• (2) IK(ACh) current stimulation -> hyperpolarization of MDP and slower SDD
• (3) Leads to If inhibition

Heart Rate at Rest

• Resting heart rate, a "heart in situ" is approximately 70 BPM
• Heart rate of the denervated heart is higher than resting HR
• Under typical resting conditions the Vagal tone is higher than sympathetic tone

Sympathetic and Parasympathetic Tone

• SA node inherent discharge is 100/min
• Beta-1 receptor antagonist decreases heart rate
• Muscarinic receptor-antagonist increases heart rate

Autonomic Regulation of the Heart

• Sympathetic effects on the heart all involve β1 receptors and increase heart rate, contractility, and AV node conduction velocity
• Parasympathetic effects on the heart all involve muscarinic receptors and decrease heart rate, contractility (atria only), and AV node conduction velocity
• Vascular smooth muscle in the skin/splanchnic regions constricts via α1 receptors under sympathetic influence
• Skeletal muscle is constricted via α1 sympathetic stimulation and relaxed via β2

Regulation of Stroke Volume

• The primary factors regulating stroke volume include:
  • Preload – Frank-Starling law
  • Afterload
  • Heart rate
  • Autonomic innervation
  • Drugs and hormones
  • Energy

Regulation of Stroke Volume: Preload & the Frank-Starling Law

• Preload, equivalent to end-diastolic volume, contributes to the contractile force developed by a muscle fiber depending on its initial length
• Otto Frank and Ernest Starling’s “Frank-Starling relationship” describes the mechanism responsible for matching cardiac output to venous return by stating that increased venous return leads to distension of the ventricle, increased EDV, and increased contraction

Contributors to the Frank-Starling Law

• Theodor Schwann (1832): Length-tension relationship in skeletal muscle and recognition of the role of resting length in subsequent contraction
• Carl Ludwig (1856): A strong heart that is filled with blood empties itself more or less completely; filling of the heart with blood changes the extent of contractile power
• Julius Cohnheim (1869): Described interplay between cardiac filling and ejection
• Otto Frank (1895): Dependence of peak isovolumic pressure on ventricular volume
• Ernest Henry Starling (1914): Cardiac output remains constant over a range of arterial pressures, heart rates and stated that rise of venous pressure is a mechanical means allowing the heart to maintain an output corresponding to incoming blood
• Ernest Henry Starling (1918): The law of the heart is thus the same as the law of muscular tissue generally: energy of contraction is a function of the length of the muscle fiber

Frank-Starling-Maestrini Law of the Heart

• Dario Maestrini (1914-1915) performed snail and frog heart experiments which suggest that a direct relationship exists between blood volume contained in heart cavities and the contractile energy of the heart
• Within certain limits the lengthening of heart fibers, cause of dilatation of the heart, corresponds to a greater contractile energy

Frank-Starling Law: Cellular Mechanisms

• Calcium sensitivity - sensitivity of thin filaments to Ca increases with increasing length of sarcomeres
• Role of titin and its position in the thick myofilament

Tension-Length Curves

• Cardiac muscle has high resistance to stretch when compared with skeletal muscle
• When either cardiac or skeletal muscle is stretched, there is an increase in resting (passive) tension
• Maximally stimulated muscle generates more tension in total
• Force produced by contraction is the difference between total tension and resting tension
• The sliding filament theory suggests that the bell-shaped dependence of active tension on muscle length is consistent
• Stretching becomes difficult beyond the cardiac muscles optimal sarcomere length

Regulation of Stroke Volume: Afterload

• Afterload is the force required to begin ventricular ejection, which includes aortic pressure, flow resistance through the aortic valve orifice, distensibility of the vascular system, and peripheral vascular resistance
• In simplified model, afterload is equal to the arterial pressure
  • Sudden increase in BP will decrease Stroke Volume and increase End Systolic Volume if venous return remains constant
  • Increased End-Diastolic Volume yields stronger Frank-Starling contractions
  • Untreated hypertension causes increased afterload, leading to left ventricle hypertrophy and cardiac failure

Regulation of Stroke Volume: Heart Rate

• Increased heart rate leads to accumulation of intracellular calcium that normally leaves the cell via the Na/Ca exchanger during diastole.

Regulation of Stroke Volume: Autonomic Innervation

• Sympathetic stimulation involves:
  • Noradrenaline → Beta 1 adrenergic receptor → Gs protein → adenylate cyclase activation
• cAMP activates cAMP-dependent protein kinase (PKA) leading to:
  • (1) ICaL phosphorylation
  • (2) increased sensitivity to Ca
  • (3) increased phospholamban phosphorylation → increased SERCA activity
  • (4) sarcolemmal Na-K-ATPase stimulation → effective restoration of intracellular ionic composition
  • (5) stimulation of enzymes of energy metabolism

Regulation of Stroke Volume: Autonomic Innervation & Parasympathetic Stimulation

• Parasympathetic system's influence on inotropy is mainly indirect, involving heart rate manipulation
  • Reduction in heart rate increases diastolic calcium loss
• Direct effect leads to negative inotropic effects on atrial myocardium only, by increasing the permeability for potassium ions causing shortened depolarization
• (IKACH, which also shortens AP, reduces the flow of calcium into the cell)

Parasympathetic Signal Transduction

• Acetylcholine → M-receptor stimulation → Gi protein
• Gi inhibits Adenylate cyclase
• Activation of IK(Ach) causes increases in potassium current and shortening of AP
• Ultimately leads to a shorter Ca entry and a lack of cAMP dependent protein kinase activation
• A direct Negative Inotropic Effect occurs

Regulation of Stroke Volume: Drugs and Hormones

• Cardiac glycosides such as digitalis
• Catecholamines
• Phosphodiesterase inhibitors
• Glucagon
• Hormones of the thyroid gland
• PGE2
• Beta-blockers
• ICaL inhibitors
• Acetylcholine

Na/Ca Exchanger

• Digitalis purpurea affects the force of heart contraction
• By modulating the sodium and calcium levels

Regulation of Stroke Volume: Energy Supply

• A lack of energy known as hypoxia causes:
• Slowing down of contraction and relaxation (calcium handling)
• Slower detachment of myosin head → increased diastolic tension
• Decreased contraction force
• Insufficient phosphorylation of L-type calcium channels → risk of arrhythmia
• Opening of metabotropic potasium channels → risk of arrhythmia

Pressure-Volume Loops

• Pressure and volume are related in the ventricle
• Increased preload (or increased venous return) leads to increase in End Diastolic Volume (EDV) and increase in stroke volume
• Increased afterload or hypertentsion leads to decreased stroke volume and increase in ESV
• Increased contractility and sympathetic stimulation leads to increase in stroke volume and decrease in ESV