The heart as a pump: outline Structure of cardiac muscle Excitation contraction coupling Autonomic...

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


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


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


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


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


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


Preload

Stroke volume

afterload

End systolic volume

Contractility


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


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


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.

The heart as a pump: outline Structure of cardiac muscle Excitation contraction coupling Autonomic...

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