Pathophysiologic Mechanisms
Heart Failure:
By Janis Carelock
Angela P. Clark,
The same neurohormaonal actions that initially preserve cardiac output subsequently cause functional deterioration. New drug breakthroughs may provide a solution.
For the 4.7 million Americans now living 'with heart failure,' the recent discovery that the same neurohormones that help a
'failing heart also contribute to deteriorat
ing cardiac function could come as stun
ningly bad news. But the treatment of heart failure
is changing as a result. The Food and Drug
Administration (FDA) has already approved at least
one new drug aimed at modifying neurohormonal
effects, and research is ongoing.'
Heart failure remains the only cardiac disorder that is still increasing in incidence and prevalence in the United States;' with the death rate from the condition rising 135% between 1979 and 199$.' More than 500,000 new cases are diagnosed annually,' and experts predict that as many as 20 million people who have an asymptomatic impairment of cardiac function are likely to develop symptoms of heart failure within five years." Heart failure afflicts 10% of the population over age 70 and is the most common diagnosis among patients 65 or older; but
.Janis Carelock is an instructor in r clinical nursing at the University of Texas at AustinSchool r.( Nursing. From March through September of this year, Ms. C:arelork was a paid consultant for the Sc iris Corporation, developing an inpatient nursing protocol fur the use of nesiritude. Angela Clark is an associate professor )fn.rs,ng at the University of Texas at AustinSchool u( Nursing and is a clinical nurse specialist in cardiopulmonary and diabetes r are. Contact author: /amts Carelock. his tractor. the L niv ersity of Texas at Austin .C. haul of Nursing, 1700 Red River. Austin, TX78701; jcareloc .
the condition can arise at any ages And although women constitute slightly more than 50% of the population with heart failure,' they account for only about 20% of subjects in related clinical trials.','
Previously, treatment for heart failure focused on hemodynamic abnormalities, but it was recently discovered that heart failure causes a complex activation of neurohormones.^2 It's now believed that the progressive worsening of heart failure results from these neurohormonal changes, which occur as the body tries to compensate for hemodynamic abnormalities. Remodeling (structural changes in the cardiac myocytes) also occurs, altering the ventricular architecture. These discoveries have revolutionizes' heart failure treatmentb: therapy can now be directed at modifying the neurohormonal milieu? This article will describe some of the current evidence regarding the role of neurohormones in heart failure and discuss the treatments now recommended for delaying progression of the syndrome.
DEFINITION AND COMMON ETIOLOGIES
Heart failure is a complex clinical syndrome that can result from any cardiac or chronic metabolic disorder, such as ischemic heart disease, hypertension, cardiomyapathy, or hyperthyroidism, that impairs the ability of the ventricle to eject blood. It's a pathophysiologic state in which the heart is either unable to pump enough blood at a rate sufficient try
26AJN I December 2'O.)1 4e,1 ': 0' , No 1 2http: // cm
lcardiac output
l
Isystemic blood pressure l perfusion to kidneys
lenirhangiotensinaldosterone
stem activated
angiotensin I
lungs
iin,
angiotensin 11
tangiotensin ll
aldosterone _
• retain sodium and water
• arginine vasopressin
• endothelin
• cytokines
(tumor necrosis factora)
Myocardial dysfunction leads to activation of the reninangiotensinaldosterone and sympathetic nervous systems and the release of neurohormones such as angiotensin II, aldosterone, cytokines, and catecholamines. These neurohormones contribute to the ventricular
remodeling seen in heart failure. Arrows at left of text indicate increases and decreases.
Myocardial
• ischemic heart disease
• hyperthyroidism
• myocardial infarction
• valve disease
• alcohol, cocaine abuse
• hypertension
baroreceptors activated
• left ventricle
• aortic arch
• carotid sinus
vasomotor regulatory centers in medulla stimulated
Sympathetic nervous
system activated
t catectiolamines
(epinephrine and
norepinephrine)
• vasoconstriction t aftertoad
t blood pressure t heart rate
Ventricular
remodel
Vasoconstriction
Remodeled Normal
hypertrophy and dilation of ventricle genetically large cells impaired contractility
hlrp://
AJN v December 2001 v Vol. t O 1, No. 12
Class 1. Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or angina) pain.
Class 11. Patients with cardiac disease resulting in slight limitation of physical activity. They ore comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina) pain.
Class 111. Patients with cardiac disease resulting in marked (imitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or angina) pain.
Class IV. Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the angina) syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
No objective evidence of cardiovascular disease.
Objective evidence of minima) cardiovascular disease.
Objective evidence of moderately severe cardiovascular disease.
Objective evidence of severe cardiovascular
disease.
:" tion u ono ca ..': is
ry>, S .s .. ent" are indepe ndent cat ories. Accordin to the American Heart Associa . .. . . F ncti I:
ate. ,. Functional 'ca p` acity and objectice as e3 m peg ., _ . . e9...pac ty
> th . e r r 'I lesions or n inion as:
estimate of what he tient's heart. W ll allow the tient to do and shoud n of be influenced b . the character of a str cut a op
' f ` X=r ` s echocardi ams =
Y or is.. O b ective assessment ` : , is based .on measurements such as electrocardi fame, Stress tes s, , ay , ogra ,
to treatmen :.prognos1. j I°$
i I im es." x::
. and radical r
olof
ag
of t
' he heart.
1 ificatio h of functional ca i ' and objective assessment of tients with diseases
Source: American Heart Association. 1494 revisions to c ass o pac ty j
AHA medical/scientific statement. 1994. Reprinted with permission.
meet the metabolic needs of the body or can do so only with an elevated filling pressure. Although heart failure may be associated with newonset, acute changes in the heart (such as those caused by a severe myocardial infarction), it more commonly results from chronic, progressive changes as pumping ability declines. Currently, systolic and diastolic heart failure are the most accurate terms used to describe the condition. In general, the syndrome of heart failure occurs either because there is difficulty emptying the left ventricle (systolic dysfunction), which implies impairment of myocardial contractility, or because it is unable to fill and relax the left ventricle sufficiently to accommodate an adequate amount of oxygenated blood returning from the lungs (diastolic dysfunction)." Many clinicians continue to use the term congestive heart failure, but heart failure is more accurate because pulmonary congestion may not be present.' Stevenson reports chat about 80% of patients with chronic heart failure who are hospitalized with an exacerbation do not have rales.'°
Conditions that cause some type of ischemia to the heart muscle account for approximately two thirds of all cases of left ventricular systolic dysfunction.' Coronary artery disease and hypertension are the most common contributing factors in the development of heart failure; effective treatment of these conditions, along with smoking cessation, can decrease the risk of developing heart failure.' " Conditions that accelerate atherosclerosis, particularly hypertension and diabetes, are major culprits in the eventual development of heart failure. The American Heart Association reports that 75%> of
heart failure cases have antecedent hypertension.' Several clinical trials have shown that controlling hypertension is beneficial in preventing heart failure. For example, the Systolic Hypertension in the Elderly Program (SHED) study found that antihypertensive therapy reduced the risk of developing heart failure by 49%.° And recent clinical trials have proved that early detection of heart failure can delay its progression."
Numerous classification systems have been developed to describe the progression of heart failure and other chronic heart disease. The New York Heart Association (NYHA) Functional Classification, which, though it lacks precision, is still widely used, groups patients with heart failure according to degree of impairment in classes I to 1V; the 1994 revisions added an objective assessment category." A more recent system discussed by Francis and colleagues describes subsets of patients with heart failure more succinctly and comprehensively.' (See New York Heart Association Functional Classification System, above, and Heart Failure Staging System, page 29, for full descriptions.)
DESCRIBING HEART
FAILURE
Describing the syndrome of heart failure brings to mind the parable of the blind men who were shown an elephant. Each man gave a vastly different description of the elephant, depending on where he had touched it: the man who felt the tusk said the elephant was like a ploughshare, whereas the man who felt the foot described the animal as a pillar. Each impression contained some truth but did not yield a complete picture. Similarly, many different
28AJN v December 2001 V Vol. 10 1 , N,) 12 ngcenter.com
30
', Differences Between Systolic and Diastolic Heart Failure 1
Systolic Heart FailureDiastolic Heart Failure
j(Normal Systolic Function)
S3 gallop / S4 gallopTreatment guidelines available; solid evidence base / Treatment guidelines la
Poor prognosis / Prognosis not as grim
large, dilated heart / Small or normal-sized, d
Blood pressure normal or possibly low / Blood pressure elevated
Less common in women than diastolic heart failure / More common in wom
Ejection fraction < 40~o / Ejection fraction normal
Sources: Francis GS, et ol. Pathophysiology and diagnosis of heart failure. In: Fuster V, et al., ed
York: McGraw-Hill; 2001. p. 655-85; Consensus recommendations for the management of chroni
membership of the advisory council to improve outcomes nationwide in heart failure. Am l Cardic
eking; less evidence available
ickened left ventricle
d (systemic hypertension)
en than systolic heart failure
I or near normal >_ 40%
hors. Hurst's the heart. 10th ed. New
heart failure. On behalf of the 1999;8312A1: t A38A.
cles' inability to relax during diastole impairs ventricular filling. Approximately onethird of people with heart failure have diastolic failure only. Recent studies show that women and elderly people are increasingly presenting with diastolic dysfunction (diastolic heart failure) but preserved systolic function?''i
In the past, a diagnosis of heart failure was often based on decreased ejection fraction. But patients with heart failure may have normal ejection fractions and cardiac output, yet still manifest signs of heart failure.' Clinicians now evaluate all of a patient's data for diagnosis, including the medical history, history of the present illness, and the patient's reports. (See Differences Between Systolic and Diastolic Heart Failure, above.)
THE REAL CULPRIT:
NEURONORMONAL RESPONSES
Heart failure should be regarded as a complex process involving continually emerging symptoms and deterioration." The sequence of events in heart failure has been described as daunting, and distinguishing primary from secondary etiologies is difficult."
Myocardial dysfunction initially results from any number of triggers (such as myocardial infarction, valve disease, ox a toxin such as alcohol or cocaine). As the heart starts to fail, the body tries to compensate for the impaired circulation. Three significant events occur during this compensatory process: sympathetic nervous system stimulation leading to an increase in circulating neurohormones, activation of the reninangiotensinaldasterone (RAA) system, and ventricular remodeling. The same compensatory mechanisms that initially preserve cardiac output and blood pressure actually cause progressive deterioration of myocardial function later on.
Sympathetic nervous system stimulation. First, as the heart begins to fail, the decreased cardiac output
AJN v December 2001 v Vol 10 1. No.
and reduced systemic blood pressure activate baroreceptors in several placesthe left ventricle, the aortic arch, and the carotid sinuseswhich then stimulate the vasomotor regulatory centers in the medulla. The net effect is activation of the sympathetic nervous system with a resulting increase in circulating catecholamines (a type of neurohormone). These catecholamines cause vasoconstriction, increase the heart rate, and directly affect the heart muscle cells (cardiac myocytes), resulting in ventricular remodeling and hypertrophy, increased myocardial oxygen consumption, and myocardial necrosis; all of these advance heart failure over time. Both sympathetic nervous system stimulation and elevated levels of catecholamines can trigger arrhythmias and sudden death.'
Reninangiotensinoldosterone activation. Second, as perfusion to the kidneys is decreased, the RAA system is activated, raising the levels of angiotensin II and aldosterone.^18 Aldosterone levels in patients with heart failure can reach 20 times the normal level.' Higher than normal levels of both angiotensin II and aldosterone will adversely affect the heart over time. Angiotensin II, a potent vasoconstrictor, increases blood pressure and afterload; aldosterone causes the retention of sodium and water. In addition to these systemic effects, these compensatory neurohormones trigger structural changes in cardiac myocytes (a process called ventricular remodeling, discussed below)," as well as electrical instability. Other neuroharmones that contribute to progressive heart failure include arginine vasopressin, endothelia, and cytokines such as tumor necrosis factora.9
Ventricular remodeling is now thought to begin long before clinical evidence of heart failure appears! Remodeling essentially involves hypertrophy of the myocytes, yielding large, genetically abnormal cells that cannot contract as efficiently as
hnp://
Long-term Detrimental Neurohormonal Effects / on Heart FailureNeurohormone Long-Term Effects / Drugs that Counter these Effects
(partial list)
V
Aldosterone Promotes sodium retention / Angiotensin-converting enzyme-V
Prevents the uptake of norepinephrine by the myocordium / (ACE) inhibitors'
Induces parasympathetic inhibition / captopril
Promotes the release of cytokines and growth factors / enalapril
Causes progressive remodeling of the heart and vasculature / lisinopril
Induces myocardial and vascular fibrosis / quinapril
Produces baroreceptor dysfunction / fosinopril
May be directly orrhythmogenic / Angiotensin 11 receptor blockers*
losartan
valsortan
Aldosterone receptor Mockers
spironoloctone
Angiotensin II Causes vasoconstriction / ACE inhibitors'
Increases afterload / (same as above)
Leads to cardiac myocyte toxicity / Angiotensin I) receptor blockers*
Causes progressive remodeling of the heart and vasculature / (same as above)
Aldosterone receptor blockers
p / (some as above)
Epinephrine, Increases afterload through peripheral vasoconstriction / (3-blockers'
norepinephrine Impairs sodium excretion by kidneys / bisoprolol
Raises myocardial oxygen consumption / metoprolol succinate (Toprol-XL)
Causes progressive remodeling of the heart and vosculature / Combination P-bkocker and a-1 Mocker'
Results in loss of cardiac myocytes by apoptosis / carvedilol
Produces arrh hmias _._- / .. __.__
Tumor necrosis factor-a Contributes to skeletal muscle myopathy (cardiac cochexia) / Cytokine inhibitor
Other cytokines that accompanies severe heart failure / (a clinical trial with etonercept is
May contrite to remodeling of the heart and vasculoture / underway; no others approved)
Impairs protein synthesis and accelerates catabolism / _ -
Endothelin Causes vasoconstriction / ACE inhibitors'
Decreases contractility / quinapril
May play a role in myocardial damage after myocardial / Endothelia receptor antagonists
infarction / (animal model success)
Promotes atrial notriuretic peptide, orginine vasopressin,
and aldosterone release
Arginine vasopressin Acts as a potent vasoconstrictor, increasing afterload / Vasopressin antagonists
Leads to hyponatremia / (two vasopressin antagonists are
currently in clinical trials; none yet
approved)
*Proven benefit in reducing morbidity and mortality.
tProven benefit in reducing morbidity and mortality when added to standard therapy.
Sources: Consensus recommendations for the management of chronic heart failure. On behalf of the / membership of the advisory council to improve out-
comes nationwide in heart failure. Am J Cordial 1999;83(2A):1 A-38A ; Ward RP, AndersonAS. Slowing / the progression of CHF. Drug therapy to correct
neurohormon
al
abnormalities.
Postgrad Med
2001;10913):
36-8, 41-5;
Francis GS, et
al.
Pathophysiolo
gy and
diagnosis of
heart failure.
In: Fuster V,
et al.,
of
and
in
editors. Hurst's the heart. 10th ed. New York: McGraw-Hill; 2001. p. 555-85; Pitt B, et al. The effect / mortality
spironolactone on morbidity
patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341(10):709-17.
normal ones." This eventually leads to increased ventricular muscle mass, changes in ventricle shape, and impaired contractility." Despite its larger size, the ventricle becomes a less effective pump, causing increasing chamber wall stress and need for oxygen." Experts believe the most reliable measure of disease progression is assessment of the degree of cardiac remodeling.' Changes in chamber size and geometry can be evaluated by twodimensional ,: hocardiography. .
http: //nursin9cenrer.com
Apoptosis. Impaired myocardial function may also be caused by a decrease in the number or strength of myocytes.^12 This phenomenon, known as apoptosis, may be defined as preprogrammed cell death without inflammation or scarring. =" (Apoptosis is one of the two basic ways that body cells die; the other, necrosis, usually follows a sudden catastrophic event such as myocardial infarction.) In the past it was believed that apoptosis never occurred in the heart, '= but it has recently been
AJN V De=e" be, 200. 1 v ~ ,; , r
found to occur randomly in the ventricles of patients with heart failure and is now recognized as an important cause of cell death in the failing heart.'' Certain neurohormones, such as angiotensin 11 and catecholamines, promote apoptosis; thus administering drugs that antagonize them, such as angiotensinconverting enzyme (ACE) inhibitors and 0adrenergic antagonists, appears beneficial in heart failure treatment."
THE GOOD GUYS: NATRIURETIC PEPTIDES
Atrial and brain natriuretic pep
tides. Although most neurahor
monal responses further the
progression of heart failure, natri
ureticpeptides, natural substances
produced in the body, have been
found beneficial. Two atrial
natriuretic peptide (A NP) and
brain natriureticpeptide (BNP)
are produced primarily by the
heart itself, ANP in the atria, BNP
in the ventricles."2' (The term
brain natriuretic peptide is somewhat misleading; the substance was so named because it was first identified in the porcine brain.)" Various neurohormones, including endothelia and catecholamines, prompt ANP secretion; its release is mainly triggered by increased atrial wall tension such as that caused by increased intravascular volume. The ventricles secrete BNP in response to increased ventricular pressure and the myocardial stretching that occurs with heart failure.