Current Understanding of the Role of Frailty in Cardiovascular Disease
Article ID: CJ-20-0594
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Article ID: CJ-20-0594
The elderly population is increasing because of increasing life expectancy, and the prevalence of frailty increases with age. Frailty commonly coexists with cardiovascular diseases (CVDs), such as coronary artery disease (CAD), heart failure (HF), aortic stenosis (AS), and atrial fibrillation (AF). Frail patients who undergo revascularization for CAD have higher complication rates; those with HF have a high prevalence of poor outcomes, and those with AF are vulnerable to increased stroke incidence. Moreover, frailty and asymptomatic severe AS were independent factors for mortality. The presence of frailty can lead to poor clinical outcomes, and frailty has been identified as a risk factor for mortality. Thus, the identification of frail patients who are at higher risks of disability and adverse clinical outcomes is important. In this review, the relationship between frailty and CVD is appraised and optimal treatments for frail patients are discussed.
Aging is associated with physical, psychological, and social changes, which ultimately affects life expectancy. The incidence of neurological diseases, such as dementia and Parkinson’s disease, cardiovascular disease (CVD), and motor disorders, increase with age and constitute “geriatric syndrome,” which cause symptoms that require additional medical examinations and nursing care, and are associated with delirium, falls, incontinence, and frailty.1 Frailty is defined as a clinically recognizable state among older adults with increased vulnerability, resulting from age-associated declines in physiologic reserve and function across multiple organ systems, compromising the ability to cope with daily or acute stressors.2 Sarcopenia contributes to the development of physical frailty and is defined as the loss of skeletal muscle mass and function with age.3 Apart from the physical aspects of frailty that are predominantly caused by sarcopenia, the other contributing factors include social and cognitive aspects. Social changes include an increasing prevalence of nuclear families, along with a greater number of the elderly living alone, whereas cognitive elements may be age-related dementia or illness.4 We need to address not only physical frailty but also social and cognitive frailty; therefore, this review extensively discusses frailty. In Japan, the number of CVD cases has recently increased because of the aging population and the diffusion of the Western diet, and CVD is now the second-highest cause of death. In this review, we summarized current knowledge regarding the relationship between frailty and CVD.
Increased life expectancy and a rapidly aging population have increased the number of elderly patients requiring complex cardiovascular interventions, such as coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). Older patients are more likely to present with multiple comorbidities and multivessel coronary artery disease (CAD), contributing to poorer outcomes following revascularization.5 Because elderly patients represent the fastest-growing cohort to experience death due to CAD, we must assess preoperative physiological reserves, to determine a patient’s suitability for CABG, PCI, or medication.6 Besides conventional risk assessment, frailty assessment is increasingly recognized as an available indicator for the prediction of outcomes after cardiac surgery.7
Frailty has been detected in 25–50% of CAD patients.8 Conversely, CAD is present in 62% of male patients with frailty and 28% of males with non-frailty.9 These findings indicate that CAD and frailty are possibly associated with each other. Consistent with these findings, a recent meta-analysis has shown that frailty is a risk factor for CVD;10 therefore, it is plausible that certain rehabilitation approaches for improving frailty, including resistance training or nutrition therapy, involving high protein and amino acid intake, can contribute to an improvement in the prognosis of CVD patients with frailty. Although there are many reports about cardiac rehabilitation improving functional capacity in addition to quality of life in patients with frailty, those evaluating whether cardiac rehabilitation contributes to an improvement in the prognosis of CVD, including CAD, by ameliorating frailty are few. We hypothesize that the underlying reasons for this absence include the fact that resistance training is not recommended in most CVD patients because it increases cardiac afterload.
As described above, frailty is common in patients with CAD. In addition, frailty is reported as a risk factor for poor outcomes after interventions, such as PCI and CABG. Some researchers have reported that 20% of patients with CAD are frail, as assessed by the Fried Frailty Score (FFS), which is the most commonly used frailty assessment tool.2,5 Among 28,361 cases that underwent PCI, frailty, as assessed by using the FFS, was associated with a worse 3-year mortality.11 Nishihira et al analyzed 546 acute coronary syndrome (ACS) patients, aged ≥80 years, who underwent PCI. Frailty was classified based on impairments in walking, cognition, and activities of daily living. Frailty was detected in 27% of patients and was independently related to higher mid-term, all-cause mortality.12 Frailty evaluations can be difficult to assess based only on the routinely collected parameters available in electronic healthcare records that form the basis of many contemporary risk scores that guide PCI practices and are used for benchmarking.13 Therefore, the Hospital Frailty Risk Score (HFRS) has been developed in response to these limitations. High-frailty risk, as assessed by using the HFRS, was independently related to hospital death, bleeding, and vascular injury.14
When deciding whether to conduct CABG, preoperative CAD assessments are important to ensure the best treatment options for patients.15 In a study of patients undergoing isolated CABG, the preoperative Clinical Frailty Scale (CFS) was an independent predictor of hospital/30 day mortality.16 Afilalo et al reported that slow gait speed was an independent predictor of poor outcome, even after adjusting for the Society of Thoracic Surgeons (STS) score.17 In 304 patients who underwent elective isolated off-pump CABG, preoperative sarcopenia was an independent predictor of late mortality. Preoperative sarcopenia estimation was also a useful tool for predicting mortality after CABG, and was effectively able to predict postoperative prognosis, similar to various frailty assessments.18
As described above, frail patients who undergo revascularization have higher rates of procedural failure, complications, morbidity, and mortality. Increasing evidence indicates that the presence of frailty is a recognized indication that may guide treatment decisions in elderly patients. We did not find sufficient data for establishing an association between stable angina and frailty and for determining whether frail patients who undergo revascularization have higher rates of procedural failure, complications, morbidity, or mortality. Nonetheless, a study reporting on the relationship between frailty and ACS showed that PCI outcomes were better in ACS patients who were at high risk of frailty than in those who underwent medical therapy.19 Therefore, evaluating ischemia in elderly patients with frailty is imperative.
In CAD, whether patients with frailty should be provided invasive treatment such as PCI or CABG remains controversial to date. However, given that frailty is strongly associated with CAD and frailty in patients may mask symptoms of ischemic heart disease, examining if CAD is complicated in the elderly, including by the presence of asymptomatic myocardial ischemia, is important.
Frailty generally coexists with acute or chronic heart failure (HF). More than half of all patients with acute decompensated HF were identified as frail, and many reports have described the relationship between chronic HF and frailty.20,21 For both HF and preserved ejection fraction (HFpEF) and HF and reduced ejection fraction (HFrEF), frailty is associated with a higher risk of adverse outcomes. HFpEF is the most common type of HF among the elderly.22 In the TOPCAT trial, frailty with HFpEF conferred the greatest risks for hospitalization and all-cause mortality.23 Moreover, 63% of patients were determined to be frail, as assessed by a 42-item frailty index, among 13,625 participants in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). The frailest group demonstrated the worst outcomes, with high rates of all-cause death and all-cause hospitalization.24 Other studies have reported that the prevalence of frailty in patients with HFpEF is higher than that in patients with HFrEF, which may be associated with the elderly and the higher comorbidity burden observed among HFpEF patients than among HFrEF patients.23,25 HF is likely to enhance frailty. Moderate and severe frailty was associated with an increased risk of incident HF diagnoses in the Health, Aging, and Body Composition Study.26 Patients with frailty and HF are associated with worse outcomes. A recent meta-analysis showed that patients with HF and frailty had a 57% higher risk of hospitalization and an 80% higher risk of mortality compared with non-frail patients.27 Patients with chronic HF and frailty are significantly associated with an increased risk of mortality and incident hospitalization. Another recent meta-analysis showed that among individuals with HF, 40% were frail. The prevalence of frail individuals with HF was 31%. Two studies used the Frailty Risk Index to assess the relationship between frailty and HF.28 Older patients with HF have a high prevalence of poor functional status and worse outcomes. The treating frailty can change the prognosis and treatment approach for HF. A fundamental challenge is the limited experimental models that exist to investigate the pathophysiology of frailty. In the future, routine frailty screening during outpatient and inpatient clinical practice and new management strategies for improving outcomes and reducing the frailty burden among this high risk, vulnerable population will be necessary.
Aortic stenosis (AS) represents the most common valvular heart disease in developed countries and the prevalence increases with age.29 Severe AS increases afterload, leading to progressive left ventricle hypertrophy and decreased systemic and coronary blood flow, resulting in the causation of angina, syncope and HF development with a high risk of sudden death.30
Studies have examined the relationship between AS and frailty. One study reported the prevalence of frailty among older people (mean age 84.6±4.4 years), with severe AS to be 38.4%. Frailty in combination with severe AS is also associated with left ventricle ejection fraction, nutritional status, serum albumin, estimated glomerular filtration rate, grip strength, CAD, CVD, and musculoskeletal disorders.31 Another study showed that the prevalence of frailty among patients aged ≥70 years, who have asymptomatic severe AS, was 59.6%. Among such patients with asymptomatic severe AS, frailty was an independent factor for mortality, and the overall 1-year survival rate among this population was 76%.32 As for symptomatic severe AS, a prospective study revealed that the prevalence of frailty among patients aged ≥75 years was 49.3% and that frailty in these patients was also associated with increased mortality.33 Thus, these results call our attention to the fact that frailty is highly complicated in patients with AS, regardless of whether they are symptomatic or asymptomatic.
Severe AS can be managed by surgical aortic valve replacement (SAVR), transcatheter aortic valve implantation (TAVI), and medical (palliative) therapy. The gold standard treatment for low-risk patients is SAVR. However, patients aged ≥80 years who undergo SAVR experience increased operative complications, with a 10% 30-day mortality rate.34 Therefore, intervention decisions among the elderly population can be difficult. TAVI represents a viable alternative for patients with severe symptomatic AS, regarded as too high risk for SAVR.29 The STS score and the EuroSCORE II are commonly used to assess the risk of poor outcomes in patients with severe AS;35 however, these tools were developed for younger cohorts and excluded the use of TAVI. Therefore, the predictive scores assessed using these tools may be poorly correlated with actual results. These predictive tools only present prognostic assessments for early surgical outcomes, which may not be the key endpoint after TAVI.36 Assessing baseline frailty, particularly its severity, is important in patients with severe AS who are being considered for TAVI. A recent meta-analysis showed that assessing frailty among already vulnerable TAVI patients detected individuals with greater risk of poor outcomes. Frailty was associated with elevated early mortality, in 4 studies, and with late mortality, in 7 studies. Objective frailty tools detected an even higher risk group for late mortality.37 Controversy exists regarding the management of asymptomatic patients with severe AS, and current evidence does not sufficiently support treatment choices for patients with severe AS, despite the risk of sudden death. A study reported that 6-month mortality was closely associated with frailty assessed using both CFS and a 34-item Frailty index, whereas severity of AS was not.38 Another study reported that 1-year mortality risk increased progressively with higher CFS scores, and that there was no significant difference in prognosis between palliative therapy and TAVI (CFS ≥7).39 Therefore, frailty assessment during preoperative evaluation is essential in AS patients undergoing TAVI, and only frail patients with severe AS (CFS ≤6) may be considered for TAVI. Frailty assessments can be important for patients with severe AS when considering treatment. Currently, despite variations in the definitions and measurements for frailty, there is no systematic frailty measurement. Additional studies examining TAVI-specific surgical risk assessments, including frailty assessments, are necessary.
Atrial fibrillation (AF) is the most common cardiac arrhythmia observed among the elderly, and its prevalence increases with age, ranging from 4.2% of those aged 60–70 years to 17% of those aged ≥80 years.40 AF patients are at high risk of complications, such as ischemic stroke, HF, and dementia, leading to reduced quality of life.41 A recent meta-analysis showed that the prevalence of frailty among AF patients ranged widely, from 4.4% to 75.4%,42 which may be due to differences in the ages of subjects in individual studies. The prevalence of frailty is strongly influenced by age, with very low prevalence (4.4%) among younger subjects, as demonstrated in a study by Ng et al (the mean age in this study was 66.7±7.8 years).43 Another meta-analysis reported that there was a mean prevalence of 39% for frailty among patients with AF.44 Both AF and frailty increase with age. Polidoro et al reported that AF was strongly associated with frailty status, independent of multiple confounders (age, sex, hypertension, diabetes, stroke, ACS, and HF), suggesting that AF can exacerbate frailty.45 Hung et al reported that AF was an independent risk factor for falls.46 The influence of AF on frailty status, especially among the elderly population, may be associated with the higher prevalence of falls, compared with those without AF. Patients with AF had higher levels of C-reactive protein than those without AF.47 Renin-angiotensin-aldosterone system activity also increases during AF, and these alterations may play key roles in the pathophysiological state of frailty among AF patients, because increased inflammation and renin-angiotensin system activity can induce skeletal muscle remodeling, through increased fibrotic change.48,49 By contrast, Madhavan et al indicated that frail patients experienced an increased prevalence of persistent or permanent AF than non-frail patients (54.1% vs. 44.2%).50 Some researchers have suggested that frailty is associated with increased left atrial volume, causing atrial remodeling and inflammation, which is a pivotal mechanism for the development of AF.51
In people with AF, frailty has been associated with adverse clinical outcomes. Frail patients with AF had increased stroke incidence and higher 6 month mortality, in comparison to non-frail patients with AF.52 To prevent stroke, the CHA2DS2-VASc score, which measures congestive HF, hypertension, age, diabetes, previous stroke/transient ischemic attack, may be used to identify patients who may benefit from anticoagulation. One study indicated that frail patients with AF had a higher mean CHA2DS2-VASc score than non-frail patients with AF.53 The use of oral anticoagulants (OACs) effectively prevents stroke risk, by 64%.54 By contrast, the HAS-BLED score has been recommended to estimate bleeding risk factors. One study reported that frail patients were associated with a higher risk of bleeding complications;55 however, the effect of frailty on the risk of bleeding is controversial. A recent meta-analysis showed that frail patients with AF at hospital admission demonstrated the reduced use of OAC prescriptions compared with non-frail patients with AF,56 which appeared to be associated with a fear of falls and the consequent risk of intracranial hemorrhage.53 Because no defined frailty assessment tool exists, frailty assessment is often left to the physician’s discretion, which is a major problem underlying OAC under-prescription and associated consequences. Conflicting results regarding OAC prescriptions among patients with frailty have been reported. Compared with frail patients using OACs, those who were not prescribed OACs had significantly more ischemic stroke events and clinically relevant bleeding after 1 year of follow up.57 However, other studies reported no significant differences between frail and non-frail AF patients using OACs, in terms of the risk of bleeding at baseline and the risk of hemorrhage.52,58 Because of a lack of evidence to guide the best treatments, anticoagulation treatment remains a challenge among patients with both AF and frailty. The establishment of a standard frailty assessment tool that can be applied to all patients remains necessary. Because many AF patients have concurrent frailty and vice versa, the management of AF and frailty has become a central concern for this aging society.
This study reviewed the close relationship between frailty and CVD (Figure). However, other CVDs, such as PAD, have not been well explored relative to frailty. PAD is a manifestation of atherosclerosis, and critical limb ischemia (CLI) is the most advanced form of PAD. PAD/CLI patients have poor prognosis because of the high prevalence of concomitant vascular disease, including CAD and/or cerebrovascular disease.59 Although the number of patients with PAD/CLI is increasing, few reports have examined the relationship between PAD/CLI and frailty because of the difficulty of assessing frailty status in PAD/CLI patients, who present with gait disturbances. Another CVD for which the correlation with frailty remains unknown is pulmonary hypertension (PH). PH refers to the inappropriate elevation of pressure in the pulmonary vascular system, resulting in right ventricular dysfunction development and HF.
Relationship between cardiovascular disease (CVD) and frailty.
Malnutrition is the primary cause of frailty and sarcopenia,60 and nutritional risk assessments have been reported to predict prognosis in patients with HF or CAD.61–63 Sze et al have reported that, among 3,386 HF patients, 6.7% were moderately or severely malnourished, as assessed by the Geriatric Nutritional Risk Index (GNRI), and that their 1-year mortality was 41%, which was much higher than the 9% observed in those with mild malnutrition or normal nutritional status.61 Another study that analyzed GNRI in 152 consecutive patients who were hospitalized for HFpEF demonstrated that patients in the low GNRI group had lower physical activity at discharge, as measured by the Barthel Index, than those in the high GNRI group. In addition, lower GNRI predicted greater mortality.62 As for CAD, Kunimura et al evaluated GNRI at baseline in 802 patients who underwent elective PCI and revealed that lower GNRI scores were associated with greater frequency of cardiac events after elective PCI.63 Recently, we reported that malnutrition, assessed using GNRI, affected the prognosis of patients with either PAD/CLI or PAH.64,65 We investigated 137 CLI patients who had previously undergone successful revascularization for CAD. Twenty-three (17%) patients died, and the GNRI level among the deceased group was significantly lower than that among the surviving group. Malnutrition, as defined by a GNRI <92, was significantly associated with cerebrovascular or cardiovascular death.64 In another clinical study, investigating 104 patients with either PAH or chronic thromboembolic PH, the incidence of PH rehospitalization was higher in the low GNRI group (<92) than that in the high GNRI group (≥92). The cumulative event-free rate was significantly lower in the low GNRI group.65 Because nutritional status is crucial for skeletal muscle maintenance, nutritional status intervention may be an important strategy for the treatment of CVD patients with frailty. Several clinical studies have attempted to improve muscle strength and performance in patients with chronic HF, through the administration of protein and/or essential amino acids. However, the effects of these administrations on muscle condition in HF patients remain controversial.66 Skeletal muscle and cardiomyocytes are highly dependent on ATP, produced by mitochondria, which also contributes to glucose and fatty acid metabolism. By contrast, chronic HF is associated with inflammation, which leads to mitochondrial dysfunction in skeletal muscle, reducing exercise capacity, and facilitating sarcopenia.10,67 Thus, improving nutritional status and mitochondrial function, combined with decreased inflammation, may be effective for improving CVD in patients with frailty.
Frailty and several CVDs are closely associated, and frailty affects clinical outcomes, including prognosis in CVD patients. Patients who develop CVD are vulnerable to reductions in exercise intolerance because of cardiopulmonary disorders. Therefore, besides curing CVD, frailty status must also be estimated, and interventions should be targeted to reduce frailty in CVD patients during treatment. Drug efficacy for CVDs must be determined in patients with frailty because it would be useful in improving patient prognosis. Recent basic experimental studies in animal models have demonstrated the importance of autophagy, an intracellular system for recycling and protein quality control, in mediating skeletal muscle homeostasis, which contributes to preventing frailty/sarcopenia. Maintaining satellite cell quiescence and avoiding senescence are crucial for muscle stem-cell regeneration. Physiologically aged satellite cells have impaired autophagy, leading to loss of proteostasis, increased mitochondrial dysfunction, and oxidative stress, which then result in a decline in the number and function of satellite cells. Of note, re-establishment of autophagy can reverse senescence and restore regenerative functions in geriatric satellite cells.68 Given such beneficial effect of autophagy on skeletal muscle, further clinical experiments to identify drugs that can induce autophagy may help improve frailty and prognosis in patients with CVD.
In conclusion, frailty and CVD are closely associated and assessment of frailty is vital for the treatment of CVD. However, future initiatives to develop optimal intervention strategies for the treatment of CVD patients with frailty are needed.
The authors would like to thank Enago for English-language review.
This work was supported, in part, by the Japan Society for the Promotion of Science KAKENHI (Grant No. 19K07891).
M.O. is a member of Circulation Journal ’ Editorial Team. The authors declare no conflicts of interest.
