13 The risk of developing HF was six times greater in hypertensive versus
The terms contractility and inotropic state are used synonymously to describe the
myocardium’s ability to develop force and shorten its fibers independent of preload
or afterload. Myocardial contractility is decreased when myocardial fibers are
diminished or poorly functioning as may occur in patients with primary
cardiomyopathy, valvular heart disease, CAD, or after a myocardial infarction (MI).
Defects in contractility play a major role in systolic HF, but are not a factor for
diastolic dysfunction. Drugs such as β-adrenergic blockers or anthracyclines
precipitate HF by decreasing myocardial contractility.
An increased HR is a reflex mechanism to improve CO as EF declines. The
sympathetic nervous system is the major mediator of this response. The workload and
energy demands of a rapid HR ultimately place strain on the heart and can eventually
When the heart begins to fail, the body activates several complex compensatory
mechanisms in an attempt to maintain CO and oxygenation. These include increased
sympathetic tone, activation of the renin–angiotensin–aldosterone system (RAAS),
sodium and water retention, and other neurohormonal adaptations, which lead to
cardiac “remodeling” (ventricular dilatation, cardiac hypertrophy, and changes in LV
shape). The consequences of these adaptive mechanisms can create more harm than
good (Fig. 14-2). The relative balance of each of these adaptive processes varies
depending on the type of HF (systolic versus diastolic dysfunction) and from patient
to patient with the same disorder. An understanding of the potential benefits and
adverse consequences of these compensatory mechanisms is essential to
understanding the signs, symptoms, and treatment of HF.
SYMPATHETIC (ADRENERGIC) NERVOUS SYSTEM
The body’s normal physiologic response to a decreased CO is generalized activation
of the adrenergic (sympathetic) nervous system as evidenced by increased circulating
levels of norepinephrine (NE) and other catecholamines. The inotropic (increased
and myocardium. Adverse consequences of NE activation include impaired sodium
excretion by the kidneys, restricted ability of the coronary arteries to supply blood to
the ventricle (myocardial ischemia), increased arrhythmias, hypokalemia, and
oxidative stress triggering cell death (apoptosis).
Chronic high levels of catecholamines are harmful to the heart because they
-receptor sensitivity and reduce β1
-receptor density on the surface of
myocardial cells by 60% to 70% in severe HF.
receptors in the heart is ˜80:20. As a response to overstimulation, this balance is
shifted to a ratio of ˜70:30 in the failing myocardium by downregulation of β1
subtype receptors. This selective downregulation of β1
-receptor activity,” whereby the number of β2
is unchanged but the responsiveness of these receptors can be reduced by 30%.
Over time, this leaves the myocyte less responsive to adrenergic stimuli and further
decreases contractile function. β-Blockers cause the upregulation of the
receptors and, the re-sensitization of the uncoupled β2
protecting the heart from the deleterious effects of catecholamines.
Alterations in sympathetic adrenergic receptors are partially determined by genetic
phenotype. Among African American patients with HF, a disproportionately high
incidence of polymorphisms for variants of the β1
-receptor that are associated with
increased function is seen. Additionally, the combined presence of a variant of the
-receptor (β1Arg389) and α2C-adrenergic receptor (α2cDel322–325) results in
adrenergic overstimulation and increases the risk of HF. These combined defects are
found less often in whites, perhaps partially explaining a higher incidence of HF in
African Americans. A better understanding of α- and β-receptor phenotypes may
someday lead to improved prevention and treatment of HF.
RENAL FUNCTION AND THE RENIN–ANGIOTENSIN–ALDOSTERONE
The reduced CO in HF leads to the stimulation angiotensin II, which is a potent
vasoconstrictor. Angiotensin II is also a potent stimulator of the sympathetic nervous
system, which increases SVR. Renal vascular resistance is increased, and the
glomerular filtration rate (GFR) is decreased. As the GFR decreases, more sodium
and water are reabsorbed. A diminished effective circulating plasma volume and
angiotensin II also stimulate release of antidiuretic hormone (ADH) from the
pituitary, resulting in the retention of free water in the collecting ducts.
ADH, antidiuretic hormone; CO, cardiac output; HR, heart rate; H2O, water; Na
angiotensin–aldosterone system; SNS, sympathetic nervous system; SV, stroke volume.
The kidney releases renin when renal perfusion pressure is decreased. Renin
converts angiotensinogen into angiotensin I. Angiotensin I is metabolized to
angiotensin II, under the influence of angiotensin-converting enzyme (ACE) (Fig. 14-
2). Angiotensin II has multiple effects favoring sodium and water retention. Its
vasoconstricting effect decreases GFR, and it stimulates the adrenal glands to secrete
aldosterone, which increases sodium reabsorption. Angiotensin II stimulates
increased synthesis and release of vasopressin, thereby increasing free water
retention and stimulation of thirst centers in the CNS. Finally, angiotensin II
stimulates NE release. The net result of decreased renal perfusion is detrimental.
Increased sodium and water retention increase preload, whereas angiotensin II–
induced vasoconstriction increases SVR and afterload.
A chronic excess of aldosterone causes fibrosis in the myocardium, kidneys, and
23 Thus, aldosterone promotes remodeling of organs and fibrosis
independent of angiotensin II.
Several other regulatory hormones and cytokines have been identified as playing a
role in the pathogenesis and adaptation to HF. The first of these are the
24,25 Endothelin-1 (ET-1) is the most active. ET-1 is synthesized by
vascular and airway smooth muscle, cardiomyocytes, leukocytes, and macrophages.
Serum concentrations of ET-1 are elevated in HF, pulmonary HTN, MI, ischemia,
and shock, and cause vasoconstriction, potentiation of cardiac remodeling, and
decreased renal blood flow (RBF). Although the effects of ET-1 are detrimental in
HF, its pharmacology is complex and dependent on the relative balance of two
distinct G protein–coupled receptor subtypes referred to as ETA and ETB. As
illustrated in Table 14-2, ET-1 can elicit opposing effects from each receptor, with
the net effect being dependent on the relative density of the two receptors.
Possible future therapeutic agents could be specific inhibitors of one or more of
the enzymes to prevent activation of ET-1. Alternatively, selective inhibitors of ET A
receptors could shift responses toward the favorable aspects of ETB receptor
activation. Bosentan and tezosentan are nonselective dual ETA/ETB antagonists.
Bosentan has U.S. Food and Drug Administration (FDA) approval for the treatment
of pulmonary HTN and is being investigated for use in HF.
Natriuretic peptides (NPs) are a family of peptides containing a common 17–amino
acid ring. A-type natriuretic peptide, previously referred to as atrial natriuretic
peptide or atrial natriuretic factor, is secreted by the atria in response to dilatation.
Similarly, B-type natriuretic peptide (BNP) is produced by the ventricular
myocardium in response to elevations of end-diastolic pressure and volume. Type-C
natriuretic peptide (CNP) is secreted by lung, kidney, and vascular endothelium in
response to shear stress. Collectively, the NPs are considered to be a favorable form
of neurohormonal activation. Among their positive attributes are antagonism of the
renin–angiotensin system, inhibition of sympathetic outflow, and ET-1 antagonism.
The net effect is peripheral and coronary vasodilation decreasing preload and
afterload. As their name implies, they also have diuretic or natriuretic properties,
with improved RBF and glomerular filtration resulting from afferent arteriolar
dilation and possibly efferent arteriolar constriction. Sodium reabsorption is blocked
in the collecting duct due to indirect aldosterone inhibition. NPs also inhibit
vasopressin secretion and block salt appetite and thirst centers in the CNS which
contributes to diuresis. CNP has minimal diuretic properties.
The BNP precursor is cleaved to produce the biologically active C-terminal
fragment (BNP) and an inactive N-terminal fragment (NT-proBNP). Plasma level
measurement of either BNP or NT-proBNP can be used as a biologic marker to
differentiate HF-induced dyspnea from other causes of respiratory distress.
levels less than 100 pg/mL usually indicate absence of HF, whereas levels greater
than 400 pg/mL are highly indicative of HF. However, the interpretation of BNP
levels between 100 and 400 pg/mL can be challenging because elevated levels are
also associated with renal failure, pulmonary embolism, pulmonary HTN, and
30 Higher concentrations correlate with the severity of HF. Clinical
resolution of symptoms is often accompanied by a decline in BNP concentration.
Natriuretic hormone analogs or inhibitors of their metabolism have been
investigated for drug therapy of HF. Nesiritide is a recombinantly produced human
BNP approved by the FDA for IV management of acute HF exacerbations in
31,32 Downregulation of NP receptors, however, occurs during
chronic HF, reducing the protective benefit of their actions and possibly limiting their
usefulness as therapeutic entities.
Vasopressin Receptor Antagonists
Volume overload is associated with increased hospitalization. The potent
vasoconstrictor ADH (arginine vasopressin) is inappropriately elevated in HF. Early
studies with tolvaptan (selective vasopressin subtype V2 receptor antagonist)
demonstrated improvement in congestive symptoms of HF and overall hemodynamic
profile but no improvement in long-term outcome.
Biologic Effects of Endothelin-1
Organ System ETA Receptor Effects ETB Receptor Effects Other Effects
Blood vessels Potent vasoconstrictor Vasodilation mediated
rate; RBF, renal blood flow; +/–, positive/negative.
The EVEREST trial studied the efficacy of vasopressin antagonism in HF.
Tolvaptan was evaluated in 4,133 patients with acute decompensated heart failure
(ADHF) with NYHA class III or IV and LVEF of less than 40%. All patients also
received standard therapy (ACE inhibitors [ACEIs], angiotensin receptor blockers
[ARBs], β-blockers, diuretics, nitrates, and hydralazine). The patients were
randomly assigned within 48 hours of hospitalization to 30 mg/day tolvaptan or
placebo. The trial was a composite of three distinct analyses. The primary end point
for the two identical short-term trials was to assess the change in global clinical
status and body weight at day 7 or the day of discharge. The primary outcome for the
long-term trial was all-cause mortality and cardiovascular (CV) death or HF
hospitalizations. The results of the short-term trial showed modest improvement in
the global clinical score compared with placebo. The main clinical benefit was
change in body weight. The long-term trial failed to show any significant difference
between the study drug and placebo in the primary end points. Common side effects
of tolvaptan were dry mouth and thirst. In a small number of patients, hyponatremia
was corrected. Because long-term mortality benefits are lacking and the cost of the
drug is high, the use of tolvaptan is restricted to patients with hypervolemic
hyponatremia associated with HF despite fluid restriction and diuretic use.
Calcium sensitizers represent another class of drugs investigated for the treatment of
ADHF. They exert positive inotropic effects by stabilizing the calcium–troponin C
complex and facilitating actin–myosin cross-bridging without increasing myocardial
consumption of adenosine triphosphate.
36 Levosimendan, the prototype for this drug
class, has a dual mechanism of action to increase myocardial contractibility and
induce vasodilation. Unlike other inotropic agents, it does not affect the intracellular
calcium concentrations and, therefore, has a lower potential for proarrhythmia. The
decompensated HF, levosimendan significantly reduced the incidence of worsening
HF and improved hemodynamic indices.
In addition, mortality was lower in the
levosimendan group. These trials, however, were not powered to show a difference
in mortality as an end point. A subsequent trial comparing levosimendan with
dobutamine in ADHF, designed to confirm the beneficial effects on morbidity and
mortality, did not reduce all-cause mortality, which contrasts with earlier studies.
The most common adverse effects associated with levosimendan are headache and
hypotension. Currently, levosimendan is approved in Europe for ADHF.
Inflammatory Cytokines, Interleukins, Tissue Necrosis Factor, Prostacyclin, and
Vascular endothelial cells release pro-inflammatory cytokines, vasodilator and
vasoconstrictor substances, including interleukin cytokines (IL-1β, IL-2, IL-6), tumor
necrosis factor (TNF-α), prostacyclin, and nitric oxide (NO; also known as
endothelium-derived relaxing factor).
41–43 The role of these mediators in the
pathogenesis of HF is unclear. Recent studies have shown that patients with HF have
elevated levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α that
correlate with the severity of disease.
Initial enthusiasm for use of the TNF-α
receptor antagonist etanercept as a treatment for HF has been abandoned after
disappointing results in trials.
46 At least 47 adverse event reports were made to the
FDA describing new-onset HF or exacerbation of existing HF with etanercept and
infliximab in patients being treated for either Crohn’s disease or rheumatoid
Other investigators have tried using either NO or prostacyclin (epoprostenol) as
vasodilators with mixed success.
48–50 There was a trend toward increased death rates
with prostacyclin despite improved hemodynamic status during the Flolan
International Randomized Survival Trial (FIRST).
Progression of HF results in cardiac remodeling, characterized by changes in the
shape and mass of the ventricles.
51 The three primary manifestations of cardiac
remodeling are chamber dilatation, LV myocardial hypertrophy, and a resulting
spherical shape of the LV (Fig. 14-3). Cardiac remodeling, which starts before the
appearance of clinical symptoms, contributes to the progression of the disease.
Cardiac dilatation results from hypervolemia. End-diastolic volume increases,
myocardial fibers are stretched, and the ventricle(s) become dilated. In the healthy
heart, the end-diastolic volume is 110 to 120 mL. With an EF of 60%, the SV would
be 70 mL, leaving an end-systolic residual volume in the ventricle of 40 to 50 mL.
With HFrEF, the end-diastolic volume increases resulting in an enlarged heart.
Cardiac dilatation is less evident in HFpEF because normal contractility is
maintained and the stiffened LV is resistant to filling and less likely to dilate (Fig.
The Frank–Starling curve (Fig. 14-4) demonstrates a curvilinear relationship
between LV myocardial muscle fiber “stretch” (wall tension) and myocardial work.
As stretch increases, the volume of blood ejected (SV) with each contraction
increases. In systolic HF, the work capacity for any degree of stretch is diminished.
A simple analogy is drawn using a balloon. The greater amount of air blown into a
balloon, the more it stretches and, if released, the farther it flies around a room. As
the balloon gets old, it loses its elasticity and thus has less recoil. Similarly,
dilatation of the ventricles initially may serve as an effective compensating
mechanism in systolic failure, but becomes inadequate as the elastic limits of the
muscle fibers are reached. HR also increases to maintain CO when SV is low. The
disadvantage of cardiac dilatation is increased myocardial oxygen demand.
Theoretically, as cardiac dilatation progresses beyond a certain point, CO could
decrease (as visualized on the descending limb of the Starling curve), but this is
Cardiac hypertrophy represents an absolute increase in myocardial muscle mass and
muscle wall thickness (Fig. 14-3). This is analogous to increased skeletal muscle
mass in response to weightlifting. Cardiac hypertrophy should not be confused with
FUNCTIONAL LIMITATION CLASSIFICATION AND STAGES OF HEART
New York Heart Association Classification
The NYHA classification scheme identifies four categories of functional disability
associated with HF. Patients in class I are well compensated with no physical
limitations and lack symptoms with ordinary physical activity. In class II, ordinary
physical activity results in mild symptoms and imparts slight limitations on exercise
tolerance. Patients in class III are comfortable only at rest; even less than ordinary
physical activity leads to symptoms. In class IV, symptoms of HF are present at rest
and no physical activity can be undertaken without symptoms. Determination of class
is subjective and will vary among observers.
Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.)
A shortcoming of the NYHA classification scheme is that it does not include
asymptomatic individuals who are at high risk for developing HF and may benefit
from preemptive lifestyle changes and drug therapy. The 2001 ACC/AHA guidelines
introduced a new staging system that can be used in conjunction with the NYHA
4 Patients in stage A have HTN, CAD, diabetes mellitus, or other
conditions that, if left untreated, can result in the development of overt HF. HF
symptoms or identifiable abnormalities of the myocardium or heart valves are absent
in stage A. Patients in stage B remain asymptomatic but have structural defects within
the heart (LV hypertrophy, dilatation, low EF, or valvular disease). Patients in stage
C exhibit varying degrees of HF along with structural changes in the heart. Stage D in
the ACA/AHA scheme roughly correlates with NYHA class IV. Patients in this latter
category are frequently hospitalized, and are considered to have end-stage disease.
Figure 14-1 summarizes these two classification schemes and how they overlap. The
1 expand the definition of HF and add two subgroups to the
HFpEF category: those with borderline EF (LVEF 41%–49%), and those with
improved EF (patients with previously reduced EF, but now with an LVEF >40%).
Figure 14-4 Representation of Frank–Starling ventricular function curve.
Overview of Treatment Principles
1,5,6 updated their previous recommendations and expanded
the role of both aldosterone antagonists and cardiac-resynchronization therapy (CRT)
in patients with milder symptoms of HF. A clinical algorithm from the ACC/AHA
guidelines is found in Figure 14-5.
1 The ACC/AHA Task Force recommends that
most patients with HFrEF should routinely receive GDMT including an ACEI or an
ARB, a β-adrenergic blocker, and an aldosterone receptor antagonist. Diuretics are
recommended for patients with congestion. The combination of hydralazine and
nitrate should be considered in in black patients with symptoms despite receiving
other GDMT therapy or in patients unable to tolerate and ACEI or ARB. Digoxin is
potentially beneficial in symptomatic patients with HFrEF already receiving optimal
medical therapy to decrease HF hospitalizations.
The goals of therapy for HF are to abolish disabling symptoms, avoid
complications such as arrhythmias, improve the quality of life, and prolong survival.
Short of a heart transplant, none of the treatment measures are curative.
Nonspecific medical management of HF includes addressing CV risk factors,
correcting underlying disease states (HTN, ischemic heart disease, arrhythmias, lipid
disorders, anemia, or hyperthyroidism), performing moderate physical activity as
tolerated, undergoing immunization with influenza and pneumococcal vaccines, and
discontinuing possible drug-induced causes. The role of NPs, endothelin inhibitors,
vasopressin receptor antagonists, and calcium sensitizers continues to be
investigated. Non-digitalis inotropic agents and TNF-α inhibitors, although
theoretically valuable, have yielded disappointing results and significant
complications, including arrhythmias and increased mortality rates.
further reduce morbidity and mortality, must wait at least 36 hours of the last dose of ACEI
βNYHA II-IV unless est. CrCl < 30 mL/min and serum potassium > 5.0 mEq/L
cNYHA III or IV in black patients
Treatment of HFpEF is less well defined.
12,52–54 A sodium-restricted diet and
diuretics are indicated for symptomatic relief of SOB or edema. Because these
patients typically present with comorbid conditions (atrial fibrillation [AF], HTN,
diabetes mellitus, and CAD), treatment of comorbidities with available therapies
should aim to decrease CV events and improve survival.
Patients should be encouraged to exercise to maintain physical conditioning.
Treatment goals include prolonging life and improving quality of life. The results of
The Effects of Exercise Training on Health Status in Patients with Chronic Heart
trial showed that a highly structured exercise program in HF
patients did not reduce all-cause mortality or all-cause hospitalization when
compared with patients who were getting the usual care in which exercise was
simply encouraged. However, according to the HF-ACTION substudy, the structured
exercise training program improved the overall Kansas City Cardiomyopathy
Questionnaire (KCCQ) score (a test that includes questions on physical limitations,
symptoms, quality of life, and social limitations). The improvement occurred early on
and was sustained for 3 years. The ACC/AHA HF guidelines
training as safe and effective for patients with HF who are able to participate in
1,5,6 However, during acute exacerbations, bed rest and restricted
physical activity decrease the metabolic demands, and minimize gravitational forces
contributing to edema. Renal perfusion is increased in the prone position, resulting in
diuresis and mobilization of fluid.
Dietary indiscretion (high salt intake) is often cited as the cause of HF exacerbations
and hospital admissions. Several observational studies have demonstrated
associations between lower dietary sodium intake and reduced hospitalizations and
In contrast, several randomized trials imply that dietary sodium
mg/day), the sodium-restricted groups (1,800 mg/day) had increased morbidity and
58 The trials included in this analysis had several limitations. High doses of
diuretics were used in conjunction with strict fluid restriction, which could have
resulted in intravascular volume depletion and adverse outcomes. Also, many
patients were not on optimal doses of GDMT. There is limited evidence to support
sodium restriction in the inpatient setting. In one trial, sodium restriction greater than
the standard 2,000 mg/day in hospitalized HFrEF patients did not affect clinical
stability or decrease length of stay.
59 For these reasons, further randomized trials are
needed to elucidate the impact of sodium restriction on outcomes in HF patients.
Because high sodium intake leads to HTN, LV hypertrophy, and CV disease, the
recommend 1.5 g/daily sodium restriction for patients
with stage A and B HF. In patients with advanced HF (stages C and D), <3 g/daily is
recommended due to lack of sufficient data to support any specific degree of
Furosemide Bumetanide Torsemide
IV loading doses 40 mg 1 mg 20 mg
Maximum total daily dose 600 mg 10 mg 200 mg
Normal renal function 80–160 mg (PO/IV) 1–2 mg (PO/IV) 20–40 mg (PO/IV)
: 20–50 mL/minute 160 mg (PO/IV) 2 mg (PO/IV) 40 mg (PO/IV)
: <20 mL/minute 200 mg (IV), 400 mg (PO) 8–10 mg (PO/IV) 100 mg (PO/IV)
Bioavailability 10%–100% 80%–90% 80%–100%
Duration of action 6–8 hours 4–6 hours 12–16 hours
, creatinine clearance; IV, intravenous; PO, oral.
Even though adherence to dietary sodium restriction is considered “a cornerstone
of HF disease management,” there are many challenges in implementing dietary
sodium restriction. Barriers such as lack of knowledge, interference with
socialization, limited access to appropriate food selections, and increased taste
preference for salty foods all contribute to lack of adherence to low sodium diet.
Although less than 1 g of sodium chloride (NaCl) is required to meet physiologic
needs, the average U.S. diet contains 10 g. Dietary sodium can be reduced to 2 to 4 g
of NaCl by eliminating cooking salt. This diet is more palatable and leads to better
adherence than a severely salt-restricted diet.
Only those points salient to the treatment of HF are included in this chapter. Diuretic
use is discussed in Chapter 9, Essential Hypertension and Chapter 27, Fluid and
Diuretics are indicated in HF patients with congestion (pulmonary and/or
peripheral edema). They produce rapid symptomatic relief. Because activation of the
RAAS and sympathetic nervous system contributes to the progression of HF,
diuretics should be combined with an ACEI and a β-blocker unless contraindications
Initially, the goal of diuretic therapy is symptomatic relief of HF by decreasing
excess volume without causing intravascular volume depletion. Once excess volume
is removed, therapy is aimed at maintaining sodium balance and preventing
accumulation of new fluid, while avoiding dehydration. The rate at which volume can
be removed is limited by its rate of mobilization from the interstitial to the
intravascular fluid compartment. If diuresis is too vigorous, intravascular volume
depletion, hypotension, and a paradoxical decrease in CO may result. Diuretic doses
are titrated so that urine output increases and weight decreases, generally by 0.5 to
The effectiveness of diuretics depends on the amount of sodium delivered to their
site of action and the patient’s renal function.
62,63 Proximal tubular reabsorption of
sodium is increased in patients with severe HF when RBF is compromised,
rendering thiazide and potassium-sparing diuretics (which act primarily on the distal
tubule) minimally effective. Thiazides are believed to lose their effectiveness when
creatinine clearance decreases to less than 30 mL/minute. Metolazone is an exception
in that its activity may be preserved in these patients. The loop diuretics (furosemide,
bumetanide, and torsemide) are more potent than thiazides, and retain their
effectiveness in renal insufficiency. Thus, in most patients with HF, loop diuretics
are preferred. In addition to having activity in the ascending limb of the loop of
Henle, furosemide has vasodilating properties that decrease renal vascular
resistance. The usual recommended doses for the loop diuretics are found in Table
The effectiveness of diuretics depends on active secretion of the drug in the
proximal tubule. Slow absorption (even if bioavailability is high) or protein binding
impairs tubular delivery and compromises diuretic response. Once the drug is in the
tubule and the threshold for diuresis is met, further drug delivery produces no greater
diuresis. Increasing single doses beyond the ceiling dose produces no additional
diuretic response; however, improved diuresis may be obtained by giving the drug
A combination of diuretics (a loop diuretic and thiazide) is used in patients who
are refractory to high-dose loop diuretics.
62,63 Despite their effects on reducing HF
symptoms, loop diuretics do not counteract the underlying cause of HF or modify
The aldosterone antagonists eplerenone and spironolactone exert a mild diuretic
effect by competitive binding to the aldosterone receptor site in the distal convoluted
renal tubules. The Randomized Aldactone Evaluation Study (RALES) investigators
found that spironolactone reduced both morbidity and mortality in patients in NYHA
64 The authors speculated that the beneficial effect of spironolactone
was related to a reduction in aldosterone-induced vascular damage and myocardial
or vascular fibrosis rather than its diuretic effect. Similarly, reduced mortality was
observed in patients with LV dysfunction after a recent MI who were treated with
aldosterone antagonist in all patients with HFrEF who are already on ACEIs (or
ARB) and β-blockers irrespective of the severity of symptoms and in patients
immediately after MI who have LV dysfunction or diabetes.
aldosterone receptor antagonists, GFR should be>30 mL/minute/1.73 m2 and
potassium levels <5 mEq/dL to avoid the risk of hyperkalemia or renal insufficiency.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND
Drugs with vasodilating properties are a primary treatment for HF. Arterial dilation
provides symptomatic relief of HF by decreasing arterial impedance (afterload).
Venous dilation decreases LV congestion (preload). The combination of these two
properties provides additive benefits to alleviate the symptoms of HF and increase
exercise tolerance. The first vasodilator drugs to be studied were hydralazine (an
arterial dilator) and nitrates (predominately venous dilators). By combining these
two drugs, significant reductions in HF symptoms can be achieved along with a
reduction in mortality rates. With the advent of ACEIs, the use of hydralazine and
nitrates has been relegated to a secondary role.
nitrate combination as a single agent, favorably modify cardiac remodeling, and have
side effect profile. These advantages led to the recommendations that ACEIs are
the drugs of choice for initial therapy, even in patients with relatively mild LV
1,5,6 state that ACEIs should be prescribed to all patients
with HFrEF unless they have a contradiction to their use or are unable to tolerate
these drugs. In general, ACEIs are used with β-blockers. ACEIs should be initiated at
low doses, and titrated to target doses if well tolerated. Fluid retention can blunt the
therapeutic effects, and volume depletion can potentiate the adverse effects of ACEIs.
Clinicians should attempt to use doses that have been shown to reduce CV events in
clinical trials, but they should not delay the initiation of β-blockers in patients
because of a failure to reach target ACEI doses.
The pharmacologic actions of all the ACEIs are essentially identical, but some of
them have not been studied or received FDA approval for use in HF (Table14-4).
Their value in HFpEF still is unclear. A related class of drugs is the ARBs.
ARBs offer theoretic advantages compared with ACEIs by being more specific for
angiotensin II blockade (preferentially bind to AT1
ARBs can be used as alternatives to ACEIs in patients who are intolerant
(angioedema or cough). Triple combination of an ACEI, ARB, and an aldosterone
receptor antagonist is potentially harmful for patients and therefore is listed as a
class III (avoid) recommendation in the ACC/AHA guidelines.
candesartan and valsartan are FDA-approved for the treatment of HF.
Until the mid-1990s, β-blockers were contraindicated in patients with HFrEF. This
was based on the belief that sympathomimetic agonists and other positive inotropic
drugs were the logical choices to counteract systolic failure and that negative
inotropic drugs would exacerbate HF. A better understanding of the pathophysiology
of HF led to a rethinking of this logic.
In combination with ACEIs, β-blockers
are considered first-line agents in patients with HFrEF. The ACC/AHA guidelines
state that β-blockers should be prescribed to all patients with HFrEF unless they
have a contraindication to their use or are unable to tolerate the treatment. Intolerance
1 Although some patients can have a temporary
worsening of symptoms, continued use results in improved quality of life, fewer
hospitalizations, and most importantly, a reduction in mortality by approximately
34% when added to other HF therapies. Extended-release metoprolol succinate,
carvedilol, and bisoprolol are FDA approved for use in HFrEF. Metoprolol and
bisoprolol are both partially selective β1
-blockers, and carvedilol is a mixed α1
nonselective β-blocking agent.
DIGITALIS GLYCOSIDES (DIGOXIN)
Digoxin has several pharmacologic actions on the heart. It binds to and inhibits
) adenosine triphosphatase (ATPase) in cardiac cells,
decreasing outward transport of sodium and increasing intracellular concentrations of
calcium within the cells. Calcium binding to the sarcoplasmic reticulum causes an
increase in the contractile state of the heart.
At one time, the primary benefit of digoxin in HFrEF was assumed to be an
increase in the force of contraction (positive inotropic effect). We now know that
digoxin has beneficial neurohumoral and autonomic effects caused by reducing
sympathetic tone and stimulating parasympathetic responses at serum concentrations
below those associated with positive inotropism.
vagal afferent fibers sensitizes cardiac baroreceptors, resulting in reduced
sympathetic outflow from the CNS. Similarly, inhibition of Na
cells reduces renal tubular reabsorption of sodium and indirectly suppresses renin
secretion. This has led to the suggestion that the positive benefits of digoxin can be
obtained by using small doses.
Digoxin decreases the conduction velocity and prolongs the refractory period of
the atrioventricular (AV) node. This AV node–blocking effect prolongs the PR
interval and is the basis for use of digoxin in slowing the ventricular response rate in
patients with AF and other supraventricular arrhythmias (see Chapter 15, Cardiac
Several studies have confirmed a clinical benefit for digoxin in reducing HF
symptoms, independent of rhythm status, but there are no data that demonstrate a
beneficial effect on survival. Digoxin is used for symptom management in patients
optimally treated with ACEIs, β-blockers, and aldosterone antagonists. In
symptomatic patients in stage C or stage D, digoxin can reduce HF-related
1 Digoxin can also be considered in patients with HF who also have
AF, although β-blockers are more effective than digoxin in controlling the ventricular
response, especially during exercise.
OTHER VASODILATING DRUGS: HYDRALAZINE AND NITRATES
Although ACEIs are drugs of choice, the first vasodilators evaluated in HFrEF were
hydralazine and nitrates. Hydralazine provides symptomatic relief of HF by
decreasing afterload. Nitrates have venous dilating properties that decrease preload.
Used in combination, these two agents have additive benefits in alleviating the
symptoms of HF and increasing exercise tolerance. Importantly, the hydralazine–
isosorbide dinitrate combination was the first treatment regimen to show improved
survival in severe HF compared with placebo
(while patients continued their
diuretic or digitalis therapy). The African American Heart Failure Trial (AHeFT)
showed that the addition of hydralazine combined with isosorbide dinitrate to
standard HF therapy with an ACEI or a β-blocker improved survival and reduced HF
hospitalizations. Based on the results of AHeFT, the FDA approved the combination
product of hydralazine and isosorbide dinitrate (BiDil) for the treatment of HFrEF as
an adjunct to standard HF therapy in African American patients. The combination of
hydralazine and nitrate is reasonable in patients with current or prior HF symptoms
and reduced LVEF who cannot tolerate ACEIs or ARBs, and is also recommended
for patients self-described as African American with moderate to severe symptoms
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