Cardiac Output and Cardiac Index

Cardiac Output

• Cardiac output is the product of stroke volume and heart rate.
• Cardiac Output = Stroke Volume * Heart Rate
• A cardiac output of 5040 ml/min can be achieved with a stroke volume of 70 ml and a heart rate of 72 min^-1.
• Typical cardiac output is about 5 litres/min.
• The flow of blood from the left ventricle into systemic circulation equals the flow from the right ventricle into pulmonary circulation.

Cardiac Index

• Resting cardiac output is related to body size, specifically body surface area
• Cardiac index normalizes cardiac output (CO) based on body surface area (BSA)
• Cardiac Index = CO/BSA
• Normal cardiac index range is 2.5 – 3.5 L/min/m^2.

Systolic and Diastolic Volumes

• End-diastolic volume is the volume of blood in either ventricle at the end of diastole.
• A typical end-diastolic volume is 120 ml, but can range from 65-240ml
• A greater end-diastolic volume leads to greater distension of the ventricle
• End-diastolic volume is a determinant of PRELOAD, specifically the length of the sarcomeres in cardiac muscle before contraction.
• Venous return, venous compliance, ECF volume, and filling time are determinants of the end-diastolic volume
• Increased venous compliance decreases venous return and the end-diastolic volume
• Increase ECF volume increases the end-diastolic volume
• Stroke volume is the blood volume pumped from one ventricle per beat.
• Stroke volume is calculated by subtracting the end-systolic volume from the end-diastolic volume, typically measured from an echocardiogram.
• While the term "stroke volume" can apply to either ventricle, it usually refers to the left ventricle.
• The stroke volumes for each ventricle are generally equal
• Stroke volume is an important determinant of cardiac output
• Stroke volume correlates with cardiac function
• Stroke volume has a typical value of 70 ml
• normal range is 55-100ml

Determinants of Stroke Volume

• Heart size
• Preload (end-diastolic volume)
• Reduced heart rate prolongs ventricular filling, illustrating the effect of preload
• Afterload
• Aortic pressure during systole
• Duration of contraction
• Duration of contraction is affected by calcium and potassium channels.
• Contractility
• Contractility is affected by cardiac glycosides, catecholamines, prostaglandins, and phosphodiesterase inhibitors.
• Contractility is the heart's ability to eject a stroke volume at a given afterload and preload.
• End-systolic volume (ESV) is the volume of blood in either ventricle at the end of ejection (systole).
• End-systolic volume has a typical value of 50 ml
• normal range is generally 16 - 140 ml
• Afterload and contractility affect end-systolic volume.

Ejection Fraction

• Ejection fraction is the fraction of end-diastolic volume ejected per stroke volume.
• Ejection Fraction = Stroke Volume / End-Diastolic Volume
• An ejection fraction of 70/120 equates to roughly ~ 58%.
• Ejection fraction is related to contractility.

Measuring Cardiac Output with the Fick Principle

• Oxygen consumption (VO2) in ml/min
• Oxygen concentration of blood from the pulmonary artery (Cv)
• Oxygen concentration of blood in a peripheral artery (Ca)
• VO2 = (CO x Ca) - (CO x Cv)
• CO = VO2 / (Ca - Cv)
• Ca - Cv is the arteriovenous oxygen difference

Indicator Dilution Method

• Heart output is equal to the injected indicator amount divided by its average concentration in arterial blood after one circulation.
• CO (ml/min) = (mg of dye injected x 60) / (average conc. of dye in each ml of blood for the duration of curve x duration of curve (s))

Pulmonary Artery Thermodilution

• This process is a Modification of the indicator dilution method.
• The indicator diluted is cooled or heated fluid.
• A pulmonary artery catheter (Swan-Ganz) is inserted.
• Cold fluid is injected into the right atrium, and the temperature is measured at approx 6-10 cm away with a temperature sensor
• Calculation of cardiac output from a measured time/temperature curve is called ("thermodilution curve")
• A high CO registers a temperature change rapidly
• The degree of temperature change is directly proportional to the cardiac output

Regulation Of Cardiac Output

• Cardiac output is regulated through heart rate and stroke volume.
• The regulation of heart rate involves cardiac chronotropy.
• Regulation of stroke volume includes cardiac contractility, or inotropy.

Regulation of Heart Rate

• Chronotropic effects produce changes in heart rate.
• Positive chronotropy increases the rate of spontaneous diastolic depolarization.
• Increased heart rate reduces the duration of the cardiac cycle, with diastole shortening more than systole.
• Critical heart rate value is 180/min
• Negative chronotropy decreases the rate of spontaneous diastolic depolarization or shifts the maximum diastolic potential.
• Sympathetic stimulation, noradrenaline release, and Beta 1 receptors lead to faster spontaneous diastolic depolarization.
• Adrenaline from the adrenal medulla also acts via Beta 1 receptors.
• Phosphodiesterase inhibitors like methylxanthines (caffeine) decrease cAMP degradation.
• The decrease in cAMP degradation increases HR
• Increased body temperature also increases heart rate.
• Noradrenaline operates through Beta 1-adrenergic receptors, Gs protein, adenylate cyclase.
• Activation of cAMP activates cAMP-dependent protein kinase (PKA) and ICaL phosphorylation, which leads to faster depolarization
• IK current stimulation then leads to repolarization faster
• Faster repolarization also causes hyperpolarization and a more negative value of Maxium Diastolic Potential
• All of this leads to faster spontaneous diastolic depolarization, shorter spontaneous diastolic depolarization, and faster action potential depolarization with ICaL phosphorylation.
• Acetylcholine operates through M cholinergic receptors and Gi protein to adenylate cyclase inhibition.
• Decreased ICaL phosphorylation causes a slower spontaneous diastolic depolarization and action potential depolarization
• IK(ACh) current stimulation from acetylcholine causes hyperpolarization of the Maximum Diastolic Potential
• Hyperpolarization causes slower spontaneous diastolic depolarization

Sympathetic and Parasympathetic Tone

• Resting heart rate is approximately 70 BPM (heart in situ).
• The denervated heart rate is higher than the resting heart rate.
• Vagal tone is higher than sympathetic tone under resting conditions.
• The inherent discharge of the SA node is 100/min.

Factors that Regulate Stroke Volume

• Preload
• Frank-Starling Law
• Afterload
• Heart rate
• Autonomic innervation
• Drugs and hormones
• Energy Supply

Contributors to the Frank-Starling Law

• Otto Frank extended work by Ernest Starling to describe the Frank-Starling relationship.
• Increased venous return leads to distension of the ventricle.
• Ventricular distension increases end-diastolic volume and is followed by increased contraction.
• Mechanism matches cardiac output to venous return.
• 1832 – Theodor Schwann formulated cell theory and identified Schwann cells and pepsin.
• Schwann described the length-tension relationship in skeletal muscle and the role of resting length in subsequent contraction.
• 1856 – Carl Ludwig stated that a strong heart is filled with blood.
• A ventricular filling with blood changes the extent of contractile power.
• 1869 - Julius Cohnheim described the interplay between cardiac filling and ejection.
• A diminution in the quantity of blood present in the ventricle at the start of cardiac contraction limits the ability of the quantity of blood to be ejected during systole.
• Blood reaching the ventricle during diastole determines work done by the heart and the amount of resistance in propelling it into arteries.
• 1895 - Otto Frank showed the dependence of peak isovolumic pressure on ventricular volume.
• 1914 - Ernest Henry Starling determined cardiac output remains constant over a fairly broad range of arterial pressures
• Venous pressure must be regarded as the mechanical means helpful to assist the heart in maintaining an output corresponding to the blood it receives from the venous system.
• 1918 - "The law of the heart is thus the same as the law of muscular tissue generally, that the energy of contraction, however measured, is a function of the length of the muscle fibre.”
• 1914 to 1915 - Dario Maestrini performed snail/frog-heart experiments and identified the direct relationship between blood volume in the heart cavity and contractile energy/dilatation of the heart corresponds to greater contractile energy
• Ernest Starling came to same conclusions

About Frank-Starling Law

• In heart muscle, there is high resistance to stretch compared to skeletal muscle.
• Stretching cardiac or skeletal muscle increases passive (resting) tension.
• The muscle generates more tension, termed total tension, when stimulated to contract maximally.
• The difference between total and resting tension is force produced by contraction, active tension.
• The bell-shaped dependence of active tension on muscle length is consistent with the sliding filament theory of cardiac and skeletal muscle.
• It is difficult to stretch cardiac muscle beyond its optimal sarcomere length.
• Calcium sensitivity in thin filaments increases with increasing length of sarcomeres.
• Titin and its position in the thick myofilament also are important

Factors to Regulate with Afterload

• Afterload is the force required to begin ventricular ejection
• Afterload opposition of ejection includes aortic pressure.
• It also includes aortic valve orifice flow resistance, distensibility of the vascular system, and peripheral vascular resistance.
• Afterload is equal to the arterial pressure in a simplified model.
• Sudden BP increase decreases stroke volume and increases end systolic volume if venous return remains constant
• Increased end diastolic volume, results in stronger contraction via Frank-Starling law
• Untreated hypertension, which leads to chronically increased afterload, may cause left ventricle hypertrophy and cardiac failure.

Factors to Regulate with Heart Rate

• Increased heart rate results in accumulation of intracellular calcium
• Normally, calcium leaves the cell via the Na+/Ca+ exchanger during diastole.

Sympathetic Nerve Stimulators

• Noradrenalin
• This stimulates the B1 adrenergic receptor
• Increases adenylate cyclase, cAMP
• dependent protein kinase (PKA)

Parasympathetic Nerve Stimulators

• Parasympathetic effect on intropy is mainly indirect that changes in heart rate
• The effect on direct atrial myocardium is negative inotropic
• This is achieved via increasing permeability for potassium ions which reduced flow of calcium into the cell

Drug and Hormones to Influence Stroke Volume

• Cardiac glycosides (digitalis)
• Catecholamines
• Phosphodiesterase inhibitors
• Glucagon
• Thyroid hormones
• PGE2 (prostaglandin E2)
• Beta-blockers
• ICaL inhibitors
• Acetylcholine

Energy Supply

• Slowing down contraction/relaxation is a characteristic from a lack of energy
• Detachment of myosin head slows, and increases diastolic tension
• Contraction force decreases
• Phosphorylation of L-type calcium channels is insufficient, and may increase risk of arrhythmia
• Rhythm of opening metabotropic potassium channels may increase risk of arrhythmia

Pressure-Volume Relationship

• Pressure and volume in the ventricle has some important relationships
• Increased preload (increased venous return) increases both end-diastolic and stroke volume.
• Increased afterload (hypertension) decreases stroke volume and increases end-systolic volume.
• Increased contractility (sympathetic stimulation) increases stroke volume and decreases end-systolic volume.