Abstract
Purpose
Cognitive impairment is an exceedingly prevalent condition among patients with heart failure, independently associated with disability and mortality. However, the determinants of cognitive dysfunction associated with heart failure are still unclear. We assessed the correlates of cognitive impairment among patients with heart failure enrolled in a multicenter pharmacoepidemiology survey.
Methods
The association with cognition of demographic characteristics, objective tests and measures, medications, and comorbid conditions was assessed in 1511 patients with heart failure who had been admitted to 81 hospitals throughout Italy. Cognitive impairment was defined by a Hodkinson Abbreviated Mental Test score < 7.
Results
According to multivariate logistic regression modeling, age (per each decade: OR = 2.01; 95% confidence interval [CI] 1.72–2.35), the comorbidity score (OR 1.11; 95% CI 1.03–1.20), education (OR 0.88; 95% CI 0.84–0.2), low serum albumin (OR 1.78; 95% CI 1.35–2.34), sodium (OR 1.56; 95% CI 1.06–2.29), and potassium levels (OR 1.58; 95% CI 1.09–2.29), hyperglycemia (OR 1.33; 95% CI 1.02–1.73), anemia (OR 1.38; 95% CI 1.09–1.75), and systolic blood pressure levels ≥ 130 mm Hg (OR 0.60; 95% CI 0.37–0.97) were independently associated with cognitive impairment, after adjusting for potential confounders. Among participants with abnormal laboratory findings on admission, restoration of normal glucose, potassium, and hemoglobin levels during hospital stay was associated with improved cognitive performance at discharge.
Conclusions
Cognitive impairment among patients with heart failure is associated with several comorbid conditions, some of which are potentially treatable. This highlights the key role of comprehensive approach to the assessment and treatment of patients with heart failure.
Keywords
Over recent years, an abnormal prevalence of cognitive dysfunction, ranging from 35% to over 50%, has been repeatedly described among patients with heart failure.
1
, 2
To date, the etiology of cognitive impairment associated with heart failure is mostly unclear. The reported association of cognitive dysfunction with severe left ventricular dysfunction and systolic hypotension in older subjects with heart failure,3
, 4
along with studies documenting cerebral hypoperfusion in patients with heart failure,5
, 6
have revived the old concept of “cardiogenic” dementia., 8
However, data so far available suggest that left ventricular dysfunction does not represent the only determinant of cognitive impairment associated with heart failure, as left ventricular ejection fraction accounts for only a fraction of the variations in cognitive functioning among patients with heart failure,3
and because several factors might influence cerebral metabolism in these subjects.5
The issue of cognitive impairment associated with heart failure does not represent a mere academic question. The prevalence rates of heart failure in western countries have increased steeply, mostly among subjects older than 80 years of age, and the prevalence of patients with heart failure is expected to double within the next 40 years.
9
According to this epidemiological scenario, subclinical cognitive impairment associated with heart failure has been estimated to affect over 1 million subjects in the United States alone.2
Among older patients with heart failure, cognitive dysfunction has been associated with a fivefold increase in the risk of mortality10
and a sixfold increase in the probability of dependence for the activities of daily living.11
These figures are important, because, despite recent advances in pharmacological treatment, heart failure in older populations is still associated with high rates of mortality and disability.12
, 13
Noticeably, disability is a major determinant of the increased resource consumption associated with heart failure that currently represents the most costly medical illness in the United States.14
Therefore, reducing the burden of cognitive dysfunction associated with heart failure might allow substantial gains in term of survival rates, quality of life, and resource consumption. Some studies have suggested that pacemaker implantation and cardiac transplantation might improve cognitive functioning in selected patients with heart failure.15
, 16
However, no interventions are yet known to improve cognitive performance in the majority of subjects with heart failure, chiefly because of the incomplete knowledge about the pathophysiology of cognitive dysfunction in these patients.We analyzed the association of demographic characteristics, objective tests and measures, medications, and comorbid conditions with cognitive functioning, as well as with in-hospital variations in cognitive performance among 1511 patients with heart failure who had been enrolled in a collaborative pharmacoepidemiology study.
Methods
Study methods
We analyzed the database of the Gruppo Italiano di Farmacoepidemiologia nell’Anziano (GIFA), a large collaborative hospital study. This study has been approved by the Bioethical Committee at the Catholic University of the Sacred Heart in Rome. The methods of the GIFA have been described in detail elsewhere.
17
Briefly, all 32 243 patients admitted to 81 clinical centers (either geriatric or internal medicine hospital wards) throughout Italy in several surveys were enrolled on admission and followed until discharge without exclusion criteria. In the present study we analyzed data of participants enrolled in 1993, 1995, and 1997. For each patient, a questionnaire was completed on admission and updated daily by a study physician who had received specific training. Data were recorded using a dedicated software;18
the variables recorded included demographic characteristics, objective tests and measures, drugs taken before admission, during hospital stay and at discharge, and admission and discharge diagnoses. Creatinine clearance was estimated according to the Cockcroft & Gault formula.19
Diagnosis of heart failure
In the present study we considered the discharge diagnosis of heart failure that was verified by the study researchers. The accuracy of such a diagnosis was tested in the 1993 GIFA survey against a “definite” diagnosis based upon a validated series of physical and laboratory data; using a score ≥ 8 as reference diagnosis, the clinical diagnosis of heart failure among 1687 subjects yielded > 95% specificity.
20
Assessment of cognitive function
Cognitive performance was assessed using the Hodkinson Abbreviated Mental Test.
21
This test has been proven reliable for detecting both mild cognitive impairment and dementia in older populations22
and has been adopted in epidemiological surveys.23
Use of this test has also been validated for detection of cognitive impairment in Italian populations.24
As in previous analyses, we adopted a cut-off score of 7,4
, 10
, 11
as this threshold level yielded 100% sensitivity and 71% specificity in an older Italian population.24
Coding of drugs and diseases
Drugs were coded according to the Anatomical Therapeutic and Chemical codes.
18
Diagnoses were coded according to the International Classification of Diseases, 9th Edition, Clinical Modification codes.25
Comorbidity was quantified using the Charlson comorbidity index score by adding scores assigned to specific discharge diagnoses.26
In addition, coronary disease, hypertension, diabetes, renal disease, liver disorders, and atrial fibrillation were analyzed as separate variables. Patients with diagnosis of cerebrovascular disease or stroke or Alzheimer disease were excluded from analyses.Statistical analyses
Data of continuous variables are presented as mean values ± SD. Statistical analyses were performed using SPSS for Windows 10.1.0 software (SPSS Inc., Chicago, Illinois); differences were considered significant at the P <0.05 level. Variables with homogeneous variance, as assessed by the Levene statistics, were compared by ANOVA comparisons; otherwise, the Kruskal-Wallis H was adopted. Chi-squared analysis was used for dichotomous variables. Logistic regression analysis was used to estimate the association of variables of interest with cognitive impairment. To assess potential confounders, groups of variables (demographic characteristics, comorbid conditions, medications, and objective tests) were examined in separate age- and sex-adjusted regression models with simultaneous introduction of covariates, as depicted in Table 2. Those variables, significant at the P <0.1 level in these initial models, were simultaneously entered into a summary age- and sex-adjusted regression model (Table 2).
Angiotensin-converting enzyme.
Table 2Association (odds ratios [OR] and 95% confidence intervals [CI]) between patient characteristics and the presence of cognitive impairment at the time of admission, as calculated by logistic regression modeling (all the covariates were entered simultaneously into the regression models)
| OR (95% CI) | ||||
|---|---|---|---|---|
| Age- and sex-adjusted models | Multivariate model | |||
| Demographics | ||||
| Age (per decades) | 1.98 | 1.71–2.29 | 2.01 | 1.72–2.35 |
| Sex (male) | 0.96 | 0.75–1.22 | 0.87 | 0.68–1.12 |
| Education (years) | 0.87 | 0.83–0.92 | 0.88 | 0.84–0.92 |
| Comorbid conditions | ||||
| Coronary disease | 0.60 | 0.46–0.78 | 0.62 | 0.47–0.82 |
| Hypertension | 0.78 | 0.60–1.01 | ||
| Atrial fibrillation | 0.84 | 0.65–1.10 | ||
| Diabetes | 0.83 | 0.62–1.13 | ||
| Renal disease | 0.94 | 0.63–1.42 | ||
| Hepatic disease | 0.84 | 0.42–1.65 | ||
| Comorbidity score index | 1.19 | 1.10–1.29 | 1.11 | 1.03–1.20 |
| Medications | ||||
| ACE - inhibitors | 0.73 | 0.56–0.94 | 0.79 | 0.61–1.03 |
| Digoxin | 0.86 | 0.67–1.10 | ||
| Calcium antagonists | 0.73 | 0.55–0.97 | 0.88 | 0.65–1.19 |
| Diuretics | 0.87 | 0.69–1.11 | ||
| Beta-blockers | 0.59 | 0.269–1.33 | ||
| Antiplatelet | 1.04 | 0.73–1.48 | ||
| Anticoagulants | 0.99 | 0.68–1.44 | ||
| Nitrates | 0.83 | 0.64–1.06 | ||
| Objective tests | ||||
| Systolic blood pressure (<110 mm Hg) | 1 | 1 | ||
| (110–129 mm Hg) | 0.78 | 0.48–1.24 | 0.76 | 0.47–1.23 |
| (≥130 mm Hg) | 0.63 | 0.39–1.00 | 0.60 | 0.37–0.97 |
| Sodium (135–145 mEq/L) | 1 | 1 | ||
| (<135 mEq/L) | 1.62 | 1.11–2.37 | 1.56 | 1.06–2.29 |
| (>145 mEq/L) | 1.33 | 0.85–2.08 | 1.28 | 0.81–2.02 |
| Potassium (3.6–5.0 mEq/L) | 1 | 1 | ||
| (<3.6 mEq/L) | 1.51 | 1.05–2.17 | 1.58 | 1.09–2.29 |
| (>5.0 mEq/L) | 1.16 | 0.80–1.68 | 1.08 | 0.74–1.58 |
| Albumin (<3.5 g/dL) | 1.94 | 1.48–2.54 | 1.78 | 1.35–2.34 |
| Glucose (>110 mg/dL) | 1.39 | 1.08–1.79 | 1.33 | 1.02–1.73 |
| Anemia | 1.42 | 1.12–1.79 | 1.38 | 1.09–1.75 |
| Creatinine clearance (≥30 mL/min) | 0.76 | 0.56–1.04 | 0.79 | 0.57–1.08 |
† Below 12 g/dL for women, or 13 g/dL for men (27).
‡ Not introduced in the summary model because of collinearity with blood pressure levels.
Eventually, we assessed among participants who had abnormal objective tests on admission the mean changes in cognitive functioning that occurred throughout the hospital stay (calculated as the difference between discharge and admission cognitive performance scores), according to the restoration of normal values at discharge (Table 3). Anemia was defined for hemoglobin levels below 12 g/dL for women or 13 g/dL for men, according to the World Health Organization (WHO) criteria.
Serum glucose <65 or >110 mg/dL. Systolic blood pressure <130 or >150 mm Hg (4).
27
According to our previous report on the association between systolic blood pressure and probability of cognitive impairment among participants in the GIFA study with heart failure, target systolic blood pressure was considered to be between 130 and 150 mm Hg.4
Table 3Differences in the variations occurring in cognitive performance during hospital stay among participants with abnormal objective tests on admission, according to the persistence or resolution of the abnormalities
| Laboratory abnormality | Mean change in cognitive function among those in whom the abnormality “normalized” during hospitalization | Mean change in cognitive function among those in whom the abnormality did not “normalize” | Mean difference (95% CI) | P Value | ||
|---|---|---|---|---|---|---|
| n | Mean ± SD | n | Mean ± SD | |||
| Hypo-hyperglycemia | 154 | 0.50 ± 1.52 | 337 | 0.16 ± 1.52 | 0.34 (0.02–0.67) | 0.04 |
| Hypo-hyperkalemia | 149 | 0.57 ± 1.77 | 56 | −0.38 ± 2.36 | 0.95 (0.34–1.55) | 0.002 |
| Hypo-hypernatremia | 109 | 0.12 ± 1.76 | 57 | −0.22 ± 2.37 | 0.34 (−0.30–0.98) | 0.30 |
| Renal failure | 25 | 0.14 ± 1.50 | 553 | −0.24 ± 2.30 | 0.38 (−0.53–1.29) | 0.44 |
| Hypoalbuminemia | 146 | 0.41 ± 1.31 | 187 | 0.28 ± 2.74 | 0.13 (−0.36–0.61) | 0.60 |
| Anemia | 393 | 0.43 ± 1.39 | 228 | −0.13 ± 1.75 | 0.56 (0.30–0.81) | <0.0001 |
| Hypo-hypertension | 261 | 0.35 ± 1.15 | 266 | 0.23 ± 1.81 | 0.12 (−0.14–0.37) | 0.37 |
† Serum potassium <3.6 or >5.0 mEq/L.
‡ Serum sodium <135 or >145 mEq/L.
§ Creatinine clearance <30 mL/min.
∥ Serum albumin <3.5 g/dL.
¶ Hemoglobin <12 g/dL for women or 13 g/dL for men (27).
Results
Prevalent cognitive impairment according to diagnosis of heart failure
Among the 16 913 participants in the GIFA database who were suitable for analysis during the years of interest, cognitive dysfunction was detected in 35% (526/1511) of participants with diagnosis of heart failure and in 29% (3448/11 790) of the remaining subjects (P <0.0001).
Correlates of cognitive impairment among participants with heart failure
The main characteristics, according to presence of cognitive impairment, of the 1511 participants with a verified diagnosis of heart failure are depicted in Table 1.
Angiotensin-converting enzyme.
Table 1Characteristics of participants with heart failure by cognitive impairment on admission
| Cognitive impairment (n = 526) n (%) or mean ± SD | Normal cognition (n = 925) n (%) or mean ± SD | P Value | |
|---|---|---|---|
| Demographics | |||
| Age (years) | 82 ± 8 | 76 ± 10 | <0.0001 |
| Sex (female) | 320 (61) | 489 (50) | <0.0001 |
| Education (years) | 4 ± 2 | 6 ± 3 | <0.0001 |
| Comorbid conditions | |||
| Coronary disease | 116 (22) | 299 (30) | 0.01 |
| Hypertension | 122 (23) | 294 (30) | 0.006 |
| Atrial fibrillation | 119 (23) | 243 (25) | 0.38 |
| Diabetes | 93 (18) | 211 (21) | 0.09 |
| Hepatic disease | 16 (3) | 39 (4) | 0.39 |
| Renal disease | 60 (11) | 94 (10) | 0.25 |
| Comorbidity score index (26) | 2.4 ± 1.6 | 2.1 ± 1.5 | 0.008 |
| Medications | |||
| Digitalis | 276 (53) | 532 (54) | 0.57 |
| Diuretics | 291 (55) | 586 (60) | 0.12 |
| ACE- inhibitors | 131 (25) | 350 (36) | <0.0001 |
| Antiplatelets | 59 (11) | 113 (12) | 0.88 |
| Anticoagulants | 49 (9) | 113 (12) | 0.20 |
| Calcium antagonists | 93 (18) | 220 (22) | 0.03 |
| Beta-blockers | 8 (2) | 35 (4) | 0.02 |
| Nitrates | 148 (28) | 336 (34) | 0.02 |
| Objective tests | |||
| Serum sodium (mEq/L) | 139 ± 5 | 140 ± 4 | 0.05 |
| Serum potassium (mEq/L) | 4.2 ± 0.7 | 4.3 ± 0.6 | 0.27 |
| Serum creatinine (mg/dL) | 1.4 ± 0.8 | 1.3 ± 0.8 | 0.04 |
| Serum albumin (g/dL) | 3.4 ± 0.6 | 3.7 ± 0.5 | <0.0001 |
| Hemoglobin (g/dL) | 12.0 ± 2.2 | 12.7 ± 2.2 | <0.0001 |
| Systolic blood pressure (mm Hg) | 144 ± 21 | 147 ± 21 | 0.01 |
In the initial age- and sex-adjusted logistic regression models, age, sex, education, diagnosis of coronary disease, the comorbidity score, use of ACE-inhibitors and calcium antagonists, anemia, systolic blood pressure, and creatinine, albumin, sodium, potassium, and glucose serum levels were associated with cognitive impairment at a P <0.1 level (Table 2). Thus, all these variables, except for diagnosis of hypertension, which was collinear with systolic blood pressure, were entered simultaneously into the “summary” age- and sex-adjusted regression model. In this “summary” model, age, education, diagnosis of coronary disease, the comorbidity score, systolic blood pressure, anemia, and sodium, potassium, glucose, and albumin levels were still associated with cognitive dysfunction after adjusting for potential confounders (Table 2).
Normalization of laboratory parameters and variations in cognitive functioning
The length of hospital stay did not differ according to the presence of cognitive impairment on admission (15 ± 11 days among participants with heart failure; 15 ± 10 days among other participants). The cognitive performance score increased during hospital stay (1.8 ± 1.5 points) in 363 (24%) participants. Among participants with abnormal laboratory tests on admission, correction of abnormal glucose and potassium serum levels and restoration of normal hemoglobin levels were associated with greater increases in cognitive performance score at discharge (Table 3).
Discussion
Despite advances in the care of patients with heart failure, uncertainty remains about effective management of elderly subjects with comorbidities.
14
In fact, heart failure in older populations is still associated with impressive hospitalization and mortality rates, as well as prevalent functional disability.12
, 13
Noncardiac comorbidity has been proven a major determinant of such persistently poor outcomes of treatment, and it has been hypothesized that comprehensive approaches might reduce hospitalization rates, mortality, and incident disability in older subjects with heart failure.13
, 14
Nevertheless, no information is currently available on which comorbid conditions should be evaluated and treated.28
The issue of cognitive impairment associated with heart failure (formerly referred to as “cardiogenic dementia”) is relevant to this setting. In fact, cognitive impairment has been recognized to affect over one-third of older patients with heart failure.
1
, 2
This figure is impressive, considering the increasing prevalence of heart failure, which tripled through the 1990s.9
Among older patients with heart failure, cognitive impairment, even when subclinical, has been independently associated with increased 1-month and 1-year mortality and with increased probability of functional disability.10
, 11
These findings are in keeping with the observed effect of cognitive impairment on survival and functional ability in older populations.23
, 29
As suggested by several studies, cerebral hypoperfusion might account for the disproportionate prevalence of cognitive impairment among patients with heart failure.
1
, 2
, 8
Noticeably, autoregulation of cerebral circulation is impaired in older age;30
in addition, heart failure is associated with reduced cerebrovascular reactivity, even in younger patients.6
This hypoperfusion etiology of cognitive impairment associated with heart failure implies potential reversibility,8
which has been confirmed by some reports on the effects on cognitive functioning of pacemaker implantation and cardiac transplantation.15
, 16
However, no information is available regarding potentially treatable noncardiac determinants of cognitive impairment among patients with heart failure. This issue is relevant, as left ventricular function has been proven only a partial determinant of cognitive dysfunction in patients with heart failure.2
, 3
Indeed, several observations suggest that other factors might influence cerebral perfusion.5
, 31
, 32
According to our results, cognitive impairment is associated with several factors among older subjects with heart failure (Table 2). Some of these factors (namely lower blood pressure levels, anemia, abnormal serum electrolyte levels, hyperglycemia, and hypoalbuminemia) are of interest, because of their prevalence and potential reversibility. In this setting, our data indicate that normalization of glucose, potassium, and hemoglobin levels during hospital stay is associated with increased cognitive performance at discharge (Table 3). Indeed, the GIFA database does not include other variables, including the arterial oxygen content,
32
which might influence cerebral perfusion and metabolism in heart failure. Also, the observational nature of the GIFA study does not allow ascertainment of a causal relationship between these factors and cognitive dysfunction.An inverse association between systolic blood pressure and cognitive performance has been reported in prospective studies;
33
in the GIFA study this association can only be detected among subjects with heart failure.4
Low systolic blood pressure levels in these patients might simply reflect reduced left ventricular systolic function, which has been associated with cognitive impairment in older subjects with heart failure.3
However, hypotension per se might further reduce cerebral perfusion in the presence of impaired cerebrovascular autoregulation.6
, 8
Our finding of an association between abnormal electrolyte serum levels and cognitive dysfunction (Table 2) is in keeping with previous reports in general older populations. The association of normalization of potassium levels with improved cognition at discharge in this study (Table 3) further supports the role of vigilance to electrolyte serum levels in the management of older patients with heart failure.
The association of low albumin and hemoglobin levels with cognitive impairment (Table 2) is also of interest. These abnormalities are currently included in the “malnutrition-inflammation complex syndrome” that has been reported to affect 24% of patients with heart failure.
35
Thus, hypoalbuminemia and anemia might simply represent markers of poor general conditions or even reflect higher cytokine serum levels.35
Noticeably, increased serum and cerebral proinflammatory cytokine levels have been associated with both Alzheimer’s disease and multi-infarct dementia.36
In addition, anemia might aggravate the effects of hypoperfusion on cerebral metabolism directly or through further deterioration of left ventricular function. In fact, treatment of anemia in patients with heart failure has been proven to increase peripheral oxygen delivery,37
and, in older patients undergoing hemodialysis, to increase cerebral blood flow, oxygen extraction, and metabolic rate for oxygen.38
However, normalization of hemoglobin levels in anemic patients with heart failure has also been found to improve left ventricular ejection fraction, stroke volume, and cardiac output.39
On the other hand, it has also been suggested that low hematocrit might be associated with increased cerebral perfusion in patients with heart failure, which highlights the complexity of cerebral circulation in these subjects.
31
In this study, restoration of normal hemoglobin levels among participants who were anemic on admission was associated with greater increases in cognitive performance score at discharge (Table 3). If confirmed, results of this study might support randomized trials aimed at assessing the impact of treatment of anemia on the cognitive functioning of elderly subjects with heart failure.The advantages of a comprehensive approach to older patients with heart failure have been documented.
40
Nevertheless, assessment of noncardiac comorbidity is generally disregarded in the management of these patients.40
, 41
For instance, the reported prevalence of any diagnoses of cognitive impairment (which is known to affect 35–50% of elderly with heart failure) in a recent large study of older Medicare patients with heart failure was as low as 9%.13
Results of this study might support research aiming at implementing multidisciplinary strategies for the assessment and treatment of older patients with heart failure.42
References
- The mind of a failing heart.Intern Med J. 2001; 31: 290-295
- Brain hypoperfusion.Neurol Res. 2004; 26: 454-458
- Left ventricular dysfunction.J Neurol Neurosurg Psychiatry. 1997; 63: 509-512
- Hypotension and cognitive impairment.Neurology. 2001; 59: 1986-1992
- Prognostic significance of cerebral metabolic abnormalities in patients with congestive heart failure.Circulation. 2001; 103: 2784-2787
- Cerebrovascular reactivity is impaired in patients with cardiac failure.Eur Heart J. 2000; 21: 407-413
- Cardiogenic dementia.Lancet. 1981; 2: 1171
- Cognitive impairment in congestive heart failure? Embolism vs hypoperfusion.Neurology. 2001; 57: 1945-1946
- Confirmation of a heart failure epidemic.J Am Coll Cardiol. 2002; 39: 60-69
- The effects of cognitive impairment on mortality among hospitalized patients with heart failure.Am J Med. 2003; 115: 97-103
- Cognitive dysfunction as a major determinant of disability in patients with heart failure.J Neurol Neurosurg Psychiatry. 2001; 70: 109-112
- Progress in heart failure management? Lessons from the real world.Circulation. 2000; 102: 1076-1078
- Noncardiac comorbidity increases preventable hospitalizations and mortality among Medicare beneficiaries with chronic heart failure.J Am Coll Cardiol. 2003; 42: 1226-1233
- Heart failure in the 21st century.J Gerontol A Biol Sci Med Sci. 2001; 56: M88-M96
- Improvement of cerebral blood flow and cognitive function following pacemaker implantation in patients with bradycardia.Gerontology. 1994; 40: 279-285
- Cyclosporine may affect improvement of cognitive brain function after successful cardiac transplantation.Circulation. 1996; 94: 1339-1345
- Pharmacosurveillance in hospitalized patients in Italy. Study design of the ’Gruppo Italiano di Farmacovigilanza nell’Anziano’ (GIFA).Pharmacol Res. 1999; 40: 287-295
- Drug data coding and analysis in epidemiologic studies.Eur J Clin Epidemiol. 1994; 10: 405-411
- Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41
- Reasons prompting digitalis therapy in the acute care hospital.J Gerontol A Biol Sci Med Sci. 2001; 56: M361-M365
- Evaluation of a mental test score for assessment of mental impairment in the elderly.Age Ageing. 1972; 1: 233-238
- Value of Hodkinson’s test for detecting dementia and mild cognitive impairment in epidemiological surveys.Neuroepidemiology. 1994; 13: 64-68
- Cognitive impairment and mortality in a cohort of elderly people.BMJ. 1996; 12: 608-611
- Validation of the Hodkinson abbreviated mental test as a screening instrument for dementia in an Italian population.Neuroepidemiology. 1992; 11: 288-295
- International Classification of Diseases. Public Health Service, Health Care Financing Administration, Washington, DC1980 (9th Revision.)
- Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.J Clin Epidemiol. 1992; 45: 613-619
- The prevalence of anemia in the world.World Health Stat Q. 1985; 38: 302-316
- Delivering the cumulative benefits of triple therapy to improve outcomes in heart failure.J Am Coll Cardiol. 2003; 42: 1234-1237
- Association of stroke with dementia, cognitive impairment, and functional disability in the very old.Stroke. 1998; 29: 2094-2099
- Reduction in regional cerebral blood flow during normal aging in man.Stroke. 1980; 11: 31-35
- Cerebral blood flow and neurological change in chronic heart failure.Stroke. 2001; 32: 2462-2464
- Fundamental importance of arterial oxygen content in the regulation of cerebral blood flow in man.Brain. 1985; 108: 81-93
- Low blood pressure and the risk of dementia in very old individuals.Neurology. 2003; 61: 1667-1672
- Reversible dementias.Med Clin North Am. 1993; 77: 215-230
- Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure.J Am Coll Cardiol. 2004; 43: 1439-1444
- Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer’s disease and vascular dementia.Lancet. 2001; 357: 436-439
- The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron.J Am Coll Cardiol. 2001; 37: 1775-1780
- Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients.J Am Soc Nephrol. 1999; 10: 854-863
- Anemia—not just an innocent bystander?.Arch Intern Med. 2003; 163: 1400-1404
- Looking at the relationship between hemoglobin concentration and prevalent mobility difficulty in older women. Should the criteria currently used to define anemia in older people be reevaluated?.J Am Geriatr Soc. 2002; 50: 1257-1264
- Cost-effectiveness analysis in clinical practice. The case of heart failure.Arch Intern Med. 1999; 159: 1690-1700
- Do we practice geriatric cardiology?.J Am Coll Cardiol. 1997; 29: 217-218
Article info
Footnotes
The GIFA study was partially supported by a grant from the National Research Council (n.94000402). The work of Dr. Cesari was supported by the Wake Forest University Claude D. Pepper Older Americans Independence Center (NIA grant P30-AG-021332-03).
Identification
Copyright
© 2005 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
