Cardiac Output and Cardiac Index

Cardiac Output (CO)

• Cardiac output is the product of stroke volume and heart rate.
• The value can be calculated as: CO = stroke volume x heart rate.
• An example calculation is 5040 ml/min = 70 ml x 72 min-1
• It represents the volume of blood the left ventricle (LV) pumps into systemic circulation.
• Normal cardiac output is approximately 5 liters/min.
• The blood flow delivered by the right ventricle (RV) into pulmonary circulation is equal to cardiac output.

Cardiac Index

• Resting cardiac output correlates with body size, especially body surface area.
• Cardiac index is a normalized cardiac output value based on body surface area (BSA).
• Cardiac index is calculated as CO/BSA.
• Normal range for cardiac index is 2.5 – 3.5 L/min/m².

Systolic and Diastolic Volumes

• Systolic volume is the volume of blood during systole.
• End-diastolic volume is the total amount of blood in the ventricles at the end of diastole, or filling.
• End-systolic volume is the amount of blood remaining in the ventricles at the end of systole, or ejection.

End-Diastolic Volume (EDV)

• EDV represents the volume of blood in right and/or left ventricle at the end of diastole.
• Greater EDV causes greater distension of the ventricle.
• EDV is a determinant of preload, and represents 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.
• Venous compliance; increased capacitance of veins decreases venous return and EDV.
• Extracellular fluid (ECF) volume, or blood volume, increases EDV.
• Filling time.

Stroke Volume (SV)

• Stroke volume is the volume of blood pumped from one ventricle with each beat.
• Stroke volume can be calculated using measurements from an echocardiogram by subtracting end-systolic volume (ESV) from end-diastolic volume (EDV).
• Stroke volume typically refers to the left ventricle
• Stroke volumes for each ventricle are generally equal.
• Stroke volume is an important determinant of cardiac output and correlates with cardiac function.
• Typical value is 70 ml.
• Normal range is 55 –100 ml.

Determinants of Stroke Volume

• Heart size (varies between males and females).
• Preload, or end-diastolic volume, is a determinant. Reduced heart rate prolongs ventricular filling, impacting preload.
• Afterload is the aortic pressure during systole.
• Duration of contraction, influenced by calcium and potassium channels.
• Contractility is the ability of the heart to eject a stroke volume at a given afterload and preload; contractility is influenced by cardiac glycosides, catecholamines, prostaglandins, and phosphodiesterase inhibitors.

End-Systolic Volume (ESV)

• ESV represents the volume of blood remaining in the right and/or left ventricle at the end of ejection (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 is the fraction of the end-diastolic volume ejected in each stroke volume.
• Ejection fraction is calculated as stroke volume / end-diastolic volume.
• Normal ejection fraction is approximately 70/120 or 58%.
• It is related to contractility.

Determination of Cardiac Output: Fick Principle

• The Fick principle is used, derived from Fick's law of diffusion.
• Variables for measurement include:
  • Oxygen consumption in ml/min (VO2).
  • Oxygen concentration of blood from the pulmonary artery (deoxygenated blood; Cv).
  • Oxygen concentration of blood in a peripheral artery (oxygenated blood; Ca).
• VO2 = (CO × Ca) – (CO × Cv)
• CO = VO2 / (Ca - Cv)
• (Ca – Cv) is the arteriovenous oxygen difference.

Determination of Cardiac Output: Indicator Dilution Method

• Cardiac output is determined by dividing the amount of indicator injected by its average concentration in arterial blood after a single circulation through the heart.

Determination of Cardiac Output: Pulmonary Artery Thermodilution

• Pulmonary artery thermodilution is a modification of indicator dilution method.
• The indicator is cooled or heated fluid.
• A pulmonary artery catheter (Swan-Ganz) is used.
• Cold fluid is injected into the right atrium (RA) and temperature is measured at a known distance away (6–10 cm) with a temperature sensor.
• Cardiac output is calculated by a measured time/temperature curve termed "thermodilution curve".
• High cardiac output registers temperature change rapidly.
• The degree of temperature change is directly proportional to the cardiac output.

Regulation of Cardiac Output

• Cardiac output is regulated via 2 major controls.
• Control of heart rate, otherwise known as cardiac chronotropy.
• Control of stroke volume, otherwise known as cardiac contractility or inotropy.

Regulation of Heart Rate: Chronotropic Effects

• Chronotropic effects produce changes in heart rate.
• Positive chronotropic effects increase heart rate via an increase in the rate of spontaneous diastolic depolarization (SDD).
• An increased heart rate reduces duration of the cardiac cycle, reducing diastole more than systole.
• Critical value of heart rate = 180/min.
• Negative chronotropic effects decrease heart rate via a decreased rate of SDD or shift in maximum diastolic potential (MDP).

Regulation of Heart Rate - Positive Chronotropic Effect

• Speeds up spontaneous diastolic depolarization (SDD)
• Sympathetic stimulation causes noradrenaline release, activating β1 receptors.
• Adrenaline from the adrenal medulla activates β1 receptors.
• Phosphodiesterase inhibitors like methylxanthines (caffeine) decrease cAMP degradation and increase heart rate.
• Increased body temperature can also increase heart rate.
• Noradrenaline acts on β1-adrenergic receptors, activating Gs protein, leading to adenylate cyclase activation.
• cAMP activates cAMP-dependent protein kinase (PKA).
• PKA causes ICaL phosphorylation, leading to faster depolarization.
• PKA causes IK current stimulation, leading to faster repolarization and a more negative MDP value.
• Stimulation leads to faster SDD, faster AP depolarization (ICaL phosphorylation), shorter SDD, and AP.

Regulation of Heart Rate - Negative Chronotropic Effects

• Slower rate of spontaneous diastolic depolarization (SDD) or a shift in maximum diastolic potential (MDP).
• Parasympathetic stimulation activates IK(Ach) channels and M receptors coupled to Gi protein.
• Decreased body temperature will also cause negative chronotropic effects.
• Acetylcholine acts on M cholinergic receptors, activating Gi protein and inhibiting adenylate cyclase.
• Leads to decreased ICaL phosphorylation, and slower SDD and AP depolarization.
• IK(ACh) current stimulation leads to hyperpolarization of MDP and slower SDD.

Resting Heart Rate

• Resting heart rate for a heart in situ is approximately 70 BPM.
• The denervated heart's heart rate is higher than normal resting HR.
• Vagal tone is higher than sympathetic tone under resting conditions.

Sympathetic and Parasympathetic Tone

• The heart's inherent sinoatrial Node discharge frequency is 100/min.

Autonomic Regulation of the Heart

• Involves sympathetic and parasympathetic nervous system effects on heart rate, conduction velocity through the AV node and contractility.
• Sympathetic effect increases heart rate, conduction velocity, and contractility.
• Parasympathetic effect decreases heart rate, conduction velocity, and contractility (atria only).
• Vascular smooth muscle is constricted by sympathetic activity on alpha 1 receptors.
• Skeletal muscle experiences constriction via alpha 1 receptors and relaxation via beta 2 receptors.

Regulation of Stroke Volume

• Preload (Frank-Starling law).
• Afterload.
• Heart rate.
• Autonomic innervation.
• Drugs and hormones.
• Energy availability.

Regulation of Stroke Volume: Preload

• Preload is equivalent to end-diastolic volume. The contractile force developed by a muscle fiber is related to its initial length.
• Otto Frank and Ernest Starling determined an increased venous return causes distension of the ventricle (increased EDV) that is followed by an increased contraction.
• The Frank-Starling relationship mechanism matches cardiac output to venous return.

Contributors to Frank-Starling Law

• 1832 – Theodor Schwann described the length-tension relationship in skeletal muscle, recognizing the role of resting length in subsequent contraction.
• 1856 – Carl Ludwig stated that “… a strong heart that is filled with blood empties itself more or less completely, in other words, [filling of the heart with blood] changes the extent of contractile power.”
• 1869 – Julius Cohnheim described the interplay between cardiac filling and ejection in his textbook on general pathology, explaining a lessening in the quantity of blood in the chambers during diastole is determined by the quantity of blood reaching the ventricle during diastole.
• Physiologists agreed normal ventricles expel the whole, or nearly the whole, of its contents in each contraction.
• 1895 – Otto Frank showed a dependence of peak isovolumic pressure on ventricular volume.
• In 1914, Ernest Henry Starling stated the rise of venous pressure is regarded as one of the mechanical means which are operative in enabling the heart to maintain an output corresponding to the blood it receives from the venous system, determining the output of the heart depends on the amount of blood flowing into the heart.
• In 1918, Ernest Henry Starling stated, "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 fiber."
• Between 1914 and 1915 - Dario Maestrini demonstrated how the lengthening of the heart fibers, cause of the dilatation of the heart, corresponds to a greater contractile energy and formulated his "Law of the Heart""

Frank-Starling Law: Calcium Sensitivity & Titin

• Thin filaments' sensitivity to Ca increases with increasing sarcomere length.
• Titin's role and position in the thick myofilament

Regulation of Stroke Volume: Afterload

• Is the force required to begin ventricular ejection.
• In the left ventricle, opposition of ejection includes aortic pressure, flow resistance by the aortic valve orifice, distensibility of the vascular system, and peripheral vascular resistance.
• In a simplified model, afterload is equal to arterial pressure.
• Sudden increase in blood pressure leads to a decrease in stroke volume and increase in end systolic volume, if venous return remains the same, which leads to an increased end diastolic volume and stronger contraction through the Frank-Starling law.
• Untreated hypertension leads to chronically increased afterload, leading to left ventricle hypertrophy, eventually leads to cardiac failure.

Regulation of Stroke Volume: Heart Rate

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

Regulation of Stroke Volume: Autonomic Innervation

• Sympathetic stimulation causes noradrenaline to activate β1 adrenergic receptors, activating Gs protein.
• Gs protein activates adenylate cyclase, increasing cAMP levels.
• cAMP-dependent protein kinase (PKA) activation occurs.
• PKA causes ICaL phosphorylation.
• Increases sensitivity to Ca
• Increases phospholamban phosphorylation leading to increased SERCA activity;
• Na-K-ATPase stimulation causes effective restoration of intracellular ionic composition.
• PKA stimulates enzymes of energy metabolism.

Regulation of Stroke Volume: Parasympathetic Stimulation

• Indirectly influences inotropy through changes in heart rate, where a reduction increases diastolic calcium loss.
• Directly causes a negative inotropic effect on the atrial myocardium by increasing the permeability for potassium ions (IKACH; shortening of the AP reduces the flow of calcium into the cell).

Regulation of Stroke Volume: Drugs and Hormones

• Cardiac glycosides (digitalis).
• Catecholamines.
• Phosphodiesterase inhibitors.
• Glucagon.
• Hormones of the thyroid gland
• PGE2
• ß-blockers.
• ICaL inhibitors
• Acetylcholine

Na/Ca Exchanger & Digitalis

• Digitalis is a cardiac glycoside derived from the plant digitalis purpurea and increases calcium contractility and force.

Regulation of Stroke Volume: Energy Supply

• Includes lack of energy and hypoxia
• Lead to a 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 potassium channels creates a risk of arrhythmia.

Pressure-Volume Loops

• Illustrate the relationship between pressure and volume changes in the ventricle.