The role of autonomic function in the onset of frailty in older persons

Aging is a natural and universal process marked by the gradual accumulation of biological changes that lead to a decline in physical and cognitive abilities. Complicating matters, the complex interplay of underlying biological changes and the presence of multiple diseases can lead to several health conditions that do not fit into traditional disease classifications. These conditions, known as geriatric syndromes, are often overlooked in health assessments focused on specific diseases. Among these syndromes, frailty has emerged as a critical yet complex condition. Frailty is characterized by a loss of physiological reserve and an increased vulnerability to stressors, arising independently of specific diseases. Its prevalence varies widely depending on the population and definition used, ranging from 4-59% among community-dwelling older adults and 19-76% in nursing home residents.

A healthy individual maintains homeostasis through the complex interplay between physiological systems. In frailty, these systems become dysregulated, resulting in reduced ability to react to internal and external stressors. While frailty’s pathophysiology is distinct from that of specific pathologies, it often coexists with chronic diseases. Several previously conducted studies reported that frailty was associated with several negative health outcomes, such as mortality and reduced quality of life. Given the importance of frailty within aging populations, it is crucial to examine predictors of frailty incidence. Such research facilitates the development of strategies for early detection and timely intervention.

In Chapter 2, we conducted a systematic review to examine the association between autonomic dysfunction and frailty. The analysis revealed that consensus orthostatic hypotension (OH) was associated with 1.6-fold higher odds of frailty (odds ratio (OR) = 1.61, [95% CI: 1.15-2.24]; n=3,488). Notably, initial OH demonstrated a particularly strong association with frailty (OR = 3.08, [95% CI: 1.50-6.36]; n=497). These findings suggest that frailty is accompanied by diminished stress resilience, evidenced by increased blood pressure variability and a lower chronotropic index in heart rate variability (HRV). Early detection of conditions like OH through continuous blood pressure (BP) monitoring and targeted interventions can play a crucial role in managing frailty and its associated risks. In Chapter 3, we identified a clear association between frailty and BP, although the effectiveness of antihypertensive medications in preventing frailty remains uncertain. Long-term hypertension impairs baroreceptor function, increasing the complexity of achieving optimal BP control in this population. These findings highlight the need for a nuanced approach to managing hypertension in older adults.

In Chapter 4, our cross-sectional study showed that the Elixhauser Comorbidity Index was the only index associated with elevated levels of high-sensitivity C-reactive protein (hsCRP, >3mg/L), while no comorbidity index showed significant associations with low gait speed. In Chapter 5, we presented the results of our prospective observational study. Our analysis revealed that the symptoms of OH at baseline were associated with an almost 3-fold higher odds of frailty. Additionally, the use of drugs affecting autonomic function was found to be associated with a 78% increase in the odds of frailty. Therefore, it is recommended that these medications be used more cautiously and, if possible, discontinued as soon as possible in older adults aged 80 and older. Several tools are available to help prevent potentially inappropriate medication use in older adults.

Chapter 6 of this PhD thesis provides an in-depth discussion of the research findings and their broader implications, offering a synthesis of the main results. This chapter critically evaluates the significance of the results, addressing their relevance for practical applications.