Pathophysio of Heart Failure Cvphysio.com

8/22/2019 Pathophysio of Heart Failure Cvphysio.com

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Pathophysiology of Heart Failure

The pathophysiology of heart failure involves changes in

cardiac function

neurohumoral status

systemic vascular function

blood volume

integration of cardiac and vascular changes

Cardiac dysfunction precipitates changes in vascular function, blood volume,

and neurohumoral status. These changes serve as compensatory mechanisms to

help maintain cardiac output (primarily

by the Frank-Starling mechanism) andarterial blood pressure (by systemic

vasoconstriction). However, these

compensatory changes over months

and years can worsen cardiac function.

Therefore, some of the most effective

treatments for chronic heart failure

involve modulating non-cardiac factors

such as arterial and venous pressures

by administering vasodilatorand

diuretic drugs.

Cardiac Function

Overall, the changes in cardiac

function associated with heart failure result in a decrease in cardiac output. This

results from a decline in stroke volumethat is due to systolic dysfunction,

diastolic dysfunction, or a combination of the two. Briefly, systolic dysfunction

results from a loss of intrinsic inotropy (contractility), most likely due to

alterations in signal transduction mechanisms responsible for regulating

inotropy. Systolic dysfunction can also result from the loss of viable, contracting

muscle as occurs following acute myocardial infarction. Diastolic dysfunctionrefers to the diastolic properties of the ventricle and occurs when the ventricle

becomes less compliant (i.e., "stiffer"), which impairs ventricular filling. Both

systolic and diastolic dysfunction result in a higherventricular end-diastolic

pressure, which serves as a compensatory mechanism by utilizing the Frank-

Starling mechanism to augment stroke volume. In some types of heart failure

(e.g., dilated cardiomyopathy), the ventricle dilates aspreload pressures increase

in order to to recruit the Frank-Starling mechanism in an attempt to maintain

normal stroke volumes.

Therapeutic interventions to improve cardiac function in heart failure include the

use ofcardiostimulatory drugs(e.g.,beta-agonists and digitalis) that stimulate
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heart rate and contractility, andvasodilator drugs that reduceventricular

afterload and thereby enhance stroke volume.

Neurohumoral Status

Neurohumoral responses include activation ofsympathetic nerves and therenin-angiotensin system, and increased release ofantidiuretic hormone (vasopressin)

and atrial natriuretic peptide. The net effect of these neurohumoral responses is

to produce arterial vasoconstriction (to help maintain arterial pressure), venous

constriction (to increase venous pressure), and increasedblood volume. In

general, these neurohumoral responses can be viewed as compensatory

mechanisms, but they can also aggravate heart failure by increasing ventricular

afterload (which depresses stroke volume) and increasingpreload to the point

where pulmonary or systemic congestion andedema occur. Therefore, it is

important to understand the pathophysiology of heart failure because it serves as

the rationale for drug therapy.

There is also evidence that other factors such as nitric oxideandendothelin(both

of which are increased in heart failure) may play a role in the pathogenesis of

heart failure.

Some drug treatments for heart failure involve attenuating the neurohumoral

changes. For example, certainbeta-blockershave been shown to provide

significant long-term benefit, quite likely because they block the effects of

excessive sympathetic activation on the heart. Angiotensin-converting enzyme

inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists

are commonly used to treat heart failure by inhibiting the actions of the renin-

angiotensin-aldosterone system.
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Systemic Vascular Function

In order to compensate for reduced cardiac output during heart failure, feedback

mechanisms within the body try to maintain normal arterial pressure by

constricting arterial resistance vessels through activation of the sympathetic

adrenergic nervous system, thereby increasing systemic vascular resistance.Veins are also constricted to elevate venous pressure. Arterial baroreceptors are

important components of this feedback system. Humoral activation, particularly

the renin-angiotensin system and antidiuretic hormone (vasopressin) also

contribute to systemic vasoconstriction.

Heightened sympathetic activity, and increased circulating angiotensin II and

increased vasopressin contribute to an increase in systemic vascular resistance.

Drugs that block some of these mechanisms, such angiotensin-converting

enzyme inhibitors,angiotensin receptor blockers, improve ventricular stroke

volume by reducing afterload on the ventricle. Arterial and venous dilators such

as hydralazine and sodium nitroprussideare also used to reduce afterload on the

ventricle.

Blood Volume

In heart failure, there is a compensatory increase inblood volume that serves to

increase ventricularpreloadand thereby enhance stroke volumeby the Frank-

Starling mechanism. Blood volume is augmented by a number of factors.

Reduced renal perfusion results in decreased urine output and retention of fluid.

Furthermore, a combination of reduced renal perfusion and sympathetic

activation of the kidneys stimulates the release of renin, thereby activating therenin-angiotensin system. This, in turn, enhances aldosterone secretion. There is

also an increase in circulatingarginine vasopressin (antidiuretic hormone) that

contributes to renal retention of water. The final outcome of humoral activation

is an increase in renal reabsorption of sodium and water. The resultant increase

in blood volume helps to maintain cardiac output; however, the increased

volume can be deleterious because it raisesvenous pressures, which can lead to

pulmonary and systemic edema. When edema occurs in the lungs, this can result

in exertional dyspnea (shortness of breath during exertion). Therefore, most

patients in heart failure are treated withdiuretic drugs to reduce blood volume

and venous pressures in order to reduce edema.
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Integration of Cardiac and Vascular Changes

As described above, both systolic and diastolic heart failure lead to changes in

systemic vascular resistance, blood volume, and venous pressures. These

changes can be examined graphically by using cardiac and vascular function

curvesas shown below. The decrease in cardiac performance causes a downwardshift in the slope of the cardiac function curve. This alone would lead to an

increase in right atrial or central venous pressure (point B) as well as a large

decrease in cardiac output. The increase in blood volume and venoconstriction

(decreased venous compliance) causes a parallel shift to the right of the systemic

vascular function curve (point C). Because systemic vascular resistance also

increases, the slope of the vascular function curve shifts downward (point D).

These changes in vascular function, coupled with the downward shift in the

cardiac function curve, result in a large increase in right atrial or central venous

pressure, which helps to partially offset the large decline in cardiac output that

would occur in the absence of the systemic vascular responses. Therefore, the

systemic responses help to compensate for the loss of cardiac performance;

however, this compensation is at the expense of a large increase in venous

pressure that can lead to edemaand at the expense of an increase in systemic

vascular resistance that increases the afterload on the left ventricle, which can

further depress its output.

Measurement of Cardiac Output

Several direct and indirect techniques for measurement ofcardiac output are

available. The thermodilution technique uses a special thermistor-tipped catheter

(Swan-Ganz catheter) that is inserted from a peripheral vein into the pulmonary

artery. A cold saline solution of known temperature and volume is injected into the

right atrium from a proximal catheter port. The injectate mixes with the blood as it

passes through the ventricle and into the pulmonary artery, thus cooling the blood.

The blood temperature is measured by a thermistor at the catheter tip, which lies

within the pulmonary artery, and a computer is used to acquire the thermodilution

profile; that is, the computer quantifies the change in blood temperature as it flows

over the thermistor surface. The cardiac output computer then calculates flow (cardiac

output from the right ventricle) using the blood temperature information, and the

temperature and volume of the injectate. The injection is normally repeated a few

times and the cardiac output averaged. Becausecardiac output changes with

respiration, it is important inject the saline at a consistent time point during therespiratory cycle. In normal practice this is done at the end of expiration.
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Echocardiographic techniques and radionuclide imaging techniques can be used to

estimate real-time changes in ventricular dimensions, thus computing stroke volume,

which when multiplied by heart rate, gives cardiac output.

An old technique based on theFick Principlecan be used to compute cardiac output

(CO) indirectly from whole body oxygen consumption (VO2) and the mixed venous(O2ven) and arterial oxygen contents (O2art); however, this technique is seldom used.

The CO is calculated as follows:

CO = VO2/(O2art O2ven)

To calculate CO, the oxygen contents of arterial and venous blood samples are

measured, and at the same time, whole body oxygen consumption is measured by

analyzing expired air. The blood contents of oxygen are expressed as ml O2/ml blood,

and the VO2 is expressed in units of ml O2/min. If O2art and O2ven contents are 0.2 ml

and 0.15 ml O2/ml blood, respectively, and VO2 is 250 ml O2/minute, then CO = 5000ml/min, or 5 L/min. Ventricular stroke volume would simply be the cardiac output

divided by the heart rate.

Control of Heart Rate

Heart rate is normally determined by the pacemaker activity of the sinoatrial

node (SA node) located in the posterior wall of the right atrium. The SA node

exhibits automaticity that is determined by spontaneous changes in Ca++, Na+,

and K+ conductances. This intrinsic automaticity, if left unmodified by

neurohumoral factors, exhibits a spontaneous firing rate of 100-115 beats/min.

This intrinsic firing rate decreases with age.

Heart rate is decreased below the intrinsic rate primarily by activation of the

vagus nerve innervating the SA node. Normally, at rest, there is significant vagal

tone on the SA node so that the resting heart rate is between 60 and 80

beats/min. This vagal influence can be demonstrated by administration of

atropine, a muscarinic receptor antagonist, which leads to a 20-40 beats/min

increase in heart rate depending upon the initial level of vagal tone.

For heart rate to increase above the intrinsic rate, there is both a withdrawal of

vagal tone and an activation ofsympathetic nerves innervating the SA node. Thisreciprocal change in sympathetic and parasympathetic activity permits heart rate

to increase during exercise, for example.

Heart rate is also modified by circulatingcatecholamines acting via1-

adrenoceptorslocated on SA nodal cells. Heart rate is also modified by changes

in circulating thyroxin (thyrotoxicosis causes tachycardia) and by changes in

body core temperature (hyperthermia increases heart rate).

SA nodal dysfunction can lead to sinus bradycardia, sinus tachycardia, orsick-

sinus syndrome.

The maximal heart rate that can be achieved in an individual is estimated by
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Maximal Heart Rate 220 beats/min age in years

Therefore a 20-year-old person will have a maximal heart rate of about 200

beats/min, and this will decrease to about 170 beats/min when the person is 50

years of age. This maximal heart rate is genetically determined and cannot be

modified by exercise training or by external factors.

Regulation of Stroke Volume

Ventricular stroke volume (SV) is the difference between the ventricularend-

diastolic volume (EDV)and the end-systolic volume (ESV). The EDV is the

filled volume of the ventricle prior to contraction and the ESV is the residual

volume of blood remaining in the ventricle after ejection. In a typical heart, the

EDV is about 120 ml of blood and the ESV about 50 ml of blood. The difference

in these two volumes, 70 ml, represents the SV. Therefore, any factor that alterseither the EDV or the ESV will change SV.

SV = EDV - ESV

For example, an increase in EDV

increases SV, whereas an increase in

ESV decreases SV.

There are three primary mechanisms

that regulate EDV and ESV, andtherefore SV.

Preload

Changes inpreload affect the SV through the Frank-Starling mechanism.

Briefly, an increase in venous return to the heart increases the filled volume

(EDV) of the ventricle, which stretches the muscle fibers thereby increasing their

preload. This leads to an increase in the force of ventricular contraction and

enables the heart to eject the additional blood that was returned to it. Therefore,

an increase in EDV results in an increase in SV. Conversely, a decrease in

venous return and EDV leads to a decrease in SV by this mechanism.
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Afterload

Afterload is related to the pressure that the ventricle must generate in order to

eject blood into the aorta. Changes in afterload affect the ability of the ventricle

to eject blood and thereby alter ESV and SV. For example, an increase in

afterload (e.g., increased aortic pressure) decreases SV, and causes ESV toincrease. Conversely, a decrease in afterload augments SV and decreases ESV.

It is important to note, however, that the SV in a normal, non-diseased ventricle

is not strongly influenced by afterload. In contrast, the SV of hearts that are

failing are very sensitive to changes in afterload.

Inotropy

Changes in ventricularinotropy(contractility) alter the rate of ventricular

pressure development, thereby affecting ESV and SV. For example, an increase

in inotropy (e.g., produced by sympathetic activation of the heart) increases SV

and decreases ESV. Conversely, a decrease in inotropy (e.g.,heart failure)reduces SV and increases ESV.

It is important to note that the effects of changes in EDV and ESV on SV are not

independent. For example, an increase in ESV usually results in a compensatory

increase in EDV. Furthermore, if SV is increased by increasing EDV, this can

lead to a small increase in ESV because of the influence of increased afterload

on ESV caused by an increase in aortic pressure. Therefore, while the primary

effect of a change in preload, afterload or inotropy may be on either EDV or

ESV, secondary changes can occur that can partially compensate for the initial

change in SV. For a more detailed description of these interactions, see the web

pages describingpreload,afterload, orinotropy.

Systolic Dysfunction
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Systolic dysfunction refers to impaired ventricular contraction. In chronic heart

failure, this is most likely due to changes in thesignal transduction mechanisms

regulating cardiac excitation-contraction coupling. The loss of cardiacinotropy

(i.e., decreased contractility) causes a downward shift in theFrank-Starling curve

(Figure 1). This results in a decrease in stroke volume and a compensatory rise in

preload (often measured as ventricularend-diastolic pressure orpulmonarycapillary wedge pressure). The rise in preload is considered compensatory

because it activates the Frank-Starling mechanism to help maintain stroke

volume despite the loss of inotropy. If preload did not rise, the decline in stroke

volume would be even greater for a given loss of inotropy. Depending upon the

precipitating cause of the heart failure, there will be ventricular hypertrophy,

dilation, or a combination of the two.

The effects of a loss of intrinsic inotropy on stroke volume, and end-diastolic

and end-systolic volumes, are best depicted using ventricularpressure-volume

loops (Figure 2). Loss of intrinsic inotropy decreases the slope of the end-

systolic pressure-volume relationship (ESPVR). This leads to an increase in end-

systolic volume. There is also an increase in end-diastolic volume (compensatory

increase in preload), but this increase is not as great as the increase in end-

systolic volume. Therefore, the net effect is a decrease in stroke volume (shown

as a decrease in the width of the pressure-volume loop). Because stroke volume

decreases and end-diastolic volume increases, there is a substantial reduction in

ejection fraction (EF).Stroke work(area within loop) is also decreased.
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The force-velocity relationship provides insight as to why a loss of contractility

causes a reduction in stroke volume (Figure 3). Briefly, at any givenpreload and

afterload, a loss of inotropy

results in a decrease in the

shortening velocity of cardiac

fibers. Because there is only afinite period of time available for

ejection, a reduced velocity of

ejection results in less blood

ejected per stroke. The residual

volume of blood within the

ventricle is increased (increased

end-systolic volume) because

less blood is ejected.

The reason for preload rising as

inotropy declines is that theincreased end-systolic volume is added to the normal venous return filling the

ventricle. For example, if end-systolic volume is normally 50 ml of blood and it

is increased to 80 ml in failure, this extra residual volume is added to the

incoming venous return leading to an increase in end-diastolic volume and

pressure.

An important and deleterious consequence of systolic dysfunction is the rise in

end-diastolic pressure. If the left ventricle is involved, then left atrial and

pulmonary venous pressures will also rise. This can lead topulmonary

congestion and edema. If the right ventricle is in systolic failure, the increase in

end-diastolic pressure will be reflected back into the right atrium and systemic

venous vasculature. This can lead to peripheraledema and ascites.

Treatment for systolic dysfunction involves the use of inotropic drugs, afterload

reducing drugs, venous dilators, and diuretics. Inotropic drugs include digitalis

(commonly used in chronic heart failure) and drugs that stimulate the heart via

beta-adrenoceptor activation orinhibition of cAMP-dependent

phosphodiesterase (used in acute failure). Afterload reducing drugs (e.g., arterial

vasodilators) augment ventricular ejection by increasing the velocity of fiber

shortening (see force-velocity relationship). Venous dilators and diureticsare

used to reduce ventricular preloadand venous pressures (pulmonary

and systemic) rather than

augmenting systolic function

directly.

Diastolic Dysfunction

Ventricular function is highly

dependent uponpreloadas
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demonstrated by the Frank-Starling relationship. Therefore, if ventricular filling

(preload) is impaired, this will lead to a decrease in stroke volume. The term

"diastolic dysfunction" refers to changes in ventricular diastolic properties that

have an adverse effect on stroke volume. About 50% of heart failure patients

have diastolic dysfunction, with or without normal systolic function as

determined by normal ejection fractions.

Ventricular filling (i.e., end-diastolic volume and hence sarcomere length)

depends upon the venous return and thecompliance of the ventricle during

diastole. A reduction in ventricular compliance, as occurs in ventricular

hypertrophy, will result in less ventricular filling (decreased end-diastolic

volume) and a greater end-diastolic pressure (andpulmonary capillary wedge

pressures) as shown to the right by changes in the ventricularpressure-volume

loop. Stroke volume, therefore, will decrease. Depending on the relative change

in stroke volume and end-diastolic volume, there may or may not be a smalldecrease in ejection fraction. Because stroke volume is decreased, there will also

be a decrease in ventricularstroke work.

A second mechanism can also contribute to diastolic dysfunction: impaired

ventricular relaxation (reduced lusitropy). Near the end of the cycle of

excitation-contraction couplingin the myocyte, the sarcoplasmic reticulum

actively sequesters Ca++ so that the concentration of Ca++ in the vicinity of

troponin-C is reduced allowing the Ca++ to leave its binding sites on the

troponin-C and thereby permit disengagement of actin from myosin. This is a

necessary step to achieve rapid and complete relaxation of the myocyte. If this

mechanism is impaired (e.g., by reduced rate of Ca++ uptake by the sarcoplasmic

reticulum), or by other mechanisms that contribute to myocyte relaxation, then

the rate and perhaps the extent of relaxation are decreased. This will reduce the

rate of ventricular filling, particularly during the phase ofrapid filling.

An important and deleterious consequence of diastolic dysfunction is the rise in

end-diastolic pressure. If the left ventricle is involved, then left atrial and

pulmonary venous pressures will also rise. This can lead topulmonary

congestion and edema. If the right ventricle is in diastolic failure, the increase in

end-diastolic pressure will be reflected back into the right atrium and systemic

venous vasculature. This can lead to peripheraledema and ascites. The rise invenous pressures also occur because of an increase in blood volume due to

activation of the renin-angiotensin-aldosterone system, which causes renal

retention of sodium and water. Therefore, diuretic drugs are commonly given to

patients in diastolic failure; however, care must be taken not to reduce blood

volume too much because elevated venous pressures are needed to fill the less

compliance ventricle.
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