Introduction

Frailty is a clinically identifiable state of diminished physiological reserve and ability to maintain homeostasis, leading to increased vulnerability and adverse health events.¹ It is particularly prevalent among community‑dwelling individuals, ranging from 11% in those aged 50–59 years to 51% in those aged 90 years or more.²

Arterial hypertension, a major cardiovascular risk factor, is particularly frequent among older adults, with its prevalence increasing significantly with age.^3,4 As a result, frailty is commonly observed in hypertensive patients, while hypertension is more frequent among frail individuals than in their fitter counterparts.⁵

The prevalence of frailty in hypertensive patients varies widely, from 14% to 80%, depending on population characteristics and the methods used to assess frailty.^5,6 Frail hypertensive patients represent a distinct population in geriatric care, often presenting a heightened cardiovascular risk due to age‑related risk factors and pre‑existing organ damage.⁷ However, these patients are also more prone to treatment‑related adverse events and may have shorter life expectancy, complicating diagnostic and therapeutic decision‑making.⁸

However, the management of hypertension in older and frail patients has received little attention in the literature, and mostly represents an unresolved clinical question, as underlined in the European Society of Hypertension guidelines that list this issue among the “gaps in evidence.”³

Indeed, older and frail patients often do not meet the inclusion criteria of clinical trials, and are therefore excluded from study populations.⁹ Thus, there is a lack of sufficient evidence to support tailored therapeutic recommendations for these patient subgroups, and an observational study demonstrated that hypertension in older adults is often poorly addressed.¹⁰

Another feature of blood pressure (BP) values, which seems to be enhanced in frail patients, is BP variability (BPV) over time.¹¹ Under physiological conditions, these BP variations largely represent a response to environmental stimuli and challenges of daily life aimed at maintaining cardiovascular homeostasis. However, increased BPV may also reflect alterations in cardiovascular regulatory mechanisms or underlying pathological conditions, and may be a source of damage to the cardiovascular system. In fact, previous studies have shown an independent and adverse prognostic impact of increased BPV both in younger and older patients.^12,13

Moreover, evidence indicates that increased BPV is associated with age, that is, short‑term diastolic BPV independently predicts cardiovascular mortality in hypertensive individuals across all age groups, while systolic BPV seems a particularly strong predictor of mortality in young adults.^13,14 This relationship is likely mediated by increased arterial stiffness.¹⁵

In theory, increased BPV may reflect a generalized frail condition, representing a marker of impaired BP homeostatic regulation and / or accelerated arterial aging. However, evidence linking BPV and frailty remains limited. Long‑term studies have shown that elevated visit‑to‑visit systolic BPV, independent of mean BP, is associated with an increased risk of incident frailty in healthy older adults.^16,17 In contrast, evidence on short‑term BPV is scarce. In a Chinese cohort of hospitalized hypertensive patients, increased BPV was associated with frailty assessed by a 38‑item frailty index.¹⁸ These findings, however, have not been reproduced in outpatient populations or in other ethnic groups.

Considering the above, our study aimed to explore the association between short‑term 24‑hour BPV and frailty in a cohort of older hypertensive outpatients.

Patients and methods

Blood pressure measurement and variability estimation

Office BP was assessed using a validated automated oscillometric device (UM‑211; A&D Company Limited, Kitamoto, Japan). If the between‑arm difference (verified at the first simultaneous measurement on both arms) in systolic BP (SBP) was below 10 mm Hg, then the nondominant arm was used for all subsequent BP assessments; otherwise, the arm with the higher systolic value was considered for BP measurement. An appropriate cuff size was used. After at least 5 minutes of rest, 3 BP readings were recorded at intervals of 1 minute with the participant being seated in a quiet room. The average of the second and third measurements was used for the analyses. BP was also assessed with the participant standing for 1 and 3 minutes. Orthostatic hypotension was diagnosed if a drop of 20 mm Hg in SBP or a drop of 10 mm Hg in diastolic BP (DBP) was recorded within 2 to 5 minutes of standing, or if symptoms appeared.²⁹ The data were recorded by the investigator in a standardized data collection form.

All patients underwent a 24‑hour ambulatory BP monitoring (ABPM), performed with a validated oscillometric device (Model TM‑2440, A&D). BP was measured at 15‑minute intervals during daytime (7:00 AM to 10:00 PM) and at 30‑minute intervals during night‑time (10:00 PM to 7:00 AM). The recordings were considered invalid if less than 70% of valid readings were available. All valid ambulatory BP readings were used to calculate 24‑hour, diurnal, and nocturnal BP arithmetic mean values as well as variability indices. Mean BP values indicated the average levels of SBP and DBP. Variability of SBP and DBP was estimated using the following metrics: the average real variability (ARV), the coefficient of variation (CV), SD, and weighted SD for SBP and DBP.³⁰

In detail, ARV is the mean of absolute change between successive BP readings and was calculated using the following formula:

where n is the total valid number of blood pressure readings, and BP_k and BP_k+1 denote 2 consecutive BP measurements.³¹

Data were extracted to calculate SD. Weighted SD over 24 hours was calculated with the following formula: Weighted SD = (SD of diurnal BP × daytime + SD of nocturnal BP × night‑time) / Total recording length.³² CV was calculated as 100 × SD/mean SBP and DBP.¹¹ Nocturnal BP fall (dipping) was calculated as percentage with the formula presented below.

Results

A total of 292 patients were screened for eligibility. Of these, 232 provided informed consent to participate in the study. Subsequently, 48 patients were excluded due to incomplete data required for the calculation of the FI and / or 24‑hour ABPM. The final analytical sample included 184 participants. The flowchart detailing participant selection is shown in Figure 1.

The study cohort included 58 men (32%) and 126 women (68%), at a mean (SD) age of 81.76 (4.32) years. The majority of the participants exhibited a good functional and cognitive profile (median [IQR] SPPB score of 9 [7–11] points and median adjusted MMSE score of 27 [26.3–28.4] points). According to the FI, 63 participants (34.2%) were classified as nonfrail, 79 (42.9%) as prefrail, and 42 (22.8%) as frail. Considering BP below 140/90 mm Hg as target, it was well‑controlled in 75 participants (40%). The main characteristics of the study participants are summarized in Table 1, and additional information on antihypertensive and insomnia treatment is reported in Supplementary material, Tables S2 and S3. In this descriptive section, P values for between‑group comparisons could not determine a real difference due to the sample size.³³

Sex distribution was similar in all groups. Greater frailty was associated with an increased prevalence of insomnia, previous falls, and hospitalization in the past year.

On average, BP was within normal limits except for slightly elevated nocturnal SBP. No difference between the groups was observed for all BP measurements (Table 2). Regarding BPV, greater frailty was associated with increasing point estimates of several diastolic BPV indices, not reaching significance for 24‑hour DBP CV (P = 0.05) and for nocturnal DBP SD (P = 0.08), contrary to nocturnal DBP CV (P = 0.04).

Multiple linear regression models were built to test the association between each BPV parameter and the FI (Table 3).

No significant association was observed for SBP values except for dipping (P = 0.047). Regarding diastolic BPV, only nocturnal BPV showed a marginally significant association with frailty.

Discussion

This study investigated the underexplored relationship between BPV and frailty, and found that in older hypertensive individuals, BPV is not simply associated with frailty. We showed that 24‑hour SBP pattern was not associated with frailty, while night‑time DBP SD increased significantly with raising FI.

To our knowledge, the only prior study on a similar topic was published by Zhu et al,¹⁸ who found an association between frailty and short‑term BPV, using various metrics, such as ARV, CV, SD, and weighted SD. In that study, 24‑hour and daytime BPV values were associated with frailty in older adults, while nocturnal BPV showed a significant association only for ARV, but not for CV or SD.¹⁸

Our study differs from that of Zhu et al¹⁸ in 2 main aspects. First, our cohort consisted of very old adults (mean age >80 y), representing predominantly the old‑old population, whereas Zhu et al¹⁸ enrolled older adults at a mean age just over 70 years. Second, while Zhu et al¹⁸ included inpatients, our study focused on hypertensive outpatients.

Using traditional out‑of‑office BP monitoring methods in an inpatient setting is not fully comparable with the conventional use of this technique in ambulatory conditions. This is due to the impact of several relevant factors, including activity restriction, absence of daily stress, and varying levels of anxiety related to hospital stay. These factors may affect ABPM values in hospitalized patients, potentially altering the diagnosis of dipping patterns and the interpretation of daytime / night‑time BP values, with underestimation of day‑night BP changes.³⁴

Similarly, we believe that BPV assessed in hospitalized patients may not reliably reflect normal variability patterns due to environmental and care‑related influences during hospitalization. Therefore, the similarity between daytime and night‑time BPV observed by Zhu et al¹⁸ might be a consequence of hospital setting.

The distinctive finding of our study appears to be the association between frailty and nocturnal diastolic BPV. We found that SD of night‑time DBP values is associated with frailty in an outpatient setting, suggesting that this parameter may represent a robust and clinically applicable measure in routine practice.

Previous research indicates that daytime and night‑time BPV may have different effects depending on patient age. The Dublin Outcome Study¹³ reported age‑specific variations in the significance of BPV: while diastolic BPV was significantly associated with cardiovascular events in older adults, systolic BPV was more closely associated with cardiovascular mortality in younger participants (<⁠50 y). This age‑specific shift may reflect underlying physiological changes: with advancing age, increasing arterial stiffness primarily affects SBP, while DBP becomes more sensitive to alterations in vascular tone and autonomic function.³⁵

Additionally, nocturnal BP patterns provide crucial insights into autonomic regulation. In physiological conditions, sympathetic withdrawal occurs at night; therefore, altered nocturnal diastolic BPV could reflect impaired autonomic modulation, particularly in frail individuals.³⁶ Notably, night‑time BPV assessed with ABPM has been shown to significantly reclassify cardiovascular risk independently of established risk factors, including 24‑hour BP level.³⁷

Poor sleep quality has been identified as a risk factor of frailty in a meta‑analysis of over 16 000 older adults.³⁸ Also, the relationship between sleep and BPV remains less well defined, despite evidence suggesting potential associations between increased BPV, poor sleep quality, and longer sleep duration.³⁹ To account for this potential confounder, we adjusted our analyses for the presence of insomnia, and the association remained significant. Pharmacologic treatment, particularly with antihypertensive agents, is also known to influence BPV. Several studies and meta‑analyses have shown that different drug classes can influence BPV, with the most relevant association demonstrated for CCBs, which have been associated with a significant reduction in BPV, while β-blockers may increase BPV. Following adjustment for these medications, the relationship between BPV and frailty remained significant.⁴⁰

While both our study and that of Zhu et al¹⁸ reported the association between short‑term BPV and frailty, they did not show the direction of cause‑effect relationship. Although some evidence supports the association of long‑term (visit‑to‑visit) BPV with incident frailty,⁴¹ similar information is not available for short‑term BPV.