the heart as a pump: outline structure of cardiac muscle excitation contraction coupling autonomic...
TRANSCRIPT
The heart as a pump: outline
Structure of cardiac muscle
Excitation contraction coupling
Autonomic effects on the heart
Cardiac Function Curve
Cardiac cycle
Ventricular pressure volume loops
Control of heart rate and stroke volume
Characteristics of cardiac muscle
Branching fibers with gap junctions at intercalated discs.
Electrical syncytium
Aerobic metabolism
Graded contraction
Stretch leads to increased force of contraction
Automaticity & Rhythmicity
Branching muscle fiber
Intercalated disc
Arrows show RBCs
Purkinje Fibers
Ca++ binding to troponin C allows actin and myosin to form a cross bridge
During a myocardial infarction, cardiac troponins are released into the circulation.
Cardiac and skeletal muscle TnC are identical, but cardiac & skeletal muscle TnI
& TnT have different amino acid sequences so they can be differentiated.
Detection of cardiac TNi and TnT in the circulation suggests myocardial damage.
• Tropomyosin blocks myosin binding sites on actin.
• Ca++ binds to troponin C and then Troponin I moves tropomyosin, exposing the myosin binding site on actin.
• Troponin T holds troponin complex to tropomyosin.
Tn-I Tn-T
Tn-C
actin
tropomyosin
Ca++
Pathway for Ca++ entry in myocytes
Sarcolemma (cell membrane)
Sarcomere
Transverse tubule
Sarcoplasmic reticulum stores Ca++
During excitation extracellular Ca++ enters myocytes via transverse tubules
Cytosol
Excitation contraction couplingT-tubule
Extracellular Ca++
Ca++Na+
Ca++
Ca++ stores
Ca++
Ryanodine receptor(SR Ca++ release channel)
Contractile mechanism
AP
200 msec
Ca++ influx contraction
Sarcoplasmic recticulum
SR Ca++ ATPase
Ca++
SERCA = sarcoplasmic reticulum Ca++ ATPase
Ca++-Induced Ca++ Release
L-type Ca++ channel(dihydropyridine receptor)
Sympathetic stimulation of the myocardium increases rate and force of contraction and rate of relaxation
Fo
rce
Time
Sympathetic stimulation
At rest
Sympathetic stimulation increases
Force of contraction (positive inotropic effect)
Rate of relaxation (positive lusitropic effect)
Heart rate (positive chronotropic effect)
Conduction velocity (positive dromotropic effect)
Cellular mechanism of sympathetic effects on myocardium
b1 adrenergic receptor
Ca++
Ca++ stores
Ca++
Ryanodine receptor
Contractile mechanism
Ca++
L-type Ca++ channel
SR Ca++ ATPase
NE
Gs
cAMP
Protein kinases
Adenylate cyclase
Phosphorylation
Norepinephrine inotropic effects act by [Ca++] inside:1) opening of L type Ca++ channels2) Ca++ release from sarcoplasmic reticulumNorepinephrine: activity of SERCA which removes Ca++ from tropinin C ( + lusitropic) & stores more Ca++ in SR for next contraction ( + inotropic)
+
+
+
Phases of cardiac cycle:1. Atrial contraction2. Isovolumetric ventricular contraction3. Rapid ejection4. Slow ejection5. Isovolumetric ventricular relaxation6. Rapid ventricular filling7. Slow ventricular filling
Figures courtesy of R.E. Klabunde, Ph.D.http://www.cvphysiology.com/
Systole = contractionDiastole = relaxation
EDV - ESV = Stroke Volume
Phases of the cardiac cycle
Aortic valve closes
Phases 2,3,4 = Systole
Within the normal range as ventricular muscle is stretched the force of contraction increases.
Preload: the degree to which the myocardium is stretched just before contraction.Preload for the right ventricle is estimated as central venous pressure (CVP) or right atrial pressure.Preload for the left ventricle is estimated as left atrial pressure by measuring PCWP (Pulmonary capillary wedge pressure)
Afterload: the pressure against which blood is ejected from the heart.
Afterload for the right ventricle is pulmonary artery pressure during ejection.
Afterload for the left ventricle is aortic pressure during ejection.
The Frank-Starling Mechanism: stretch (preload) affinity of troponin C for Ca++ force of contraction.An equivalent statement is: EDVV stroke volume
Initial myocardial fiber lengthor EDVV or atrial pressure
Fo
rce
of c
ontr
actio
n o
r S
tro
ke V
olu
me
Cardiac function curve
The cardiac function curve is an expression of the Frank Starling mechanism
CVP is blood pressure at the entrance to the right ventricle
Pulmonary Capillary Wedge Pressure (PCWP) estimates: left atrial pressure = preload for left ventricle left ventricular pressure during diastole
To measure PCWP a catheter is passed from the femoral vein into the right heart and advanced as far as possible into a branch of the pulmonary arteries. Blood flow around the catheter is blocked by inflating a balloon.
In the absence of flow, pressure is the same everywhere in the column of fluid between the tip of the catheter & the left atrium.
Further, when the mitral valve is open during diastole pressure at the catheter estimates left ventricular pressure (also an estimate of preload for the left ventricle).
PCWP is measured in the ICU to monitor cardiac function.
Pulmonary artery
Pressure is measured at the tip of the catheter
Left atrium & ventricle
Pulmonary vein
Venous return & cardiac output are equal except for momentary adjustments. What comes in goes out.
Equality of venous return and cardiac output is the result of
Frank Starling mechanism (intrinsic to the heart)
Autonomic reflexes (extrinsic to the heart; to be discussed in a subsequent lecture)
Venous return is the blood flow at the entrance to the right atrium
End-diastolic ventricular volume
Str
oke
Vol
ume
Cardiac function curve
Systemic vasculature
Venous return
Cardiac output
Heart
The Frank-Starling mechanism maintains equal cardiac output from the left and right heart
For example, when a person lies down blood pooled in the veins in the legs and abdomen shifts to the thorax, increasing CVP and right atrial preload.
As blood shifts to the thorax,CVP increases &SV from rt ventricle > SV from lft ventricle.Within a few heart beats, SV from the lft ventricle increases to equal SV from the rt ventricleBlood shifts to thorax
↑ central venous pressure (CVP)
↑ stroke volume from right ventricle
↑ pulmonary arterial blood flow
↑ left atrial pressure
↑ stroke volume from left ventricle
Recumbency
Preload for right side
Preload for left side
CVP is blood pressure at the entrance to the right ventricle
Any maneuver that causes a change in stroke volume in one ventricle will rapidly result in a parallel change in stroke volume in the other ventricle.
Ejection fraction and contractility
Contractility: a change in stroke volume at any given preload & afterload
Sympathetic stimulation:Positive inotropic effect
Normal
Heart failure:Negative inotropic effect
End-diastolic ventricular volume
Str
oke
Vo
lum
e
Ejection fraction:
EF = SV/EDVV
(stroke volume/end diastolic ventricular volume)
Normal EF = 0.60 or 60%
Vagal stimulation has a small negative inotropic effect.
Changes in contractility
Cardiac function curve
dP/dt, ejection fraction & contractility
Two indices of contractility:
Change in dP/dt; dP/dt = the rate of change of ventricular pressure during ejection at a given end diastolic volume (preload)
Change in EF; EF = SV/EDVV
increased dP/dt = contractility
normal dP/dt
decreased dP/dt = contractility
LV p
ress
ure
, mm
Hg
seconds
120
40
80
0.20 0.600.40
Pressure-volume work & myocardial QO2
RELATIONSHIP BETWEEN CARDIAC OUTPUT AND OXYGEN UPTAKE
R2 = 0.88 for linear regression
0
4
8
12
16
20
0 0.5 1 1.5 2 2.5 3
OXYGEN UPTAKE (QO2)2
CA
RD
IAC
OU
TP
UT,
L/m
in
Three components of cardiac workVolume work related to stroke volumePressure work related to arterial pressure during systoleKinetic work related to velocity of blood during ejectionAt rest:Cardiac work ~ stroke volume x arterial pressureKinetic component negligible(kinetic component increases in strenuous exercise)O2
requirement is greater for pressure work than volume work
Aortic stenosis
resistance
Ventricular pressure
Pressure work
Cardiac QO2 Coronary flow
angina
Ventricular pressure - volume loopA pressure-volume loop shows changes in ventricular volume and pressure during one cardiac cycle
Filling represents passive characteristics of the ventricle.Isometric contraction and ejection represent active force of myocardial contraction
Pre
ssur
e, m
m H
g
Volume, ml
Isometric con
tractionIs
omet
ric
rela
xatio
n
ESV EDV
filling
ejection
Stroke volume
Compliance
Compliance is the change in unit volume of a structure per unit change in pressure.
More compliant structures get bigger for a given increase in pressure, compared to less compliant ones.
Veins are 19 times more compliant than arteries.
The filling of the ventricles is determined partly by their compliance.
In people with chronic heart failure, ventricular compliance decreases, limiting filling and stroke volume.
P
VCompliance
Effect of an increase in preload on PV loop (change in diastolic function)
Stroke volume = end diastolic volume minus end systolic volume
Filling of the ventricle is determined by two factors:
Preload
Ventricular compliance
Pre
ssur
e, m
m H
g
Volume, ml
filling
End systolic volume
End diastolic ventricular volume
If afterload & contractility are constant, an increase in preload increases end diastolic ventricular volume & stroke volume (Frank-Starling mechanism)
Preload is increased by
Atrial contraction
Blood volume
Venous tone
Skeletal muscle pump
Respiratory pump
At constant preload & contractility, an increase in afterload decreases stroke volume (change in systolic function)
An increase in afterload requires more energy to eject blood against the increased arterial pressure so less energy is available for fiber shortening. As a result stroke volume is decreased (end systolic volume is increased).
Pre
ssur
e, m
m H
g
Volume, ml
Ventricular filling
End systolic volume
End diastolic ventricular volume
afterload
An increase in afterload decreases stroke volume so end systolic volume is greater
AP ESV SV
An increase in end systolic volume means stroke volume is decreased.
Volume, ml
Ventricular filling
End diastolic ventricular volume
Pre
ssur
e, m
m H
g
Pre
ssur
e, m
m H
g
End Systolic Volume, ml
End systolic volume
SV
Normally when afterload increases SV is maintained by an increase in contractility
HR*
MAP*
SV
CI*
TPR/100
120
100
40
20
60
80
ExerciseRest
Asterisk indicates statistically significant change
During exercise MAP (afterload) increases with no change in stroke volume. Cardiac contractility must have increased to maintain stroke volume with increased afterload. Cardiac work is increased also.
Cardiac index increased from 3.5 to 4.4 L/min x m2
3 min isometric handgrip exercise
The failing heart may not be able to increase contractility when afterload increases
UpToDate; Pathophysiology of heart failure: Left ventricular pressure-volume relationships. W. S Colucci.
Therapy for heart failure includes agents that lower afterload
SVR = systemic vascular resistance (TPR)
Beta 1 adrenergic stimulation increases stroke volume
Pre
ssur
e, m
m H
g
Volume, ml
Ventricular fillingEnd systolic volume
End diastolic ventricular volumenormal
stimulatedNorepinephrine: contractility end systolic volume stroke volume end systolic pressure
Norepinephrine (in blood & from sympathetic nerves) acts on ventricular b1 adrenergic receptors to increase contractility (positive inotropic effect)
Systolic dysfunction: a decrease in contractility
Pre
ssur
e, m
m H
g
Volume, ml
normal
decrease in stroke volume Filled shape shows smaller
pressure volume loop with systolic dysfunction
contractility
End systolic ventricular volume
stroke volume
ejection
With systolic dysfunction both stroke volume and peak arterial pressure are decreased
Compensation for systolic dysfunction
stroke volume (left ventricle)
left atrial, pulmonary & right atrial pressure
preload
end diastolic ventricular volume
stroke volume
Partial compensation occurs for the initial decrease in stroke volume. The initial decrease in stroke volume results in blood “backing up” on the venous side of the circulation which results in increased venous pressure, preload & stroke volume. Compensation occurs commonly in heart failure, for example.
Pre
ssur
e, m
m H
g
Volume, ml
normal
Initial decrease in stroke volume
Partial compensation: end diastolic volume & stroke volume are increased.
Diastolic function, compliance & relaxation
SERCA = sarcoplasmic reticulum Ca++ ATPase
Compliance is defined as how much the volume of a vessel changes per unit change in pressure:
Changes in the compliance of the heart or blood vessels affect their function.
A decrease in compliance of the ventricles occurs in heart failure due to changes in both active and passive relaxation
Active relaxation refers to the activity of the SERCA transporter that sequesters Ca++ in the sarcoplasmic reticulum during relaxation. This ATP dependent process is inhibited in ischemia, impairing relaxation of the contractile proteins.
Passive relaxation refers to the compliance of the myocardial tissue. Fibrosis or other cardiomyopathies may produce a chronic decrease in compliance
P
VCompliance
Compliance is different from conductance, also abbreviated C. Conductance is the inverse of resistance:
P
FcetanConduc
Diastolic dysfunction
Diastolic dysfunction is due to decreased compliance of the ventricle resulting from impaired active and/or passive relaxation
ventricular compliance
ventricular pressure
filling
end diastolic ventricular volume
stroke volume
cardiac output
Pre
ssur
e, m
m H
g
Volume, ml
compliance
normal
End diastolic ventricular volume
Ventricular pressure
Filling of the ventricle is determined by preload and ventricular compliance
Stroke volume is a function of preload, contractility and afterload
Stroke volume = end diastolic volume minus end systolic volume
Stroke volume
afterload
End systolic volume
Contractility
End diastolic ventricular volume
Preload
Stroke volume
afterload
End systolic volume
Contractility
End diastolic ventricular volume
Preload
Preload drives fillingContractility affects force of contractionAfterload resists ejection
Mean arterial pressure is determined by cardiac output and total peripheral resistance
Since CVP ~ zero, using MAP for the average driving pressure in the circulation, and TPR for total peripheral (systemic) resistance:
R
PF
R
)CVPAP(CO
TPR
MAPCO
TPRCOMAP
Cardiac output, heart rate and stroke volume
CO = HR x SV
CO (cardiac output, ml/min) = heart rate (beats/min) times stroke volume (ml/beat)
HR is regulated primarily by the autonomic nervous system
SV is regulated by the Frank Starling mechanism (intrinsic) and by the autonomic nervous system (extrinsic)
Sympathetic stimulation increases heart rate
Sympathetic activity
Slope of pacemaker potential
Heart rate
Threshold for AP more negative
0
-20
-60
-40
-80
Resting heart rate
Slope
0
-20
-60
-40
-80
Sympathetic stimulation
Slope
Increasing the slope of the pacemaker potential means the action potential for the next beat occurs sooner.
A more negative threshold means less depolarization is needed to elicit an action potential
Parasympathetic effects on heart rate parasympathetic activity
Slope of pacemaker potential
Heart rate
Hyperpolarize resting membrane (more negative)
Normally parasympathetic tone keeps the resting HR lower than the intrinsic HR
The intrinsic HR is the rate in the absence of nerves or hormones
Resting HR = 60 to 70 B/min
Intrinsic HR = 100 B/min
Resting HR0
-20
-60
-40
-80Slope
- - - - Threshold for AP = – 55 mV at rest
0
-20
-60
-40
-80
Parasympathetic stimulation
Slope
Summary of factors regulating heart rate
Sympathetic activity Parasympathetic activity Circulating epinephrine
Heart rate
The HR is set by the balance between sympathetic and parasympathetic tone acting on the SA node.
HR is due to parasympathetic and sympathetic stimulation
HR is due to parasympathetic and sympathetic stimulation
Blood borne epinephrine has a minor effect on HR similar to sympathetic tone
Summary of factors regulating stroke volume
Stroke volume is a determined by preload, contractility and afterload.
Contractility and rate of relaxation of the ventricles are both increased by b1 adrenergic stimulation.
Indices of contractility:Change in dP/dtChange in EF: EDVV
SVEF
Sympathetic activity Preload epinephrine
Contractility
Stroke volume
Force of contraction
Extrinsic Intrinsic
afterload
Effect of sympathetic stimulation on force & duration of contraction
Fo
rce
Time
Sympathetic stimulation
Rest
Sympathetic activity & Parasympathetic activity
Heart rate
As HR increases from 75 to 200 B/min, duration of systole decreases 41%, duration of diastole decreases 74%At HR > 180 B/min, ventricular filling is compromised.Tachycardia > 180 B/min may limit cardiac output.
Autonomic effects on ventricular myocardium
Sympathetic stimulation: Force of contraction (positive inotropic effect) Rate of relaxation (positive lusitropic effect) Conduction velocity (positive dromotropic effect)
Parasympathetic stimulation: conduction velocity in the AV node (negative dromotropic effect) Ventricular contractility (negative inotropic effect, weak effect compared to sympathetic stimulation of contractility).
Terms relating to cardiac function:
Chronotropic: affecting heart rate
Dromotropic: affecting conduction velocity
Inotropic: affecting contractility
Lusitropic: affecting rate of relaxation
Natriuretic peptides
The heart synthesizes and secretes peptide hormones in response to increased stretch of the cardiac chambers.These hormones act to increase urinary Na+ excretion.
Cardiac natriuretic hormones:
Atrial Natriuretic peptide (ANP): 28 amino acid peptide secreted from the atria
in healthy people in response to increased NaCl intake or blood volume.
B – type Natriuretic Peptide (BNP): secreted from ventricles in heart failure.
Increasing plasma BNP concentration correlates with worsening cardiac
function. BNP can be measured rapidly at the bedside:
to assist in differential diagnosis of dyspnea &
as an indication of the degree of heart failure.
C-type Natriuretic Peptide: secreted by vascular endothelial cells.
ANP was originally called ANF (atrial natriuretic factor)BNP is also called brain natriuretic peptide because it was first found in the CNS.
After cardiac transplantation the heart adapts to exercise by increasing SV
exercise exercise
QO2
Cardiac output
Heart Rate
Stroke Volume
Normal Cardiac Transplant
Normally the increase in CO with exercise is mostly due to increased HR. After
transplantation (which denervates the heart) increased SV due to the Frank
Starling mechanism maintains CO with exercise.
Effect of age on cardiac function
Problem of separating effects of aging from disease & cumulative injury
Aortic compliance resistance to ejection systolic pressure
Number of myocytes compensatory hypertrophy
Ventricular active & passive relaxation
Maximal heart rate
These changes contribute to decreased maximal oxygen consumption and exercise capacity with age.
The effects of aging can be ameliorated by exercise.