Download CONGESTIVE HEART FAILURE IN THE ELDERLY

■
REVIEW ARTICLE
CONGESTIVE HEART FAILURE IN THE ELDERLY
Chiung-Zuan Chiu1,2, Jun-Jack Cheng1,2,3*
1
School of Medicine, Fu Jen Catholic University, 2Division of Cardiology, Department of Internal Medicine,
Shin-Kong Wu Ho-Su Memorial Hospital, and 3School of Medicine, Taipei Medical University, Taipei, Taiwan.
SUMMARY
Over the past 30 years, the prevalence and incidence of heart failure (HF) have increased markedly with age,
with increases of approximately fivefold from the age of 40 to 70 years. HF is predominantly a disorder of the
elderly, and over 70% of HF patients are over 65 years old. The most important factor in the increasing prevalence and incidence of HF is the growing proportion of elderly with new-onset diastolic HF resulting from
chronic hypertension and coronary heart disease. Other predictors of HF include diabetes, prior stroke, atrial
fibrillation, renal dysfunction, reduced ankle-brachial index, increased C-reactive protein, left ventricular hypertrophy, reduced forced expiratory volume, and obesity. At least half of all elderly HF patients have preserved
left ventricular systolic function, and they are classified as diastolic HF. There was a strong female predominance (67%) in diastolic HF when compared with male HF patients. The morbidity and mortality of older HF
patients are the highest of any chronic cardiovascular disorder. Mortality increases markedly with age. Mortality
from diastolic HF is about half of that reported for systolic HF. There are some comorbidities in older HF
patients, including renal dysfunction, chronic lung disease, cognitive dysfunction, depression, postural hypotension, urine incontinence, sensory deprivation, nutritional disorders, polypharmacy and frailty, which may precipitate and exacerbate the underlying HF symptoms. Clinical diagnosis of HF may be more difficult in the
elderly because of frequently inadequate history taking, less evident HF symptoms for reduced daily activity,
and similar symptoms to other frequent disorders. The treatment goals in older HF patients resemble those for
any chronic disorder and include relief of symptoms, improvement in functional status, exercise tolerance,
quality of life, prevention of acute exacerbation, and finally, prolongation of long-term survival. [International
Journal of Gerontology 2007; 1(4): 143–152]
Key Words: chronic hypertension, coronary artery disease, diastolic heart failure, elderly, heart failure
Epidemiology and Predictors
Over the past 30 years, mortality rates for cardiovascular disease have declined dramatically. However, the
prevalence and incidence of heart failure (HF) have
increased markedly with age over this period1. In the
Framingham Heart Study, the incidence of HF increased
approximately fivefold from the age of 40 to 70 years2.
HF is predominantly a disease of the elderly; over 70%
of HF patients are aged 65 years or older. The most
*Correspondence to: Dr Jun-Jack Cheng, Division of Cardiology,
Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial
Hospital, 95, Wen-Chan Road, Shih-Lin, Taipei, Taiwan.
E-mail: [email protected]
Accepted: July 15, 2007
International Journal of Gerontology | December 2007 | Vol 1 | No 4
© 2007 Elsevier.
important factor in the increasing prevalence and incidence of HF is the growing proportion of elderly (> 50%)
with new-onset diastolic HF resulting from chronic
hypertension and coronary heart disease. Recent studies in older population have found that pulse pressure,
an index of arterial stiffness, is the strongest blood
pressure predictor of HF3,4. Coronary heart disease,
especially prior myocardial infarction, and degenerative aortic stenosis are also potent predictors of HF in
the elderly. Male sex, obesity, and diabetes mellitus
were independent predictors of HF in the Cardiovascular Health Study5. Additional predictors of HF in this
study were prior stroke, atrial fibrillation, renal dysfunction, reduced ankle-brachial index, increased Creactive protein, left ventricular (LV) hypertrophy, and
reduced forced expiratory volume5.
143
■
C.Z. Chiu, J.J. Cheng
Clinical Outcomes
The morbidity and mortality of older HF patients are
perhaps the highest of any chronic cardiovascular disorder. Mortality of HF increases markedly with age.
In community-based individuals of 65 to 74 years of age,
the 10-year mortality was 50% in women and > 70% in
men6. Among elderly persons hospitalized for HF, the
prognosis is even worse, with a 5-year mortality of > 70%.
The mortality from diastolic HF is about half of that
reported for systolic HF; in the Framingham Study, the
respective annual mortality rates were 8.9% and 19.6%7.
However, survival appears similar in elderly patients hospitalized with diastolic versus systolic HF8–10. The morbidity from HF is also very high in the elderly. Between
30% and 50% of older patients hospitalized for HF will
be rehospitalized within 3 to 6 months11–13. In contrast to mortality, the readmission rates for HF patients
with preserved systolic function appear to be the same
as those for patients with impaired systolic function.
Pathophysiology—Higher Prevalence of
Diastolic HF in the Elderly
The pathophysiology of HF in the elderly differs from
that in younger patients because of multiple age-associated changes in cardiovascular and non-cardiovascular
function and structure and multiple morbid disorders
accompanied by aging. The most evident difference
is the higher prevalence of HF with preserved systolic
LV function (diastolic HF) in the older patients. Aging is
associated with a concentric hypertrophy of the LV myocardium and reduced early diastolic relaxation and filling
rates14,15. Both of these may result in age-associated
increase in arterial stiffness16. These findings are similar
to those seen in younger hypertensive patients and provide a condition more prone to development of diastolic
HF. A recent community study indicated that advancing
age and female gender are associated with increases in
vascular and ventricular systolic and diastolic stiffness,
even in the absence of cardiovascular disease17. This
combined ventricular–vascular stiffening may contribute
to the increased prevalence of diastolic HF in elderly
persons, particularly in elderly women. In addition, reduced chronotropic, inotropic and vasodilator responses
to beta-adrenergic stimulation occur with aging18–20.
Several non-cardiovascular aging changes, including reduced ventilatory capacity, reduced glomerular
144
■
filtration rate (GFR) and impaired central nervous system
autoregulation, also contribute to the susceptibility
to HF in the elderly. Many morbidities of elderly HF
patients, including systolic hypertension, LV hypertrophy,
renal dysfunction and chronic lung disease, are exaggerations of these age-associated physiologic changes.
A reduced heart rate and increased systemic vascular
resistance at rest and a reduced heart rate response to
exercise in older patients could be seen in a previous
study21. Plasma norepinephrine also increased with age
without consistent age trends seen for plasma renin
activity or urine aldosterone. A reduction of GFR and
increases in renal vascular resistance and serum creatinine levels were seen at older ages. Echocardiography
studies in the elderly showed smaller ventricles, higher
fractional shortening, higher Doppler A wave velocity,
lower ratio of early transmitral flow velocity to atrial
flow velocity, and longer deceleration time than in the
younger group22, which reflected a better systolic function and an impaired diastolic function in the elderly.
Wong et al. indicated that about 30% of the older
group had atrial fibrillation, which may further impair
LV function in the elderly23.
Exercise intolerance, manifested as fatigue and exertional dyspnea, is the primary symptom in chronic HF
with either a reduced or a preserved ejection fraction.
Previous studies have demonstrated that diastolic HF
patients have severely reduced exercise capacity as
measured by peak VO2 during exercise, and their exercise intolerance is as severe as that of age-matched
systolic HF patients24–26. Invasive cardiopulmonary
exercise testing showed that diastolic HF patients have
a reduced ability to increase stroke volume via the
Frank-Starling law despite severely increased LV filling
pressure, indicative of diastolic dysfunction24. This resulted in severely reduced exercise cardiac output and
early lactate formation and was a significant independent contributor to the severely reduced exercise
capacity and associated chronic exertional symptoms24.
These findings indicate that diastolic HF also plays
a very important role in the pathogenesis of HF in the
elderly. One study indicated that decreased aortic distensibility, due to the combined effects of aging and
hypertension-induced thickening and remolding of
the thoracic aortic wall, is an important contributor to
exercise intolerance in chronic diastolic HF. Patients
with diastolic HF had increased pulse pressure and
thoracic aortic wall thickening and markedly decreased
aortic distensibility, which correlated with their severely
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
■
Congestive Heart Failure in the Elderly
decreased peak exercise VO225. It is very likely that systolic hypertension plays an important role in the genesis of diastolic HF in the elderly. In animal models,
diastolic dysfunction develops early in systemic hypertension, and LV diastolic relaxation is very sensitive
to increased afterload. Increased afterload impairs LV
relaxation, leading to increased LV filling pressures,
decreased stroke volume, and symptoms of congestion
and dyspnea27,28. Most diastolic HF patients (88%) have
a history of chronic systemic hypertension29. Although
the role of ischemia in diastolic HF is uncertain, it is
likely to be a significant contributor in some patients.
It has been hypothesized that patients with a normal
ejection fraction following an episode of chronic HF
may have transiently reduced systolic function and/or
ischemia at the time of acute exacerbation. However,
the more likely hypothesis indicated that acute pulmonary edema and/or chronic HF due to acute exacerbation of diastolic dysfunction caused by severe systolic
hypertension or marked elevation of blood pressure
rather than by ischemia may play the real role of diastolic HF in the elderly with normal systolic function30.
Neurohormonal activation is thought to play an
important role in the pathogenesis of systolic HF. In
a group of patients with diastolic HF, a study showed
that atrial natriuretic peptide and brain natriuretic
peptide were increased, and there was an exaggerated
response during exercise31. Another study showed that
older patients with diastolic HF have markedly increased
norepinephrine levels, equivalent to those seen in systolic HF, and had levels of atrial natriuretic peptide and
brain natriuretic peptide that were increased tenfold
compared with age-matched normal people.
Predisposing Factors for HF in the Elderly
Rare studies have reported the predisposing factors of
HF in the elderly. In a series of 154 HF patients aged
75 ± 8 years admitted to the hospital, 71% had coronary artery disease, 45% had hypertension, and 32%
had valvular heart disease32. Factors precipitating HF
included atrial fibrillation (16%), poor drug compliance
(10%), renal failure (8%), fever (7%), and anemia (6%).
Multiple studies also showed the important role of
atrial fibrillation in the development of HF in the elderly patients. In the EPESE community-based cohort,
myocardial infarction was the precipitant of HF in 49
of 173 cases (28%)4. Acute elevation of blood pressure
International Journal of Gerontology | December 2007 | Vol 1 | No 4
appears to be responsible for a significant portion of
patients presenting with acute pulmonary edema30.
The episode of acute pulmonary edema may be primarily due to elevation of blood pressure or secondary
to an elevation of sympathetic tone.
Challenges in Diagnosing Elderly HF Patients
The diagnosis of HF in the elderly is challenging for
several reasons. First, many symptoms and signs of HF
in the elderly are similar to other chronic systemic
disorders. Second, many elderly patients reduce their
daily activity because of various causes, which may
mask the two cardinal symptoms of fatigue and exertional dyspnea. Third, many elderly patients cannot
provide an adequate history taking because of dementia, or cognitive or sensory impairments. Fourth, elderly
patients with HF often present with nonspecific symptoms such as weakness, fatigue, confusion, and disorientation. Finally, the frequent occurrence of a normal
LV ejection fraction in older HF patients (diastolic HF)
may lead the clinicians to exclude the diagnosis of HF.
The many different diagnosis criteria for HF may cause
diversity in the diagnosis of HF in the elderly. McKee
et al. proposed simplified criteria for the diagnosis of HF
in the elderly33. There is a history of acute pulmonary
edema or the occurrence of at least two of the following
with no other identifiable cause and with improvement
following diuretic therapy: exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower
extremity edema or exertional fatigue. Echocardiography
is the preferred imaging study for initial diagnosis of
HF, because it can detect some important disorders,
such as valvular heart disease, hypertrophic cardiomyopathy, cardiac amyloidosis or pericardial effusion. An
echocardiography that reveals an LV ejection fraction
of < 45% to 50% represents reduced systolic function
and evidence of systolic HF. Diastolic HF is always manifested as typical clinical symptoms/signs of HF, hypertension and/or concentric LV hypertrophy, and diastolic
dysfunction as noted by echocardiography.
General Considerations in Treatment of HF
The treatment goals of older HF patients include relief
of symptoms, improvement in functional status and
quality of life, prevention of acute exacerbation and
145
■
C.Z. Chiu, J.J. Cheng
hospitalization, and finally, prolongation of long-term
survival. A systematic management plan should pay
much attention to diet, exercise and physical activity,
and other life style factors, avoidance of aggravating
conditions, and careful titration of medications and
frequent follow-up. Adequate education of patient and
family can also gain some benefits. The management
team might involve the attending physician, nurse,
dietitian, pharmacist, social worker, and physical therapist. Other strategies, such as cessation of smoking
and drinking, administration of influenza and pneumococcal vaccines, minimal use of sodium-retaining
medications or foods and use of cardiac rehabilitation,
should be advocated. Common HF precipitants, such as
atrial fibrillation, renal failure, anemia and pulmonary
infections, should be treated aggressively. During the
past decade, the value of multidisciplinary HF management programs has been repeatedly demonstrated
by reductions in HF exacerbations, rehospitalizations and
costs, and improvement in the quality of life11,34–36.
Diet
Excessive intake of sodium is a common cause of acute
exacerbation of HF. Moderate sodium restriction (2 g/
day) is adequate to prevent weight gain in most stable
patients. More severe sodium restriction may allow for
a reduction in diuretic dose. Water restriction is necessary when significant hyponatremia is present. The ageassociated reduction in GFR in HF patients adds to the
difficulty in maintaining sodium balance in the elderly.
Physical activity
Exercise intolerance in elderly HF patients may improve
after exercise and aerobic training programs. Although
limited number of patients were enrolled, several prospective trials demonstrated increases in peak VO2,
cardiac output, and other physiologic parameters in
older patients with systolic HF37,38. A representative
large, multicenter, randomized trial (HF-ACTION) involving 2 years of aerobic exercise training in 3,000 systolic
HF patients with LV ejection fraction of 35% will provide
the outcome of aerobic exercise training in improving
functional class in elderly patients with HF.
■
enzyme (ACE) inhibitors, beta-blockers, digitalis,
angiotensin-receptor blockers (ARBs), and vasodilators
in patients with systolic HF. More recent trials also
reported the effect of these drugs in older patients
with systolic HF.
Diuretics
Diuretics provide rapid symptomatic relief and control
of pulmonary edema and peripheral edema in most
HF patients. Diuretics, especially in the elderly, should
be titrated to the lowest effective dose for preventing
renal function deterioration, electrolyte imbalance, and
hyperactivity of the renin–angiotensin system. Thiazide
may be effective in patients with mild HF, but most
patients with HF need loop diuretics to achieve the
target effect. Patients with severe fluid retention and/or
renal dysfunction may require the addition of metolazone. In patients with nocturnal congestive symptoms,
a twice-daily regimen may be necessary. Fluid restriction may be needed if hyponatremia occurs. Careful
monitoring of fluid status, renal function, electrolytes,
and body weight should be undertaken, especially in
the elderly, during the administration of intravenous
diuretic agents. In past studies, only spironolactone has
been shown to reduce HF mortality (27%) in patients
with New York Heart Association (NYHA) Class III–IV HF39.
ACE inhibitors
Numerous studies have established the effect of ACE
inhibitors as important in the drug therapy for systolic
HF. In the first CONSENSUS trial, enalapril (10 to 20 mg
twice daily) reduced the 6-month mortality from 48%
to 29% in older patients with NYHA Class IV systolic HF
despite the use of digoxin and diuretics40. Subsequent
studies also showed that ACE inhibitors had effects on
reducing mortality and improving quality of life in the
elderly and that they should be used in older patients
if there is no contraindication. Patients with HF benefited from ACE inhibitors by the suppression of the
renin–angiotensin system and inhibition of progressive
LV dilatation and remodeling41,42. The effect is especially
evident in myocardial infarction patients with severe
systolic dysfunction (LV ejection fraction, < 35%)41.
ARBs
Pharmacologic Treatment of Systolic HF
Over the past 20 years, a large number of clinical trials
reported on the efficacy of angiotensin-converting
146
In recent trials, ARBs have not been definitely proven
to be as effective as ACE inhibitors in reducing morbidity and mortality in HF of any age. Although the ELITE-I
study suggested a survival advantage of ARB losartan
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
Congestive Heart Failure in the Elderly
over the ACE inhibitor captopril in patients ≥ 65 years
of age43, the larger ELITE-II study failed to confirm this
finding44. So, ACE inhibitors remain the preferred initial treatment in the elderly with systolic HF. An advantage of ARBs over ACE inhibitors is the lower incidence
of cough, so ARBs could be used in patients with intolerance to ACE inhibitors. However, the ELITE-I study
demonstrated that the incidence of renal dysfunction
and other side effects with ARBs was not lower than
with ACE inhibitors. The addition of ARBs in patients
who remain symptomatic despite maximal doses of
ACE inhibitors may improve symptoms and exercise
tolerance45. In the RESOLVD trial, the combination of
ARBs and ACE inhibitors was associated with more LV
remodeling than either agent alone46. However, in the
Valsartan in Heart Failure Trial (Val-HeFT) trial, the
combination of ARBs and ACE inhibitors did not reduce
the all-cause mortality but showed a 28% reduction in
hospitalization and improved quality of life47. In the
Val-HeFT trial, the small subgroup with an older mean
age of 67 years that was not given ACE inhibitors at
baseline showed a 45% reduction in all-cause mortality, confirming ARBs as an alternative treatment in
patients who are intolerant to ACE inhibitors. In the
Candesartan in Heart failure: Assessment of Reduction
in Mortality and morbidity (CHARM) study, candesartan
significantly reduced all-cause mortality, cardiovascular death, and HF hospitalizations in patients with
chronic HF and LV ejection fraction of ≤ 40% when
added to standard therapies, including ACE inhibitors,
beta-blockers, and an aldosterone antagonist. A recent
study also showed that plasma brain natriuretic peptide
concentration, 123I-meta-iodobenzylguanidine images,
and echocardiographic parameter improved significantly in systolic HF patients treated with valsartan
and implied that valsartan can improve cardiac sympathetic nerve activity and LV performance in patients
with systolic HF48.
Digoxin
In the multicenter Digitalis Investigation Group study
in which nearly 8,000 HF patients with sinus rhythm
and LV ejection fraction of ≤ 45% and given ACE inhibitors and diuretics were randomized to receive
digoxin or placebo, digoxin had no effect on mortality
but reduced HF symptoms and hospitalizations49.
Digoxin was also as effective in patients who were ≥ 80
years old in this study50. So, digoxin is recommended
in patients who remain symptomatic despite the use
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
of ACE inhibitors and diuretics. Digoxin is especially
effective in HF patients with atrial fibrillation, because
it can help in controlling ventricular rate.
Beta adrenergic blockers
Several large randomized trials have shown that betaadrenergic blockers reduce all-cause mortality and hospitalization and improve symptoms in the elderly with
systolic HF51,52. However, relative contraindications to
beta-blockade, such as bradycardia, conduction disturbance, chronic obstructive lung disease or peripheral
arterial disease, may limit the use of beta-blockade in
the elderly. So, beta-blocker should be started at very
low doses (carvedilol 3.125 mg twice daily) in elderly
clinically stable HF patients receiving appropriate doses
of ACE inhibitors and diuretics.
Synthetic catecholamines
Synthetic catecholamines, such as dobutamine and
dopamine, have been used successfully in elderly patients with refractory systolic HF53, though randomized controlled trials are lacking. In a small study by
Rich et al., dobutamine infusion gave rise to lesser increases in cardiac output in patients who were > 80 years
old than in younger patients54, compatible with the
age-associated decreased sensitivity to catecholamines
that occurs in normal population. Low dose dopamine,
as a renal vasodilator, also improved GFR and urine
output in the elderly HF patients when added to intravenous diuretics55.
Biventricular pacing and automatic
intracardiac defibrillator
Recent trials have shown that atrial-synchronized biventricular pacing can improve LV function and enhance
functional status and quality of life in HF patients with
QRS prolongation of > 120 ms. The MIRACLE study also
demonstrated a 40% reduction in death or hospitalization of severe HF patients after biventricular pacing
in a randomized double-blind trial56. Although no
age-specific analysis was performed, the mean age of
64 years and the absence of an upper age limit make
these findings relevant to the elderly.
The MADIT-II study showed that prophylactic implantation of defibrillator in patients with a prior myocardial infarction and ejection fraction of ≤ 30% reduced
all-cause mortality from 20% to 14% over a mean
follow-up of 20 months57. The benefit in older patients
(≥ 70 years) was similar to that in younger individuals.
147
■
C.Z. Chiu, J.J. Cheng
In addition to the above treatments, aortic valve
replacement in elderly HF patients with degenerative
aortic stenosis may also relieve the symptoms of HF
with low surgical mortality (< 10%) in octogenarians58,59.
Coronary artery revascularization in older HF patients
could improve myocardial ischemia and HF symptoms60. In myocardial infarction with systolic HF and
LV aneurysm, LV aneurysmectomy and partial left ventriculectomy may relieve HF symptoms by reducing
LV size and improving LV function.
Treatment of Diastolic HF
In contrast to systolic HF, treatment of diastolic HF has
been according to evidence-based medicine for the
past 30 years. There were rare, large, randomized,
multicenter trials on diastolic HF treatment in the
past61,62. Advances in therapy of diastolic HF have been
hindered by lack of standard definition, absence of a
reliable test to quantify diastolic function, and insufficient understanding of the real pathophysiology of
diastolic HF61. As we know, there is no single pattern of
diastolic HF treatment in the elderly.
General principle
The general approaches for patients with systolic HF
are the same as those with diastolic HF62. Diuretics
could also be used as an initial treatment of pulmonary
congestion and peripheral edema. Primary etiology,
such as hypertension, of diastolic HF should be investigated and treated. Most patients may have hypertension62 which should be controlled aggressively. Chronic
hypertension causes LV hypertrophy and fibrosis which
impair diastolic function and ventricular compliance.
Acute elevation of blood pressure or poor blood pressure control further impairs LV diastolic function and
may induce HF symptoms and acute lung edema.
A recent trial indicated that progressively abnormal
diastolic function is associated with reduced arterial
compliance in hypertensive patients with exertional
dyspnea63. So, arterial compliance is an independent
predictor of diastolic dysfunction in patients with
hypertensive heart disease and should be considered
a potential target for intervention in diastolic HF. The
STOP-2 trial favored the use of ACE inhibitors to control blood pressure and prevent HF simultaneously in
the elderly (70–84 years)64. The ALLHAT study showed
that diuretics were superior to alpha-blockade and
148
■
were at least equivalent to ACE inhibitors and calcium
antagonists for prevention of HF in older hypertensive
patients65,66. A noninvasive survey for coronary artery
disease should be done in patients with chest pain
and/or abrupt onset of pulmonary edema, because
ischemia is a therapeutic goal for diastolic HF. Some
patients with hypertrophic cardiomyopathy, valvular
heart disease, amyloidosis or pericardial illness could
be diagnosed by echocardiographic examination67–69.
Sinus rhythm and/or rate control should be achieved
and maintained in patients with atrial fibrillation in
order to restore atrial contraction and improve LV
ejection fraction62.
Pharmacologic therapy for diastolic HF
Digoxin
In the DIG trial, there was a subgroup of older HF
patients with preserved systolic function. The result
also showed that relief of symptoms and reduction of
rehospitalization could be achieved, but there was no
influence on all-cause mortality49. So, digoxin may be
an alternative choice in the elderly with diastolic HF.
ACE inhibitors
Several studies suggest that both ARBs and ACE inhibitors are effective therapy for diastolic HF. First,
they are a good choice for systolic HF with reduction
in mortality and rehospitalization. In addition, they
improve exercise tolerance and clinical symptoms.
Second, they block the neurohormonal activation of
renin–angiotensin system in diastolic HF31. Finally,
they control hypertension, prevent LV hypertrophy or
remodeling, and improve LV relaxation and aortic distensibility67–71. In a study of elderly patients (mean
age, 80 years) with NYHA Class III HF and diastolic HF
(ejection fraction, > 50%), Aronow et al. showed that
enalapril can improve functional class, exercise duration, ejection fraction, diastolic filling, and LV mass72.
One study (total 1,402 patients) also indicated that ACE
inhibitors used in diastolic HF can reduce all-cause
mortality and HF death73. However, another study of
elderly HF patients with preserved LV function suggested that ACE inhibitors may increase mortality in
these patients61,74. The powerful, randomized, controlled PEP-CHF trial reported the morbidity and mortality in elderly HF patients (> 70 years) with LV ejection
of ≥ 40%. By 1 year, reductions in the primary outcome
(hazard ratio [HR], 0.692; 95% confidence interval [CI],
0.474–1.010; p = 0.055) and hospitalizations for HF
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
Congestive Heart Failure in the Elderly
(HR, 0.628; 95% CI, 0.408–0.966; p = 0.033) were observed, and functional class (p < 0.030) and 6-minute
corridor walk distance (p = 0.011) had improved in
those assigned to perindopril75,76.
References
ARBs
In a small double-blind, randomized, controlled trial
of 20 elderly patients with diastolic dysfunction, the
ARB losartan improved exercise capacity and quality
of life and reduced exercise systolic and pulse pressure77. The CHARM-Preserved trial assessed the effect
of candesartan in HF patients with ejection fraction of
≥ 40% and indicated that candesartan can reduce hospital admission for HF in patients with preserved systolic function78,79. Results of recent key studies, such
as Losartan Intervention For Endpoint Reduction in
Hypertension (LIFE), Val-HeFT, CHARM and Valsartan
in Acute Myocardial Infarction (VALIANT), add to the
evidence that angiotensin II receptor blockers are
good choice for the treatment of hypertension in older
patients80,81. These trials also indicated that they are
appropriate therapy for HF patients and for patients
who have experienced acute myocardial infarction, particularly those who are unable to tolerate an ACE inhibitor. The I-PRESERVE trial is currently assessing the
effect of the ARB irbesartan in patients with diastolic
HF, and results will be reported in the near future82,83.
2.
Calcium channel antagonists
A small (22 elderly patients) randomized, double-blind,
placebo-controlled trial of verapamil in HF patients
with ejection fraction of > 45% indicated that there was
a 33% improvement in exercise duration and significant improvement in HF score and peak filling rate78,79.
Verapamil also could improve symptoms and exercise
capacity in patients with hypertrophic cardiomyopathy80–85. However, negative inotropic calcium channel
antagonists impair early relaxation and have a tendency
toward adverse outcome in patients with systolic HF86–90.
Beta-adrenergic blockers
Beta-adrenergic blockers reduce mortality in systolic HF
patients, prevent LV hypertrophy and remodeling, reduce oxygen demand, and increase diastolic filling time,
all supporting their use in diastolic HF27,29,91. However,
Cheng et al. have shown that early diastolic relaxation
is impaired by beta-adrenergic blockers92. So, the definite effect of beta-adrenergic blockers will be known
after the results of large clinical trials are reported.
International Journal of Gerontology | December 2007 | Vol 1 | No 4
1.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
■
Schochen DD. Epidemiology and risk for heart failure in
the elderly. In: Rich MW, ed. Clinical Geriatric Medicine.
Philadelphia: WB Saunders, 2000; 407–18.
Kannel WB. Epidemiological aspects of heart failure.
Cardiol Clin 1989; 7: 1–9.
Chae CU, Pfeffer MA, Glynn RJ, Mitchell GF, Taylor JO,
Hennekens CH. Increased pulse pressure and risk of
heart failure in the elderly. JAMA 1999; 281: 634–9.
Chen YT, Vaccarino V, Williams CS, Butler J, Berkman LF,
Krumholz HM. Risk factors for heart failure in the elderly: a prospective community-based study. Am J Med
1999; 106: 605–12.
Gottdiener JS, Arnold AM, Aurigemma GP, Polak JF,
Tracy RP, Kitzman DW, et al. Predictors of congestive
heart failure in the elderly: the Cardiovascular Health
Study. J Am Coll Cardiol 2000; 35: 1628–37.
Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ,
Evans JM, Bailey KR, et al. Congestive heart failure in
the community: a study of all incident cases in Olmsted
County, Minnesota, in 1991. Circulation 1998; 98: 2282–9.
Coats AJ, Anker SD, Anker S. Insulin resistance in chronic
heart failure. J Cardiovasc Pharmacol 2000; 35 (7 Suppl 4):
S9–14.
Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ,
Evans JM, Bailey KR, et al. Congestive heart failure in
the community: trends in incidence and survival in a
10-year period. Arch Intern Med 1999; 159: 29–34.
Pernenkil R, Vinson JM, Shah AS, Beckham V,
Wittenberg C, Rich MW. Course and prognosis in patients
≥ 70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction.
Am J Cardiol 1997; 79: 216–9.
Aronow WS, Ahn C, Kronzon I. Prognosis of congestive
heart failure in elderly patients with normal versus
abnormal left ventricular systolic function associated with
coronary artery disease. Am J Cardiol 1990; 66: 1257–9.
Rich MW, Beckham V, Wittenberg C, Leven CL,
Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with
congestive heart failure. N Engl J Med 1995; 333: 1190–5.
Krumholz HM, Chen YT, Wang Y, Vaccarino V, Radford
MJ, Horwitz RI. Predictors of readmission among elderly
survivors of admission with heart failure. Am Heart J
2000; 139: 72–7.
Tsutsui H, Tsuchihashi M, Takeshita A. Mortality and
readmission of hospitalized patients with congestive
heart failure and preserved versus depressed systolic
function. Am J Cardiol 2001; 88: 530–3.
Gardin JM, Arnold AM, Bild DE, Smith VE, Lima JA,
Klopfenstein HS, et al. Left ventricular diastolic filling in
149
■
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
150
C.Z. Chiu, J.J. Cheng
the elderly: the Cardiovascular Health Study. Am J Cardiol
1998; 82: 345–51.
Kitzman DW, Sheikh KH, Beere PA, Philips JL,
Higginbotham MB. Age-related alterations of Doppler
left ventricular filling indexes in normal subjects are
independent of left ventricular mass, heart rate, contractility, and loading conditions. J Am Coll Cardiol
1991; 18: 1243–50.
Little WC. Enhanced load dependence of relaxation in
heart failure: clinical implications. Circulation 1992; 85:
2326–8.
Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ,
Kass DA. Age- and gender-related ventricular-vascular
stiffening: a community-based study. Circulation 2005;
112: 2254–62.
Port S, Cobb FR, Jones RH. Effects of propranolol on left
ventricular function in normal men. Circulation 1980;
61: 358–66.
Port S, Cobb FR, Coleman RE, Jones RH. Effect of age on
the response of the left ventricular ejection fraction to
exercise. N Engl J Med 1980; 303: 1133–7.
Lakatta E. Deficient neuroendocrine regulation of the
cardiovascular system with advancing age in healthy
humans. Circulation 1993; 87: 631–6.
Cody RJ, Torre S, Clark M, Pondolfino K. Age-related
hemodynamic, renal, and hormonal differences among
patients with congestive heart failure. Arch Intern Med
1989; 149: 1023–8.
Dutka DP, Olivotto I, Ward S, Oakley CM, Impallomeni M,
Cleland JG. Effects of aging on neuroendocrine activation in subjects and patients in the presence and absence
of heart failure with left ventricular systolic dysfunction.
Am J Cardiol 1996; 77: 1197–201.
Wong WF, Gold S, Fukuyama O, Blanchette PL. Diastolic
dysfunction in elderly patients with congestive heart
failure. Am J Cardiol 1989; 63: 1526–8.
Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH,
Sullivan MJ. Exercise intolerance in patients with heart
failure and preserved left ventricular systolic function:
failure of the Frank-Starling mechanism. J Am Coll
Cardiol 1991; 17: 1065–72.
Hundley WG, Kitzman DW, Morgan TM, Hamilton CA,
Darty SN, Stewart KP, et al. Cardiac cycle-dependent
changes in aortic area and distensibility are reduced in
older patients with isolated diastolic heart failure and
correlate with exercise intolerance. J Am Coll Cardiol
2001; 38: 796–802.
Rerkpattanapipat P, Hundley WG, Link KM, Brubaker
PH, Hamilton CA, Darty SN, et al. Relation of aortic distensibility determined by magnetic resonance imaging
in patients ≥ 60 years of age to systolic heart failure and
exercise capacity. Am J Cardiol 2002; 90: 1221–5.
Shannon RP, Komamura K, Gelpi RJ, Vatner SF. Altered
load: an important component of impaired diastolic
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
■
function in hypertension and heart failure. In: Lorell BH,
Grossman W, eds. Diastolic Relaxation of the Heart.
Norwell, MA: Kluwer Academic Publishers, 1994; 177–85.
Little WC, Braunwald E. Assessment of cardiac function.
In: Braunwald E, ed. Heart Disease. Philadelphia: WB
Saunders, 1996; 421–44.
Iriarte M, Murga N, Sagastagoitia D, Molinero E, Morillas M,
Salcedo A, et al. Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension.
Am J Cardiol 1993; 71: 308–12.
Kramer K, Kirkman P, Kitzman D, Little WC. Association
with hypertension, reoccurrence despite coronary revascularization. Am Heart J 2000; 143: 451–5.
Clarkson PB, Wheeldon NM, MacFadyen RJ, Pringle SD,
MacDonald TM. Effects of brain natriuretic peptide on
exercise hemodynamics and neurohormones in isolated
diastolic heart failure. Circulation 1996; 93: 2037–42.
Cocchi A, Zuccala G, Menichelli P, Incalzi RA, Del
Sindaco D, Alimenti M, et al. Congestive heart failure in
the elderly: an intriguing clinical reality. Cardiol Elderly
1994; 2: 227–32.
McKee PA, Castelli WP, McNamara PM, Kannel WB.
The natural history of congestive heart failure: the
Framingham study. N Engl J Med 1971; 285: 1441–5.
Stewart S, Marley JE, Horowitz JD. Effects of a multidisciplinary, home-based intervention on unplanned readmissions and survival among patients with chronic
congestive heart failure: a randomised controlled study.
Lancet 1999; 354: 1077–83.
Whellan DJ, Gaulden L, Gattis WA, Granger B, Russell SD,
Blazing MA, et al. The benefit of implementing a heart
failure disease management program. Arch Intern Med
2001; 161: 2223–8.
Stewart S, Vandenbroek AJ, Pearson S, Horowitz JD.
Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among
patients with congestive heart failure: a randomized
controlled study. Arch Intern Med 1999; 159: 257–61.
Piepoli MF, Flather M, Coats AJ. Overview of studies of
exercise training in chronic heart failure: the need for
a prospective randomized multicenter European trial.
Eur Heart J 1998; 19: 830–41.
Fleg JL. Can exercise conditioning be effective in older
heart failure patients? Heart Fail Rev 2002; 7: 99–103.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A,
et al. The effect of spironolactone on morbidity and
mortality in patients with severe heart failure. N Engl J
Med 1999; 341: 709–17.
The CONSENSUS Trial Study Group. Effects of enalapril
on mortality in severe congestive heart failure. Results
of the Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS). N Engl J Med 1987; 316: 1429–35.
Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF,
Braunwald E. Effect of captopril on progressive ventricular
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
Congestive Heart Failure in the Elderly
dilatation after anterior myocardial infarction. N Engl J
Med 1988; 319: 80–6.
Levine TB, Levine AB, Keteyian SJ, Narins B, Lesch M.
Reverse remodeling in heart failure with intensification
of vasodilator therapy. Clin Cardiol 1997; 20: 697–702.
Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ,
Thomas I, et al. Randomised trial of losartan versus
captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet
1997; 349: 747–52.
Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K,
Camm AJ, et al. Effect of losartan compared with captopril on mortality in patient with symptomatic heart
failure: randomised trial—the Losartan Heart Failure
Survival Study (ELITE II). Lancet 2000; 355: 1582–7.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB,
Gilbert EM, et al. The effect of carvedilol on morbidity
and mortality in patients with chronic heart failure.
N Engl J Med 1996; 334: 1349–55.
McKelvie RS, Yusuf S, Pericak D, Avezum A, Burns RJ,
Probstfield J, et al. Comparison of candesartan, enalapril,
and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular
dysfunction (RESOLVD) pilot study. The RESOLVD Pilot
Study Investigators. Circulation 1999; 100: 1056–64.
Cohn JN, Tognoni G. A randomized trial of the
angiotensin-receptor blocker valsartan in chronic heart
failure. N Engl J Med 2001; 345: 1667–75.
Kasama S, Toyama T, Hatori T, Sumino H, Kumakura H,
Takayama Y, et al. Comparison effects of valsartan and
enalapril on cardiac sympathetic nerve activity and
plasma brain natriuretic peptide in patients with congestive heart failure. Heart 2006; 92: 625–30.
Digoxin Investigators Group. The effect of digoxin on
mortality and morbidity in patients with heart failure.
N Engl J Med 1997; 336; 525–33.
Rich MW, McSherry F, Williford WO, Yusuf S; for Digitalis
Investigation Group. Effect of age on mortality, hospitalizations, and response to digoxin in patients with
heart failure: the DIG study. J Am Coll Cardiol 2001; 38:
806–13.
CIBIS-II Investigators and Committees. The Cardiac
Insufficiency Bisoprolol Study II (CIBIS-II): a randomised
trial. Lancet 1999; 353: 9–13.
MERIT-HF Study Group. Effect of metoprolol CR/XL in
chronic heart failure: Metoprolol CR/XL Randomised
Intervention Trial in Congestive Heart Failure (MERITHF). Lancet 1999; 353: 2001–7.
López-Candales A, Carron C, Graham S, Schwartz J.
Outpatient cardiac infusion units: impact in elderly
patients with refractory heart failure. Am J Geriatr
Cardiol 2001; 10: 188–92.
International Journal of Gerontology | December 2007 | Vol 1 | No 4
■
54. Rich MW, Imburgia M. Inotropic response to dobutamine in elderly patients with decompensated congestive heart failure. Am J Cardiol 1990; 65: 519–21.
55. Varriale P, Mossavi A. The benefit of low-dose dopamine
during vigorous diuresis for congestive heart failure
associated with renal insufficiency: does it protect renal
function? Clin Cardiol 1997; 20: 627–30.
56. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon
AR, Loh E, et al. Cardiac resynchronization in chronic
heart failure. N Engl J Med 2002; 346: 1845–53.
57. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom
DS, et al. Prophylactic implantation of a defibrillator in
patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877–83.
58. Culliford AT, Galloway AC, Colvin SB, Grossi EA,
Baumann FG, Esposito R, et al. Aortic valve replacement
for aortic stenosis in persons aged 80 years and over.
Am J Cardiol 1991; 67: 1256–60.
59. Levinson JR, Akins CW, Buckley MJ, Newell JB, Palacios IF,
Block PC, et al. Octogenarians with aortic stenosis. Outcome after aortic valve replacement. Circulation 1989;
80: 149–56.
60. Baker DW, Jones R, Hodges J, Massie BM, Konstam MA,
Rose EA. Management of heart failure. III. The role of
revascularization in the treatment of patients with
moderate of severe left ventricular systolic dysfunction.
JAMA 1994; 272: 1528–34.
61. Kitzman DW. Therapy for diastolic heart failure: on the
road from myths to multicenter trials. J Card Fail 2001;
7: 229–31.
62. The ACC/AHA task force on practice guidelines (committee to revise the 1995 guidelines for the evaluation and
management of chronic heart failure in the adult: executive summary. Circulation 2001; 38: 2002–113.
63. Mottram PM, Haluska BA, Leano R, Carlier S, Case C,
Marwick TH. Relation of arterial stiffness to diastolic
dysfunction in hypertensive heart disease. Heart 2005;
91: 1551–6.
64. Hansson L, Lindholm LH, Ekbom T, Dahlöf B, Lanke J,
Scherstén B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular
mortality and morbidity in Swedish Trial in Old Patients
with Hypertension-2 Study. Lancet 1999; 354: 1751–6.
65. The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. Major cardiovascular
events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT).
JAMA 2000; 283: 1967–75.
66. The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. Major outcomes in highrisk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker
151
■
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
152
C.Z. Chiu, J.J. Cheng
vs diuretic: the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA
2002; 288: 2981–97.
Lorell BH, Grossman W. Cardiac hypertrophy: the
consequences for diastole. J Am Coll Cardiol 1987; 9:
1189–93.
Lorell BH. Cardiac renin–angiotensin system in cardiac
hypertrophy and failure. In: Lorell BH, Grossman E, eds.
Diastolic Relaxation of the Heart, 2nd edition. Norwell,
MA: Kluwer Academic Publishers, 1996; 91–9.
Oren S, Grossman E, Frohlich ED. Reduction in left ventricular mass in patients with systemic hypertension
treated with enalapril, lisinopril, or fosenopril. Am J
Cardiol 1996; 77: 93–6.
Friedrich SP, Lorell BH, Rousseau MF, Hayashida W,
Hess OM, Douglas PS, et al. Intracardiac angiotensinconverting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to
aortic stenosis. Circulation 1994: 90: 2761–71.
Lakatta E. Cardiovascular aging research: the next horizons. J Am Geriatr Soc 1999; 47: 613–25.
Aronow WS, Kronzon I. Effect of enalapril on congestive
heart failure treated with diuretics in elderly patients
with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993; 71: 602–4.
Philbin EF, Rocco TA. Use of angiotensin-converting
enzyme inhibitors in heart failure with preserved left
ventricular systolic function. Am Heart J 1997: 134:
188–95.
Dauterman KW, Go AS, Rowell R, Gebretsadik T, Gettner S,
Massie BM. Congestive heart failure with preserved
systolic function in a statewide sample of community
hospitals. J Card Fail 2001; 7: 221–8.
Cleland JG, Tendera M, Adamus J, Freemantle N, Gray CS,
Lye M, et al; for the PEP investigators. Perindopril for
elderly people with chronic heart failure: the PEP-CHF
study. Eur J Heart Fail 1999; 1: 211–7.
Cleland JG, Tendera M, Adamus J, Freemantle N,
Polonski L, Taylor J, et al. The perindopril in elderly
people with chronic heart failure (PEP-CHF) study. Eur
Heart J 2006; 27: 2338–45.
Abraham TP, Kon ND, Nomeir AM, Cordell AR, Kitzman
DW. Accuracy of transesophageal echocardiography in
preoperative determination of aortic annulus size during valve replacement. J Am Soc Echocardiogr 1997; 10:
149–54.
Setaro JF, Zaret BL, Schulman DS, Black HR, Soufer R.
Usefulness of verapamil for congestive heart failure
associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance.
Am J Cardiol 1990; 66: 981–6.
Weber MA. Angiotensin II receptor blockers in older
patients. Am J Geriatr Cardiol 2004; 13: 197–205.
■
80. Vandenberg BF, Rath LS, Stuhlmuller P, Melton HE,
Skorton DJ. Estimation of left ventricular cavity area
with an on-line, semiautomated echocardiographic edge
detection system. Circulation 1992; 86: 159–66.
81. Ostergren J. Candesartan for the treatment of hypertension and heart failure. Expert Opin Pharmacother 2004;
5: 1589–97.
82. Bonow RO, Leon MB, Rosing DR, Kent KM, Lipson LC,
Bacharach SL, et al. Effects of verapamil and propranolol on left ventricular systolic function and diastolic
filling in patients with coronary artery disease: radionuclide angiographic studies at rest and during exercise.
Circulation 1982; 65: 1337–50.
83. Carson P, Massie BM, McKelvie R, McMurray J, Komajda
M, Zile M, et al. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and
design. J Card Fail 2005; 11: 576–85.
84. Bonow RO, Dilsizian V, Rosing DR, Maron BJ, Bacharach SL,
Green MV. Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance
in patients with hypertrophic cardiomyopathy: short- and
long-term effects. Circulation 1985; 72: 853–64.
85. Udelson J, Bonow RO. Left ventricular diastolic function
and calcium channel blockers in hypertrophic cardiomyopathy. In: Gaasch WH, ed. Left Ventricular Diastolic
Dysfunction and Heart Failure. Malvern, PA: Lea &
Febiger, 1996; 465–89.
86. TenCate FJ, Serruys PW, Mey S, Roelandt J. Effects of shortterm administration of verapamil on left ventricular
relaxation and filling dynamics measured by a combined
hemodynamic-ultrasonic technique in patients with hypertrophic cardiomyopathy. Circulation 1983; 68: 1274–9.
87. Hess OM, Murakami T, Krayenbuehl HP. Does verapamil
improve left ventricular relaxation in patients with
myocardial hypertrophy? Circulation 1996; 74: 530–43.
88. Brutsaert DL, Rademakers FE, Sys SU, Gillebert TC,
Housmans PR. Analysis of relaxation in the evaluation
of ventricular function of the heart. Prog Cardiovasc Dis
1985; 28: 143–63.
89. Brutsaert DL, Sys SU, Gillebert TC. Diastolic failure:
pathophysiology and therapeutic implications. J Am
Coll Cardiol 1993; 22: 318–25.
90. Little WC, Cheng CP, Elvelin L, Nordlander M. Vascular
selective calcium entry blockers in the treatment of
cardiovascular disorders: focus on felodipine. Cardiovasc
Drugs Ther 1995; 9: 657–63.
91. Colucci WS, Ribeiro JP, Rocco MB, Quigg RJ, Creager MA,
Marsh JD, et al. Impaired chronotropic response to exercise in patients with congestive heart failure. Circulation
1989; 80: 314–23.
92. Cheng CP, Igarashi Y, Little WC. Mechanism of augmented
rate of left ventricular filling during exercise. Circ Res
1992; 70: 9–19.
International Journal of Gerontology | December 2007 | Vol 1 | No 4