Coexisting Frailty, Cognitive Impairment, and Heart Failure: Implications for Clinical Care

From the Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA.

Abstract

• Objective: To review some of the proposed pathways that increase frailty risk in older persons with heart failure and to discuss tools that may be used to assess for changes in physical and cognitive functioning in this population in order to assist with appropriate and timely intervention.
• Methods: Review of the literature.
• Results: Heart failure is the only cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients. Compared with age-matched counterparts, older adults with heart failure 4 to 6 times more likely to be frail or cognitively impaired. The reason for the high prevalence of frailty and cognitive impairment in this population is not well known but may likely reflect the synergistic effects of heart failure and aging, which may heighten vulnerability to stressors and accelerate loss of physiologic reserve. Despite the high prevalence of frailty and cognitive impairment in the heart failure population, these conditions are not routinely screened for in clinical practice settings and guidelines on optimal assessment strategies are lacking.
• Conclusion: Persons with heart failure are at an increased risk for frailty, which may worsen symptoms, impair self-management, and lead to worse heart failure outcomes. Early detection of frailty and cognitive impairment may be an opportunity for intervention and a key strategy for improving clinical outcomes in older adults with heart failure.

Approximately 5.7 million persons in the United States are diagnosed with heart failure, and the number of reported new cases is expected to increase to over 700,000 cases annually by the year 2040 [1]. This rising incidence is fueled by an aging population; by the year 2030, 1 in 5 Americans will be over 65 years of age [2]. Heart failure is prevalent among those 65 years of age and older and is the most common reason for hospitalization in this age-group. High readmission rates, approaching 50% over 6 months, are a major contributor to the the escalating economic burden associated with heart failure [3].

Persons with heart failure are more likely to be frail and experience cognitive impairment than their age-matched counterparts without heart failure. The reasons for this are not well known but may be related to hemodynamic, vascular, and inflammatory changes occurring as heart failure progresses. In this paper, we review the link between frailty and cognitive impairment in heart failure, instruments that may be useful for early detection, and interventions such as exercise that may be beneficial for attenuating both conditions.

Frailty in Heart Failure

Epidemiology

Frailty is a heightened vulnerability to stressors in the presence of low physiological reserve [4]. When exposed to stressors, persons who are frail have a much higher probability for disproportionate decompensation, negative events, functional decline, disability, and mortality [5]. Among persons with heart failure, frailty may predispose them to decompensate at a lower threshold, requiring more frequent hospitalizations. Persons with heart failure are more likely to be frail than their age-matched counterparts without heart failure [6,7].

Frailty is a powerful predictor of poor clinical outcomes and mortality in cardiovascular disease [8,9]. Compared with the non-frail, frail persons with heart failure have increased rates of mortality (16.9% vs 4.8%) and increased rates of heart failure hospitalization (20.5% vs 13.3%) [10]. Frailty has also been shown to predict falls, disability, and hospitalization in heart failure patients [6,9,11] and was found to have a negative linear relationship with health-related quality of life [12]. Frail heart failure patients are also more likely to have comorbidities such diabetes mellitus, chronic obstructive pulmonary disease, atrial fibrillation, depression, anemia, and chronic kidney disease [9,13].

Pathophysiology

There is significant overlap in the underlying pathological mechanisms of heart failure and frailty. Symptoms of heart failure, such as dyspnea, fatigue, and muscle loss, mirror components that occur with frailty. Further, cardiac cachexia, a metabolic syndrome in advanced heart failure characterized by a loss of muscle mass, is very similar to the sarcopenia that occurs in frailty.

Frailty, characterized by an increased physiologic vulnerability to stressors, may predispose frail persons with heart failure to exacerbation and worsening of heart failure due to greater susceptibility to the harmful pathophysiologic processes in heart failure, such as inflammation and autonomic dysfunction. Proposed pathophysiologic pathways in frailty include free radicals and oxidative stress, cumulative DNA damage, decreased telomere length, and nuclear fragmentation [14,15]. Frailty has been associated with low-grade chronic inflammation and increased inflammatory cytokines, such as C-reactive protein, tumor necrosis factor–alpha (TNFα), interleukin-6 (IL-6)and fibrinogen [16–18]. Heart failure also is associated with a low-grade and chronic cardiac inflammatory response that is correlated with disease progression [19].

Inflammation. IL-6 is detectable in a higher proportion of persons who are frail compared to non-frail [16] and is the most highly correlated biomarker with frailty. In addition, among those with detectable IL-6 levels, those categorized as frail have higher IL-6 levels compared to those who are non-frail [16,20]. Individuals categorized as frail were found to have significantly higher levels of TNFα than those who were non-frail [16,20]. Increased IL-6 levels are associated with decreased muscle strength, while increased TNFα levels are associated with decreased skeletal muscle protein synthesis [21,22], thus contributing to frailty.

Oxidative stress. Protein carbonyls result from protein oxidation promoted by reactive oxygen species and are markers of oxidative stress. Protein carbonylation is implicated in the pathogenesis of the loss of skeletal muscle mass; high serum protein carbonyls are associated with poor grip strength [23]. 8-OHdG is an oxidized nucleoside indicative of oxidative damage to DNA and a measure of oxidative stress. Accumulation of 8-OHdG in skeletal muscle leads to loss of muscle mass and is associated with decreased hand grip strength in the elderly [24]. Higher serum levels of 8-OHdG are present in older adults who are frail as compared to those who are non-frail [25].

Measurement of Frailty in the Clinical Setting

Frailty has been conceptualized in a number of studies using different models and measures; however, there continues to be a lack of consensus on the definition and operationalization of frailty. Prior research has led to the development of several validated models of frailty that have demonstrated good prediction of adverse outcomes in older adults. Some models, such as the Fried phenotype [6], focus solely on the physical dimension, while other models take a multidimensional approach.Single-item measures (eg, gait speed, 6-minute walk test, handgrip strength) are also commonly used to screen for frailty, but a frailty measure that incorporates more than 1 physical dimension may be more sensitive and reliable. In our opinion, the ideal measure of frailty would consist of a brief assessment that can be serially performed in most clinical practice settings that can identify change in function over time. The incorporation of sensitive physical function measures that can detect frailty early has the potential to slow physical function decline by preserving physiological thresholds.

Cognitive Impairment in Heart Failure

Epidemiology

Cognitive impairment occurs frequently in patients with heart failure, and the presence of cognitive impairment in persons with heart failure has been shown to heighten risk for adverse clinical outcomes, disability, poor quality of life, and mortality [26,27]. Heart failure negatively influences cognitive functioning in most domains [28–32]. The most common domains adversely affected by heart failure and aging are memory and executive function. Deficits in these domains can substantially diminish patient ability to carry out essential self-care behaviors [30,32].

The most common form of cognitive impairment seen in patients with heart failure is mild cognitive impairment (MCI), which is a measurable deficit with memory or another core cognitive domain. Up to 60% of persons with heart failure have been reported to have MCI. Patients with MCI have cognitive deficits that are more pronounced than those seen in normal aging, but lack other symptoms of dementia, such as impaired judgment or reasoning. MCI often will not impede patients’ ability to carry out the activities of daily living (ADLs) independently, but patients may have difficulty in performing some instrumental activities of daily living (IADLs), such as remembering medications, scheduling provider appointments. Dementia, a decline in cognitive ability severe enough to hinder an individual’s ability to perform ADLs or IADLs or engage in social activities or occupational responsibilities, occurs in approximately 25% of persons with heart failure [33].

Persons with heart failure have a fourfold greater likelihood of developing CI than persons without heart failure. Several cohort studies have shown that persons with heart failure had lower performance on cognitive tests than individuals without heart failure [34,35] and were 50% more likely to progress to dementia.

Assessment Tools

Although a comprehensive neurocognitive battery would aid in detecting cognitive impairment in heart failure, few clinical practice settings have the resources to perform such a detailed and time-consuming measurement. Most studies in heart failure have relied on global screening questionnaires such as the Mini-Mental State Examination (MMSE) [36] to assess cognitive functioning in persons with heart failure and in other cardiovascular disorders. Global cognitive measures, however, often lack sensitivity for detecting subtle cognitive deficits such as seen in MCI [28–30]. Screening that measures executive function may be the most beneficial for busy clinical settings, since declines in this domain are well established as contributing to poor outcomes in persons with heart failure.