Last edited: 8/23/2021

9. CARDIAC OUTPUT – FRANK STARLING’S LAW

Cardiovascular | Cardiac Output | Frank Starling's Law Medical Editor: Sofia Centenaro

Exercise
OUTLINE
o Generate heat → ↑metabolic rate → ↑HR
I) CARDIAC OUTPUT ↑Body Temperature
II) HEART RATE (HR) o Generate heat → ↑metabolic rate → ↑HR
III) STROKE VOLUME (SV)
IV) SUMMARY Drugs
V) REVIEW QUESTIONS o Epinephrine, Norepinephrine, Isoproterenol
VI) REFERENCES  Beta 1 agonists stimulate nodal cells→ ↑Impulses
o Atropine
 M2 antagonist stimulate Nodal cells→ ↑impulses
I) CARDIAC OUTPUT
Ions
(A) DEFINITION o Calcium
 Hypercalcemia
Cardiac Output = total volume of blood pumped out of the  ↑Ca++→ ↑depolarization rate → ↑APs rate → ↑HR
heart in one minute o Potassium
CO = Heart Rate (HR) X Stroke Volume (SV)  Hypokalemia
CO = 70 Beats/min (bpm) X 70 ml/beat = 5000 ml/min = 5 • Less K+ in the extracellular fluid → K+ exits
L/min the cell more quickly → ↑depolarization rate
→ ↑HR
II) HEART RATE (HR)
• It can cause Arrhythmia
HR = the amount of beats occurring per minute CO2, O2 and H+
60-80 beats/min o ↓pO2, ↑pCO2 & ↑pH+ → ↑Peripheral
SA node sets the sinus rhythm by generating intrinsic Chemoreceptors activity at carotid Bodies → ↑CNS
abilities, the APs, that can be sent out throughout the IX activity → Nucleus of Tractus Solitarius (NTS) in
heart the Medulla →↑Medullary Cardioacceleratory center
(A) FACTORS THAT INCREASE HR activity → ↑SNS activity →↑HR
Age & Gender
o Fetus/Infant → ↑↑HR (120-140 bpm)
o Adult (60-100 bpm)
 Male → 64-72 bpm
 Female → 72-80 bpm (Higher HR than Males)
o Older → ↑HR
Atrial Bainbridge reflex
o Positive chronotropic agent
o ↑Venous return→↑Stretch→ ↑Cardioacceleratory
center activity→ SA node→ ↑HR

(B) FACTORS THAT DECREASE HR

Parasympathetic Nervous System (SNS)→ ↓Heart
Rate
o Acetylcholine→ ↑M2- Receptor activity → ↑K+ efflux
and ↓cAMP → hyperpolarization → ↓APs rate → ↓HR
o Negative chronotropic agent
Hormones
o ↓Low Thyroid Hormone
 ↓Decreased Metabolic Rate
 ↓Decreased Body Temperature
Drugs that block AV node conduction and decrease Sinus
rate of impulses
o Beta blockers
o Calcium channel blockers
o Digitalis
Figure 1. Factors affecting Heart Rate
o Adenosine
Sympathetic Nervous System (SNS)→ ↑Heart Rate
Ions
o Norepinephrine (NE) & Epinephrine (Epi) → ↑B1-
o Calcium
Adrenergic Receptor activity → ↑Ca++ influx →
 Hypocalcemia (↓Ca++)
↑depolarization rate → ↑HR
o Potassium
o Positive chronotropic agent
 Hyperkalemia (↑K+)
Hormones • more K+ in extracellular fluid → less K+ exits
o ↑Thyroid Hormone (T3 and T4) the cell because the concentration gradient is
 Increases basal metabolic rate → ↑heat lost
 ↑body temperature • → K+ accumulates in the cell

Cardiac Output – Frank Starling’s law CARDIOVASCULAR PHYSIOLOGY : Note #9. 1 of 6

 • → makes the inside of the cell more positively
charged
• → this locks the voltage gated Na+ channels
in an inactivated state
• → prevents the nodal cell from being
stimulated again because the voltage gated
Na+ channels never returned to resting state
• it can lead to cardiac arrest
CO2, O2, H+
o ↓CO2 & ↓H+ and ↑O2→ ↓Peripheral Chemoreceptor
activity at carotid Bodies→ ↓CN IX activity→
↑Medullary Cardiac inhibitory center→ ↑PSNS activity
via Vagus Nerve→ ↓HR
Gender
o Males→ ↓lower HR than Females

(C) BRADYCARDIA
(1) Definition
Bradycardia= whenever HR<60 bpm

(2) Causes
PSNS
Drugs
Endurance Activities
o ↑preload, ↑contractility → ↑↑↑SV Figure 3. Factors affecting Stroke Volume
o CO = ↑↑SV X HR↓↓
(SV) = End Diastolic Volume (EDV) - End Systolic
 HR drops because the SV takes over the primary
Volume (ESV) = 70ml
effect of CO
 Decreased HR (to allow the heart to rest) (1) EDV: Pre-pumping volume in ventricles
(D) TACHYCARDIA Volume of blood in ventricles before contraction,
during the relaxation period
(1) Definition Based on venous return and “stretchy” myocardium
whenever HR>100 bpm ↑EDV→↑ Stroke volume (assuming normal contractility)
Normal value: 120-140 ml
(2) Causes
(2) ESV: Post-pumping volume in ventricles
SNS
↑T3 + T4 Volume of blood in ventricles after ventricle
Drugs contraction
Anxiety Based on Contractility and Afterload
o Good Contractility with afterload constant → ↓ESV &
III) STROKE VOLUME (SV) ↑SV
Stroke volume = total volume of blood (ml) pumped out o Bad contractility with ↑afterload & contractility
of the ventricle in one beat constant → ↑ESV & ↓SV
Normal value: 50-70
(3) Ejection Fraction (EF): percentage of blood ejected
out of ventricles per beat
EF= SV/EDV X100
Normal EF= 70ml/140ml X 100=50%
Decreased Left ventricular EF
o Could be due to Systolic Heart Failure
o ↓blood leaving heart→ more remains after
contraction→↑in ESV & ↓SV→ ↓ EF

(B) PRELOAD
(1) Definition
The degree of Stretch of ventricular myocardium
(2) Frank Starling’s Law of Heart

↑Stretch of heart →↑cross-bridge formation

Figure 2. Pressure-Volume loops
→↑force of contraction
(A) FACTORS REGULATING STROKE VOLUME
If Preload↑→↑SV
If Preload↓→ ↓SV
↑EDV →↑Preload

2 of 6 CARDIOVASCULAR PHYSIOLOGY: Note #1. Cardiac Output – Frank Starling’s law


Figure 4. Effect of Preload on PV loops [cvphysiology.com]
(3) Factors Increasing Preload
↑ Venous Return to heart
o Increased Blood Volume → more blood returned to
heart
o muscular milking activity
 Skeletal muscle contractions in Legs → blood
pushed up through veins into the heart
o respiratory pump
 During inspiration: ↑abdominal cavity pressure &
↓intrathoracic pressure → creates vacuum
pressure to pull up blood from abdominal veins
into the heart
o venomotor tone or venoconstriction
 SNS → NE and EPI release in the smooth muscle
in the leg area → constriction of veins → blood
pushed up into the heart
o Lying supine
 blood isn’t pulled down into lower extremities by
gravity
↑ Filling time
o If HR is slower (bradycardic)→↑diastolic
time→↑ventricular filling→↑preload
↑Muscle compliance
o “Stretchy” myocardium is able to stretch when filled
with blood
o Normal Myocardium → normal stretch → normal
preload
o Dilated “Flabby” Myocardium → ↑ stretch → ↑preload
Heart valve malfunction
o Pulmonary & Aortic Valve Abnormalities
o Stenosis→↓ blood leaves the ventricles→↑preload
o Regurgitation→↑ blood backflows into
ventricles→↑preload
Cardiac Output – Frank Starling’s law
Figure 5a. Muscular milking activity [Wikipedia.org]
Figure 5b. Respiratory pump [Slideplayer]
(4) Factors decreasing Preload
↓Venous Return to heart
o Decreased Blood Volume→ ↓blood return to heart
 Hemorrhage
 Dehydration
o Decreased SNS activity→ ↓venous constriction→
↓venous return to heart
 common in elderly
o ↑Increased Vasodilation of veins → ↓pressure in
veins → ↓blood return to heart
 Drugs like Nitroglycerin
o Expiration: ↑intrathoracic pressure removes vacuum
pressure to pull blood from abdominal veins into heart
→ ↓venous return
o ↓Decreased skeletal muscle contractions in Legs→
↓return of blood up veins into heart
 Immobility (bed ridden)
o Standing upright for long periods of time → gravity
pulls blood into lower extremities
↓ Muscle Compliance
o Damaged ventricular myocardium → ↓stretch when
filled with blood
 History of Myocardial infarction
• Healthy tissue replaced with fibrous tissue
• Fibrous tissue not “stretchy” tissue
 Super thick “hypertrophied myocardium” →
↓stretch →↓ventricular filling → ↓preload
↓Filing Time
o If the heart isn’t given enough time to fill with blood, it
doesn’t stretch properly
o If HR is faster (tachycardic)→ ↓diastolic time →
↓ventricular filling → ↓preload
CARDIOVASCULAR PHYSIOLOGY : Note #9. 3 of 6
 Heart Valve malfunction  Ex. Verapamil, diltiazem, nifedipin
o Mitral and Tricuspid Valve abnormalities Ions
o Stenosis→↓blood gets into ventricles from o Calcium (Ca++)
atria→↓preload  Hypocalcemia
(C) CONTRACTILITY • ↓Calcium in blood and muscle cells→ ↓cross
bridges→ ↓Contractility
(1) Definition o Potassium (K+)
Strength/Force of Ventricular Contraction  Hyperkalemia
↑Contractility→↑SV • ↑K+ in ECF→ ↓K+ exits the cell because the
concentration gradient is lost→ ↑K+
↑Contractility→↓SV accumulates in the cell→ ↑voltage inside of
the cell→ the voltage gated Na+ channel is
locked in an inactivated state→ ↓voltage
gated Na+ channels activity→ ↓contractile
cardiac cell activity
o Sodium (Na+)
 hypernatremia
H+
o Acidosis (↑H+)
 This is a twofold mechanism
 ↓calcium entry via competitive
inhibition→↓contractility
 ↓enzyme and protein function in the cardiac
cells→↓contractility
Hypoxia
o Hypoxia→↓O2 delivered to muscle cells→↓ATP
production→↓cross bridge formation between myosin
and actin→↓contractility

(D) AFTERLOAD
Figure 6. Effect of Contractility on PV loops [cvphysiology.com]
(1) Definition
(2) Factors increasing Contractility – positive inotropic the amount of resistance that must be overcome in
agents order for the ventricles to eject blood into the
Sympathetic Nervous System aorta/pulmonary trunk
o Norepinephrine and Epinephrine→↑B1 activity →
(2) Features
↑Ca++ in the cell → ↑cross-bridges
formation→↑contraction force Dependent primarily on Vascular Resistance and
Diastolic Blood Pressure (DBP)
Hormones
↑resistance→↑afterload
o Thyroid hormone (T3+T4) → come into myocardial
↓resistance→↓afterload
cells → ↑internuclear receptors activity → ↑specific
↑Diastolic BP→↑ afterload
genes activity → ↑expression and sensitivity of B1
↓Diastolic BP→↓afterload
adrenergic receptors
↑Afterload→↓SV
o Glucagon→↑expression and sensitivity of B1
↓Afterload→↑SV
receptors
Drugs (+ Inotropes) →↑Intracellular Calcium in muscle
cells
o Digitalis →↓Na+/K+ pumps →↑Ca++ into the cell
o Dopamine
o Atropine → blocks Ach on M2 receptor
o Dobutamine→↑B1 activity
o Milrinone→↓ PDE→↑CAMP→↑PKA→↑Ca++ entry
o Norepinephrine→↑B1 activity
o Epinephrine→↑B1 activity
o Digoxin→↓Na+/K+ pumps→↑ Na+ in ICF→↓ Na+ in
ECF→↓Na+/Ca++ exchange across muscle cell→↓
Na+ moves into cell→↓Calcium moves out of
cells→↑calcium retained into muscle cell
Ions
o Calcium (Ca++)
 Hypercalcemia
• ↑Calcium in blood and muscle cell→↑cross
bridges→ ↑Contractility
(3) Factors decreasing Contractility – negative
inotropic agents
Figure 7. Effect of Afterload on PV loops [cvphysiology.com]
Drugs (-Inotropes)
o Beta Blockers→↓B1 activity→↓intracellular (3) Factors increasing Afterload
calcium→↓contraction ↑Vascular resistance in Systemic Circulation
 Ex. Metoprolol, atenolol, propranolol Diastolic Hypertension→↑afterload
o Calcium Channels blockers→ ↓influx of calcium into Atherosclerosis→↑resistance to blood flow→↑afterload
muscle cells→ ↓intracellular calcium→ ↓contractility Drugs that vasoconstrict vessels (acting on arterials)
4 of 6 CARDIOVASCULAR PHYSIOLOGY: Note #1. Cardiac Output – Frank Starling’s law
 o Phenylephrine→↑alpha 1 activity→↑resistance to
blood flow→↑afterload ↑Contractility→↑ SV→↑ CO
o Norepinephrine and epinephrine→↑alpha 1 ↓Contractility→↓SV→↓CO
activity→↑resistance to blood flow→↑afterload
Aortic valve Stenosis ↑Afterload→↓SV→↓CO
o More resistance against a stiff and sclerotic
↓Afterload→↑SV→↑CO
valve→↑resistance to blood flow→↑afterload
Increased Vascular resistance in Pulmonary Circulation
o Pulmonary Hypertension V) REVIEW QUESTIONS
 Various causes (Lung disease, Heart failure,
Pulmonary embolism, idiopathic) Cardiac Output is equal to:
 ↑resistance to blood flow out of RV→↑resistance a. 5 L/min
to blood flow into→ pulmonary trunk b. 5000 L/min
o Pulmonary valve stenosis c. 10 L/min
 More resistance against a stiff and sclerotic valve d. 2.5 L/min
 ↑resistance to blood flow out of RV→↑resistance
to blood flow into→ pulmonary trunk Which of the following isn’t a positive chronotropic
agent?
(4) Factors decreasing Afterload a. SNS
Decreased Vascular Resistance b. Hyperkalemia
Drugs that Vasodilate vessels c. ↑pCO2
o ACE-Inhibitors→↓AT-II formation→↓vasoconstriction d. Atrial Bainbridge reflex
o Angiotensin II receptor blockers block AT-
II→↓vasoconstriction Thyroid hormone is a
o Hydralazine & Isosorbide Dinitrate→↑Nitric oxide in a. Negative inotropic agent
cells→↑cGMP→↓calcium entry→ relaxes vessels b. Positive chronotropic agent
o Phosphodiesterase Inhibitors → ↑CAMP →↑PKA → c. Negative chronotropic agent
↓calcium entry→ relaxation of vessel wall
EDV is the
Remember: a. Ejection fraction
b. Post-pumping volume
CO=HR X SV c. End Systolic volume
HR is directly proportional to CO
d. Pre-pumping volume
SV= EDV-ESV
SV is dependent on Preload, Contractility and Afterload
SV is directly proportional to CO Which of the following isn’t a factor increasing
preload?
a. Muscular milking activity
b. ↓Return to heart
c. Respiratory pump
d. Venomotor tone

Which of the following drugs is a negative inotropic

agent?
a. Digitalis
b. Atropine
c. Metoprolol
d. Dopamine
e. Dobutamine

Afterload is the
a. amount of resistence that must be overcome in order
for the ventricles to eject blood into the
aorta/pulmonary trunk
b. Strength/Force of Ventricular Contraction
c. Degree of Stretch of ventricular myocardium
d. total volume of blood (ml) pumped out of the
IV) SUMMARY ventricle in one beat

CHECK YOUR ANSWERS

↑Heart rate→↑CO
VI) REFERENCES
↓Heart Rate→↓CO

↑EDV→↑SV→↑CO

↓EDV→↓SV→↓CO

↑ESV→↓SV→↓CO

↓ESV→↑SV→↑CO

↑Preload→↑SV→↑CO

↓Preload→↓SV→↓CO

Cardiac Output – Frank Starling’s law CARDIOVASCULAR PHYSIOLOGY : Note #9. 5 of 6

6 of 6 CARDIOVASCULAR PHYSIOLOGY: Note #1. Cardiac Output – Frank Starling’s law