OH is a frequent and detrimental feature of PD; however, in clinical practice its diagnosis is still overlooked. One of the main features limiting a correct OH detection in an outpatient setting is the presence of BP circadian fluctuations. In this context, we explored the prognostic role of hypotensive episodes detected at the ABPM in predicting mortality and specific adverse outcomes in a large cohort of parkinsonian patients.
We retrospectively evaluated mortality and the occurrence of important milestones of disability during an up-to-10-year follow-up and compared them between patients with and without ABPM hypotensive episodes. Finally, we evaluated the same differences between patients with and without office nOH.
We found a significant association between ABPM hypotensive episodes and earlier onset of falls, cognitive impairment, hospitalizations, fractures, being bedridden or wheelchair-bound, and mortality. After correcting for potential confounders, hypotensive episodes retained a significant correlation with higher risk of falls, hospitalizations, and cognitive impairment. On the other hand, office nOH was associated with earlier onset of falls, cognitive impairment, and death, but only falls and cognitive impairment maintained the association after the adjusted analysis.
Association with falls. nOH is a well-known risk factor for falls in general population, and it is considered one of the main issues to be targeted to reduce the risk of falls, together with functional status, home safety, and vision disturbances [27]. In PD patients, OH is independently associated with an up-to-10-fold higher risk ok falls [5]. However, daily BP profile is characterized by significant circadian fluctuations, and is influenced by many intrinsic and extrinsic features, such as sleep, temperature, meals, fluid intake, exercise, evaluation setting (e.g., in-hospital vs. home), and drugs intake. Therefore, the simple in-office evaluation of OH could be burdened by a certain amount of inaccuracy, while the evaluation by means of ABPM could led to a more detailed identification of hypotensive episodes, besides providing important information on supine hypertension, a frequently overlooked feature of cardiovascular dysautonomia [28]. Our results seem to confirm this assumption, since both ABPM episodes and office OH were associated with higher risk of falls, but the former showed a stronger and more significant correlation.
Association with cognitive impairment. The association of OH and cognitive impairment has been detected both in general population and in patients with Alzheimer’s Disease or vascular dementia [29][30][31]. Large population studies highlighted an increased risk of developing dementia in patients with OH, ranging from 1.2-to-2-fold [32]. This association results even stronger in α-synucleinopathies, with a 3-to-8-fold higher risk of cognitive impairment in PD patients with OH [6][32][33].
Possible pathophysiological mechanisms are multiple and still to be fully clarified [8]. While some authors postulate a phenotypical association between dysautonomia, cognitive impairment, and worse motor impairment [34], other works reported that repeated bouts of cerebral hypoperfusion, along with altered regional patterns in supine cerebral blood flow and the presence of supine hypertension, could lead to greater burden of white matter lesions and cerebral atrophy, thus favoring the development of cognitive impairment [35][9][32][36]. However, these two hypotheses are not mutually exclusive, and both diffuse pathology and cerebral hypoperfusion may play a synergistic role [9]: the possibility exists that, in the context of a diffuse neurodegeneration, chronic OH and impaired dynamic cerebral auto-regulation [37] contribute to the worsening of neuropathology, probably by means of hypoxia-induced neurodegeneration, rather than by favoring α-synuclein deposition or vascular pathology [38]. In our study, we observed a significant association between ABPM hypotensive episodes (and in-office OH) and dementia, even after adjusting our analyses for many confounding variables that may explain the phenotypical association between OH and dementia (i.e., age, Charlson comorbidity index, PD duration and motor severity), thus suggesting a prevalent causative or synergistic role of OH in determining cognitive impairment. This observation seems in line with the recent findings by Ruiz Barrio and colleagues [38], who in a large pathological study on PD and Multiple System Atrophy patients observed an independent association between OH and cognitive impairment, but did not find differences in α-synuclein, β-amyloid, or tau pathology in patients with and without OH. Finally, in the present study, the strength and the significance of the association with cognitive impairment was greater for ABPM hypotensive episodes than office OH, further confirming the usefulness of ABPM in capturing the complexity of the circadian fluctuation of BP, and suggesting a possible role of BP variability in determining worse functional outcomes [39].
Association with hospitalization. About 80,000 hospitalizations in the United States each year are related to OH, mainly in the elderly population [40][41]. In PD patients, OH is an independent determinant of greater health care utilization [1], both for the potential consequences of the hypotensive episodes (falls, syncopes, head injury, fractures) and for the presence of other clinical features potentially responsible for hospitalization, which usually coexist with OH, such as ageing, diabetes, and cardiovascular comorbidities [42]. In our sample, ABPM hypotensive episodes were significantly associated with a 3-year earlier need for hospitalization and a 2-fold higher risk of hospitalization, compared to patients without episodes. Surprisingly, office OH did not show significant correlation at the adjusted Cox regression analysis, possibly due to the long-term follow-up in a relatively aged population, which resulted in a high probability of observing hospitalization for causes other than OH.
Association with fractures and bed/wheelchair confinement. Although univariate Kaplan-Meier analysis showed earlier occurrence of fractures and bed or wheelchair confinement in patients with hypotensive episodes or office OH, similarly to previous reports [43][44], these observations were not confirmed at the corrected analysis, probably due to the inclusion, among the considered confounders, of age, disease duration, and motor disability, which are well-known features associated with these detrimental disability milestones in PD and other α-synucleinopathies [45][46][47].
Association with mortality. Autonomic dysfunction [48] and, specifically, OH [49] have been associated with shorter survival in PD. In our sample, mortality was significantly associated with ABPM episodes and OH, with a 1.5-year shorter survival. However, the corrected analyses did not confirm this association, probably due to the relatively low rate of death during the follow-up.
The main strengths of our study include the long-term follow-up, with seriate and standardized clinical evaluations, as well as rigorous patients’ selection. However, some limitations should be taken into account. First, the relatively low sample size. Second, the retrospective design may have hampered the collection of important clinical data, including the disability milestones considered in the study, although we included only patients with a periodic and standardized follow-up in order to minimize this possible bias. Third, the absence of seriate collection of office OH or ABPM data, may have underestimated the incidence of new OH; however, if this were the case, we would have probably observed an even greater association between hypotensive episodes and disability milestones or mortality. Fourth, the definition of nOH was not based on cardiovascular autonomic test assessment, although the application of the recently proposed Δ HR/Δ systolic BP index [24] should have attenuated this bias. Fifth, the lack of a comprehensive evaluation of the autonomic symptoms other than OH limits firm considerations on a causal relationship between hypotensive episodes/OH and the development of disability milestones.
In conclusion, our findings highlight the potential role of repeated hypotensive episodes in determining worse outcomes in PD patients, confirming and strengthening, by means of a 10-year follow-up, previous Literature data. Though, our study introduces a novel element that has so far received little consideration. In fact, we demonstrated the usefulness of ABPM in predicting detrimental PD complications, with apparent greater accuracy compared to simple OH bedside evaluation, due to its higher capability in capturing the complexity of BP circadian fluctuations. Thus, a wider application of ABPM, both in clinical practice and in research context, is warranted to enhance the comprehension of the relationship between cardiovascular dysautonomia and PD progression trajectories.