Atrial Fibrillation and Frailty: A Look into the Future of Two Rising Conditions Free

The framework: the progressive upward shift in the age of the world’s population, with 16% of people aged 65 and over expected in 2050, imposes new challenges in the management of age-related diseases in the general population as well as in the individual patient [1]. Atrial fibrillation (AF) is the most common heart rhythm disorder, with a well-established positive correlation with age. Several factors related to the aging process can increase the complexity of the clinical management of elderly patients affected by AF. Among them, frailty, often associated with old age and multi-morbidity, is a clinical syndrome with incompletely understood pathophysiology. Indeed, frailty is characterized by reduced physiological and homeostatic reserve in multiple systems, with a high biological vulnerability and reduced resistance to stressful agents [2]. Although frailty has been shown to predict a worse prognosis in patients with AF [3], studies evaluating the mutual association between AF and frailty have yielded conflicting results [4]. Furthermore, although epidemiological and clinical differences have been reported between patients of different sexes in relation to both AF and frailty [6], a specific gender-related relationship remains to be clarified. In this framework, Tajik and colleagues conducted a prospective population-based cohort study in order to investigate frailty as a predictor of incident AF in older adults stratified by gender, utilizing data from the Kuopio Ischemic Heart Diseases Risk Factor Study (KIHD) [7]. The median age of the 839 patients enrolled (55% female) was 68.6 ± 2.9 years. The main finding of their study was an increased risk of incident AF in frail patients after a mean follow-up of 14.2 years (HR 1.46, 95% CI, 0.1.48–1.85; p = 0.002), with a significant interaction between gender (P for interaction = 0.04; HR 1.78, 95% CI, 1.28–2.48 and HR 1.12, 95% CI, 0.77–1.63, for women and men, respectively). The results of this study, which are part of the still open debate on the association between AF and frailty, bring a new perspective in the field of gender differences. In the presence of the above reported conflicting results and with the aim of implementing a clinical application, reading the data of Tajik and colleagues suggests some interesting considerations. Frailty definition: to date, two main definitions of frailty have been proposed in the literature, which identify two different approaches to the conceptualization of frailty. Fried and coworkers noticed from the Cardiovascular Health Study (CHS) a frailty “phenotype” characterized by a sarcopenia-dependent model of frailty. According to this model, frailty is diagnosed when at least three of the following five criteria are observed: slow gait speed, low physical activity, unintentional weight loss, self-reported exhaustion, and muscle weakness [8]. Vice versa, Rockwood et al. [9], with the Canadian Study of Health and Aging (CSHA)-derived Frailty Index (FI), defined frailty based on the accumulation of deficits. FI is calculated as the ratio between the number of deficits detected and the total number of deficits considered, which may include diseases, physical and cognitive impairments, psychosocial risk factors, and geriatric syndromes [9].

Although in some previous studies investigating the association between frailty and incident AF the main findings were independent of the definition of frailty used [5], the absence of a unique and globally accepted definition of frailty makes it difficult to compare interpretation of data from different studies. Furthermore, the definitions proposed in clinical studies often require evaluations that may be time-consuming or not always available in clinical practice (e.g., grip strength assessments), limiting their clinical translation. These considerations may explain why it has been reported that cardiologists often identify frailty in a rather subjective way, as a condition affecting an old person with a mix of disease burden, poor health status, and cognitive or functional impairment [2].

A concept possibly even more debatable and less well supported by epidemiological data is the one of pre-frail state. Some studies, including that of Tajik et al. [7] in order to increase the statistical power of the analysis maintaining a relatively small sample size, have included both frail and pre-frail patients in the analysis. This could lead to an overestimation of the prevalence of frail patients and limit even further the possibility to compare results between different studies.

Gender-specific considerations: the study by Tajik et al. [7] emerges a significant gender difference regarding the probability of presenting AF and a concomitant state of frailty. In fact, the results show a significantly higher incidence of AF exclusively in frail women and not in males [7].

The authors evaluated different elements to explain this finding, among which inflammatory status and obesity are of particular interest. These two elements, apparently distinct from each other, are indeed characterized by a well-documented link between them.

Inflammatory status is recognized as associated with AF and frailty, as well as presenting a gender difference that could support Tajik’s findings [10]. In addition, inflammation is an important pathophysiological element in the genesis of AF also in obesity [10]. The latter, in turn, is correlated with an increased incidence of frailty and AF [12]. However, some considerations related to these items are necessary regarding Tajik’s work.

The first is related to missed evaluation of the inflammatory state in the examined population, not even through the measurement of a simple parameter such as C-reactive protein (CRP). Thus, the evidence of a real increased inflammatory state in the female and obese population, although conceivable and plausible, turns out to be speculative.

Another consideration is related to the definition and evaluation of obesity presented by the authors. In the evaluation of confounding factors, obesity was estimated as a dichotomous variable and not as a continuous value. Moreover, obesity was identified using a body mass index (BMI, the weight in kilograms divided by the square of the height in meters) cutoff equal or superior to 25 kg/m² and not 30 or higher, as recognized by the World Health Organization.

In this way, the multivariate model 2, used by authors to control for confounding factors, could be altered. However, it should be noted that an additional adjustment for BMI was performed by authors and how this was the only significant risk factor that emerged as substantially higher in women compared to men. This highlights how not specifically obesity, but in general a pathological BMI in women and probably also the inflammatory state related to it, can be related to the condition of AF and frailty.

Certainly, despite various limitations noted by us and by Tajik and colleagues themselves, the authors need to be congratulated because their study has the great merit of drawing attention to a link of two conditions that, in future years, will become increasingly prominent. For this reason, it is desirable to plan future prospective studies to evaluate different aspects related to the association between AF and frailty starting from a solid and shared basis.

First, it will be necessary to identify a commonly recognized definition of frailty and above all easy to apply and use in real practice. This must also be dynamic in its evaluation to consider different moments of a subject’s life. Actually, clinical conditions of the patient may vary over time and consequently his definition of frail or not. This is the only possible way to promote the diffusion and awareness among healthcare professionals of a condition like the frailty, which is too often defined on a random and subjective basis.

Once the condition of frailty is clearly defined, it will therefore be possible to plan studies to confirm, or not, the data that have emerged up to the present time, such as those of Tajik. On this note, although these data are conceivable and credible, to date there is still no concrete evidence of their consistency in the literature.