Frailty, from the Latin “fragilis,” meaning “easily broken,” is a biological syndrome that reflects a state of decreased physiological reserve and vulnerability to stressors [1, 2]. Stressors are generally classified as acute or chronic illness, minor or major (e.g., myocardial infarction), or iatrogenic events (e.g., new drug therapies, minor surgery). When exposed to such stressors, frail patients global health state changes dramatically, and they become at risk for adverse outcomes such as procedural complications, adverse drug reactions, prolonged recovery, mobility decline, disability onset, and mortality [3]. Many models have arisen to define and operationalize frailty in a specific and standardized manner. Reliable frailty models should be assessed as predictors of both natural history and response to therapeutic interventions and based on biological principles of causality [4]. In fact, different models of frailty, underpinned by different theoretical constructs, capture basically different groups of older adults [5].

The two principal emerging models of frailty are the phenotype model [6] and the cumulative deficit model underpinning the Canadian Study of Health and Aging (CSHA) Frailty Index [7]:

As a matter of fact, with the population aging, recognition of frailty in older adults becomes increasingly important [4]. Recently, a consortium of a number of international societies has suggested that all persons over 70 years of age should be screened for frailty using one from a number of simple validated questionnaires available to carry out the screening [8]. At present, frailty assessment is often embedded in the comprehensive geriatric assessment (CGA). CGA is a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological, and functional capabilities of an older person in order to develop a coordinated and integrated plan for treatment and long-term follow-up. While integrating standard medical diagnostic evaluation, CGA emphasizes also problem solving, functional status, and prognosis with the aim of restoring independence and alleviating distress. It involves an interdisciplinary care team that coordinates evaluation of an older patient and develops a plan for integrated care. CGA is currently the perfect tool to detect frailty and it should be more widely employed in different settings. There is evidence that CGA improves clinical outcomes in frail older patients admitted to acute hospitals [9].

Depending on different definitions of frailty, the inclusion/exclusion criteria between the different studies, the prevalence of frailty ranges from 4 to 59 %. When the reported rates are restricted to the studies that used the phenotype model, the weighted average frailty prevalence rate is 9.9 %, and the prevalence of pre-frailty is 44.2 % [10].

Differences in frailty prevalence have been reported according to:

Chronic comorbidities and disability are often associated with frailty, but there is evidence that frailty can exist independently of these factors. In the CHS, frailty and comorbidity (defined as two or more co-occurring chronic diseases) were present in 46.2 % of the population, frailty and disability (defined as the presence of restriction in at least one activity of daily living) were present in 5.7 %, and the combination of frailty, disability, and comorbidity was present in 21.5 % of the study group, but frailty was present without comorbidity or disability in 26.6 % of the study group [11].

Dysregulation in multiple physiologic systems, especially immune, endocrine, and neurohormonal systems, is a key feature of frailty. There is a gradual decline in physiological reserve with aging, but, in frailty, this decline is accelerated, and homeostatic mechanisms start failing. Together, these dysregulated systems create an anabolic–catabolic imbalance, leading to increased muscle catabolism, weight loss, and subclinical organ dysfunction [12].

Skeletal muscle is currently one of the organ systems best studied in the development of frailty, and sarcopenia is a key component of frailty. Wasting and weight loss are manifested by loss of muscle fibers, altering muscle composition, which in turn leads to the phenotypic weakness, slowness, and functional deterioration inherent to frailty syndrome [12]. Hormonal changes, including lower levels of insulin-like growth factor-1 (IGF-1) and dehydroepiandrosterone sulfate (DHEA-S), and higher levels of cortisol as well as low vitamin D, can contribute to decrease skeletal muscle mass. Sarcopenic and frail patients have elevated levels of inflammatory markers such as interleukin 6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNFα) and increased markers of oxidative stress [13]. Inflammation is associated with anorexia and catabolism of the skeletal muscle [14].

The other organ systems often evaluated in the pathophysiology study of frailty are the neurological, endocrine, and immune systems which in turn are correlated with the skeletal muscle.

A study involving 1,002 female participants investigated cumulative physiological dysfunction in six different systems (hematological, inflammatory, hormonal, adiposity, neuromuscular, and micronutrients) using 12 measures and reported a nonlinear relationship between the number of abnormal systems and frailty, independently of age and comorbidity [15]. The presence of abnormal results in three or more systems was a significant predictor of frailty. Significantly, the number of abnormal systems was more predictive than abnormalities in any particular system, providing evidence that when physiological decline reaches an aggregate critical mass, frailty becomes evident.

Entreating clinicians away from judgments based on chronological age toward the notion of frailty is very important because there is a large between-group difference for people who are frail compared to not frail. Moreover, due to the dynamicity of the process, frailty needs to be measured at different time points in order to identify different stages of frailty in the same individual during time. Geriatricians have been struggling to identify a way to operationalize the concept of frailty into measurable variables. Standardized measures of frailty have been developed, but they are better suited for research settings—not the clinic. Researchers and clinicians, therefore, require simple, valid, accurate, and reliable tools to detect frailty. Walking speed has been investigated as potential single assessments to detect frailty; it could be administered in primary care as it does not need special equipment, and it takes few minutes to be measured, and it captures much of the clinical construct of frailty [16]. A pooled analysis of nine prospective studies (n = 34,485) [17] showed that slow gait speed successfully characterized the subgroup of older people who had adverse outcomes and had similar accuracy to complex multivariate models that included itemizing chronic conditions. Survival increased across the full range of gait speeds. In the Cardiovascular Health Study, participants ≥65 years with incident heart failure (HF) were evaluated. Impairment in gait speed measured within 1 year before the diagnosis of incident HF was independently associated with mortality, adjusting for sociodemographic and clinical characteristics [18]. Beyond mortality, gait speed has been recently studied as a useful instrument for identifying which elderly adults are most at risk for the adverse effects of hypertension. In the National Health and Nutrition Examination Survey, the association between blood pressure (BP) and mortality varied by walking speed. Among faster walkers, those with elevated systolic BP had a greater adjusted risk of mortality compared with those without. Among slower walkers, neither elevated systolic nor diastolic BP was associated with mortality [19].

Frailty is dynamic and its earlier stages are potentially reversible [8]. However, transition to a level of greater frailty is more common than reversion to a pre-frail status [4]. The 2013 consensus statement on frailty focused on some interventions which have shown some efficacy in the treatment of frailty. The most consistent benefit has been demonstrated with physical exercise. In a randomized trial, exercise-based rehabilitation decreased hospitalization and nursing home placement following hip fractures in frail patients [20]. Nutritional supplements or a dietary plan that includes 25–30 g of high-quality protein per meal have been proposed to slow or prevent sarcopenic muscle loss [21]. Nutritional supplements can work synergistically with the benefits of resistance exercises in older adults. Vitamin D supplements have been reported to improve muscle function, reduce falls, and fractures [22], but meta-analyses suggest calcium supplements with or without vitamin D may increase the risk of myocardial infarction [23]. Finally, polypharmacy or the use of multiple or duplicative or inappropriate medications increases the risk of drug–drug and drug–disease interactions and contributes to adverse health outcomes and should be limited especially in frail elderly which are at high risk of not recovering prestressor health status.

Due to the aging and increasing complexity of patients affected by cardiovascular diseases (CVDs), the identification of frailty has become a high-priority topic in cardiovascular medicine [24]. The American Heart Association and the Society of Geriatric Cardiology have called for increased understanding of the role of frailty in CVD [25]. The prevalence of frailty in older adults with CVD depends on the population studied and the frailty assessment tool used but ranges from 10 to 60 % and is about 3 times more prevalent compared to older persons in the community [26]. Among all CVD, the phenotype of heart failure (HF) is one of those most rapidly increasing. In fact, due to improved management of chronic diseases such as hypertension and coronary artery disease, as well as interventions that improve survival, the HF population is aging. HF incidence doubles with each decade, starting at 5 % between ages 65 and 74 years and rises to 20 % in those over 80 years of age [27]. Prevalence of HF is high in older persons with frailty and vice versa. In the Cardiovascular Health Study (CHS), the prevalence of HF increases from 1.8 % in the non-frail, 4.6 % in the intermediate group, to 14.0 % in the frail group [28]. Similarly, participants of the women health initiative (WHI) who have HF were 6–7 folds more likely to be frail [29]. In addition to HF precipitating frailty, the reverse is also true. Frail community-dwelling elders are more likely to develop de novo HF then their non-frail counterparts [30]. The Health ABC Study followed 2,825 older patients free of HF at baseline over a period of 11 years and found that frailty conferred a 30 % higher risk of developing new HF [30]. Excluding HF events in the first year did not alter the results, showing that frailty was not merely capturing undiagnosed/imminent cardiac dysfunction. Notably, the risk for HF-related frailty rises dramatically with age, as a 30 % prevalence has been identified in patients younger than age 70 versus a 52 % prevalence in those 70 years or older [31].

Whether there is an etiological distinction between the primary frailty of aging and frailty secondary to chronic disease such as HF is still unknown, but there is the need to address this distinction. Similar to that seen in primary frailty, the wasting process of HF is likely related to an anabolic–catabolic imbalance in which initially adaptive neurohormonal mechanisms and autonomic nervous system activation yield detrimental systemic effects over time. Inflammatory, metabolic, and autonomic abnormalities that are associated with frailty are frequently seen in patients with HF. Consistent evidence exists for tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1), and interleukin 6 (IL-6) upregulation [32], along with abnormalities in the growth-hormone/insulin-like growth factor (GH/IGF-1) axis and cortisol regulation. Furthermore, the clustering of muscle loss, weakness, and exhaustion has been a long recognized in HF. In addition to sarcopenia and frailty, cardiac cachexia, defined as loss of 5 % of one’s body weight over 6 months [33], is a third term referring to the wasting process of this population. Depending on the definition used, studies in HF find about a 20 % prevalence of sarcopenia, a 20–50 % prevalence of frailty, and 15 % prevalence of cardiac cachexia [34].

Frailty and comorbidity are clinical manifestations of two distinct, though possibly interconnected, aging-related processes, namely, diminished functional reserve and accumulation of pathological processes. Nevertheless, frailty and comorbidity often overlap in the elderly and lead to impairment in quality of life and functional status. Morley described how disease processes (HF as well as its associated comorbidities) can accelerate functional muscle loss leading to sarcopenia, the hallmark of physical frailty [35]. The burden of comorbidities in elderly patients with HF is much higher than in those without HF [36]. Braunstein et al. studied the burden of noncardiac comorbidities in 22,630 HF patients, 65 years and older, identified in a 5 % random sample of all US Medicare beneficiaries. He found that 40 % of these patients had ≥5 comorbidities, 70 % had ≥3 comorbidities, and only 4 % had no comorbidities at all [37]. Once frailty is developed, both HF and its associated comorbidities can give rise to acute stressors which can lead to rapid functional decline resulting in disability, hospitalization, institutionalization, and eventually death. Finally, frailty and comorbidities are two main reasons of persistent exclusion of HF patients in clinical trials [38, 39]. Frail patients are more likely to be excluded from trials based on their limited mobility and access to research facilities, their cognitive impairment that limits the ability to understand and sign informed consents, and their presumed intolerance of the intervention being studied [40]. This underrepresentation of elderly patients with HF in RCTs, especially those with frailty and multiple comorbidities, results in a paucity of evidence in this patient population and makes many aspects of their care still empirical [39].

Patients with chronic heart failure who were frail had a higher risk of mortality at 1 year (17 % vs. 5 %), heart failure hospitalizations (21 % vs. 13 %), and impaired quality of life [31]. Chaudhry et al. [41] showed that slow gait speed was the most powerful predictor of hospitalizations, conferring a 30 % increase; weak grip strength was also predictive, conferring a 16 % increase. In a long-term study by Cacciatore et al. [42], patients with chronic heart failure who were frail had a substantially lower probability of surviving >10 years (6 % vs. 31 %). Another study showed significantly higher rate of 1-year mortality (16.9 % vs. 4.8 %; P < 0.001) and higher rate of hospitalization (20.5 % vs. 13.3 %; P = 0.01) in elderly patients with HF who have frailty than in those who do not [43].

Therefore, given two heart failure patients with similar chronological age and comorbidities, the presence of objectively measured frailty alerts the clinician that 1 of the 2 patients has a substantially higher risk of mortality and major morbidity.

However, the importance of screening for frailty in heart disease is not only because of its prognostic value but also because a variety of therapeutic interventions is available for the components of physical frailty, which should be implemented in the framework of a comprehensive geriatric assessment [44]. In essence, frail older patients with HF should necessarily undergo comprehensive geriatric assessment followed by a personalized health plan.

Furthermore, the frail patient faces a higher risk from invasive procedures but also a potential benefit from interventions such as cardiac rehabilitation to counteract the physical weakness characteristic of frailty.

A key therapeutic intervention for frailty is exercise training. Exercise improves not only cardiac aerobic capacity and reverses the sarcopenic aspects of frailty and heart disease [45, 46] but also the energetic reflex in the muscle resulting in a decrease in fatigue [47]. Enrolment in cardiac rehabilitation improves outcomes of patients with CVD, but this intervention remains underutilized [48].

At present, evidence that interventions designed to improve frailty result in better outcomes in elderly patients with CVD is still limited and controversial. Large randomized clinical trials are needed to evaluate the optimal management of these patients and if interventions should target different groups of cardiovascular patients according to frailty [49].

Coronary artery disease (CAD) is common in older adults, representing the first cause of death also in this segment of the population. Older subjects account for 80 % of deaths for CAD. The most recent data estimated that almost one in five men and one in ten women in the age group 60–79 years have CAD, while the percentage rises to over 30 % in men and 19 % in women older than 80 years [50, 51]. The improvement of available treatments and their implementation in health care caused a progressive decline in mortality due to this condition, also in older patients, with a relevant contribution to the increase of life expectancy that occurred during the last part of the twentieth century [52]. CAD is also a leading cause of morbidity, disability, and health-care utilization in older subjects.

Frailty is common in older patients with CAD. The prevalence of frailty is reported to be up to 20 % of patients aged ≥65 years undergoing percutaneous coronary intervention (PCI) [53] and 27 % in patients aged ≥70 years with significant coronary artery disease at cardiac catheterization [54]. As in other cardiovascular conditions, the presence of frailty implies a worse prognosis, in terms of morbidity, disability, and mortality [53–56]. In 628 patients ≥65 years who underwent PCI at the Mayo Clinic, 3-year mortality was 28 % for frail patients defined according to the Fried criteria compared with 6 % for non-frail patients. Furthermore, the addition of frailty, comorbidity, and QOL significantly improves the prognostic ability of the Mayo Clinic risk score, a model based on traditionally assessed cardiovascular risk factors, for long-term mortality [53]. In other studies frailty was a better predictor of adverse outcome, particularly mortality, than other geriatric conditions, such as disability, cognitive impairment, or comorbidity in older patients with acute coronary syndromes [56]. In 4671 patients aged ≥65 years with an acute coronary syndrome managed medically who participated in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, 25 % were pre-frail (one to two items) and 5 % frail (≥3 items) according to a questionnaire based on the Fried frailty score. Frail participants were more likely to reach the composite primary endpoint (cardiovascular death, myocardial infarction, or stroke) over a period of 30 months even after adjustment for baseline variables and the Global Registry of Acute Coronary Events (GRACE) score [57].

There is some evidence of a bidirectional relationship between CAD and frailty. In the Health ABC study, older adults with frailty had increased risk to develop CAD events during the follow-up [58]. Furthermore, slow gait speed as well as impaired mobility predicted cardiovascular mortality and CAD-related mortality [59–61]. On the other hand, older women who suffered from CAD had a more than twofold higher probability to develop incident frailty during a 3-year follow-up in the Women Health Initiative study [29].

Although older patients usually have a higher degree of severity of CAD as well as more coexisting diseases and therefore a worse prognosis, medical treatment as well as invasive procedures, such as revascularization, has been associated with clinical benefits also in this population [49, 62–66]. However, older patients have also a higher probability of having multimorbidity and occurrence of complications [67, 68], and therefore they should be properly evaluated in order to identify those where the risk to benefit ratio might not be favorable. Unfortunately, chronological age alone is not a good criterion to predict the risk of adverse events. Frailty is a more suitable construct to capture the degree of vulnerability of the individual since it is closer to the biological age [49]. Nevertheless, while the prognostic importance to measure frailty in older subjects with CAD is well established, the implication that the diagnosis of frailty should have in the management of CAD in the individual patient is currently unclear [24]. A major determinant of current uncertainty is the fact that older patients with CAD have been usually excluded by clinical trials, particularly when very old, frail, and clinically complex due to the coexistence of multimorbidity and polypharmacy [69–71]. Gurwitz was the first to report that while an increasing proportion of patients with acute myocardial infarction were older subjects, the patients included in randomized trials were much younger and more often males than females [70]. A decade later, Lee and colleagues performed a reevaluation of the topic and confirmed these findings [71]. Moreover, older patients who are included in trials are highly selected and hence not representative of the population treated in clinical practice [25].

On this premise it is not surprising that older subjects in general, and particularly frail ones, with ACS are frequently undertreated in clinical practice [68, 72]. Several authors showed that effective drugs, such as ace inhibitors and beta-blockers, are less commonly prescribed to frail older patients, who are also less likely to be admitted to coronary care units and to undergo cardiac revascularization or coronary artery bypass surgery [54, 55]. Moreover, older patients are less likely to receive cardiologist specialist care [73].

Recent observational data suggest that optimal medical therapy in older men with ischemic heart disease is associated with better survival and lower probability of institutionalization independent of the presence of frailty; therefore frailty seems not to prevent the possibility to obtain the benefits of medical treatment of CAD [74]. On the other hand, it is still controversial how to choose invasive procedures, i.e., PCI versus CABG, for CAD in the presence of frailty. In this respect very interesting findings have been reported in the Acute Myocardial Infarction in Florence 2 registry study, including all acute coronary syndromes hospitalized in 1 year in the area of Florence (Italy), patients older than 75 years were selected and classified according to the Silver Code (SC), a validated tool to predict mortality based upon administrative data. In this sample for each point increase in SC score, the odds for use of PCI decreased by 11 %, whereas the hazard of 1-year mortality increased by 10 %, adjusting for predictors. On the other hand, PCI reduced 1-year mortality progressively more with increasing SC, showing that the highest risk patients were those who could benefit more from the application of invasive procedures [75].

Knowing that the patient is frail should lead to an individualized approach, in order to identify the more appropriate therapeutic strategy in each individual patient. Moreover, the frail older patient with CAD might be referred to a geriatric consultation to perform a comprehensive geriatric assessment that can allow an adequate evaluation and treatment of his or her multiple complex conditions [76].

Atrial fibrillation (AF) is an arrhythmia characterized by disorganized atrial activation, with consequent deterioration of the mechanical function of the atrium.

AF is the most common arrhythmia in older subjects: the prevalence of this condition increases with the age and ranges from 5 to 6 % in people older than 65 years reaching up to 20 % in patients aged ≥80 years [77–79]. Almost two thirds of patents are older than 75 years [77]. The prevalence of this condition is increasing in recent decades [80]. The risk of thromboembolic complications (stroke and systemic embolism) is high in AF, progressively increasing with advancing age: AF is associated with a four- to fivefold increased risk of embolic stroke with an estimated increased stroke risk of 1.45-fold per decade [81–83]. Moreover, ischemic strokes due to AF tend to be more severe, and patients suffering them are more likely to become chronically disabled, bedridden, and requiring constant nursing care [84, 85]. Recent studies found that atrial fibrillation is an independent risk factor for cognitive decline, dementia, and disability in older subjects, even in the absence of overt stroke [86, 87]. Finally, AF in older subjects increases the occurrence of hospitalization, adverse drug events, and mortality [88–90].