Orthostatic hypotension, focus on cognitive pattern

Orthostatic hypotension is frequent in the hypertensive individuals who are treated, in those who are old, in those with diseased baroreceptors and in those with increased arterial stiffness. In the elderly with arterial stiffness, prevalence of orthostatic hypotension is very high [1,2]. Although only a limited number of doctors and even of dedicated centres measure arterial blood pressure (BP) in the upright posture, simply detecting, for convenience or for negligence, sitting BP values, orthostatic hypotension is constantly demonised. It is asserted – sometimes based on studies over few patients or nonpopulation-based – that individuals with orthostatic hypotension could have a greater incidence of cardiovascular events [3]. Fear of orthostatic hypotension (and of hypotension in general) is so popular that it led de facto to excessive caution, unsatisfactory treatment of hypertension and finally unsuccessful achievement of the pressor target suggested by guidelines [4,5]. Primum non nocere has become the most common way to proceed in this field. The current general belief is mainly based on opinions, not on evidence or facts. Although it is demonstrated that it is very plausible – probably, in the long term, unavoidable – to die from untreated hypertension, it is very unlikely to die from orthostatic hypotension. In a couple of recent articles [6,7], we pointed out that, when general population is taken into consideration and analysed in multivariate models in the frame of prospective studies, orthostatic hypotension does not lead to any increase of cardiovascular events or death. This is often ignored because the confounders that can influence the risk equation are copious and often unexpected [8–10], and on the contrary, for practical reasons, very few studies are performed according to rigorous criteria. As a general rule, this does not exclude that a specific organ or apparatus can suffer as a consequence of repeated episodes of orthostatic hypotension. Actually, in the last years, concern has mainly been centred on the cerebrovascular system, and it has been suggested that people with orthostatic hypotension (more often hypertensive patients) have a greater tendency to syncope, to falls and to cerebral ischemia. It has been stated that repeated episodes of orthostatic hypotension, also when asymptomatic, are associated with cerebral ischemia, to lower brain mass, to reduced grey matter, to cognitive decline and even to a greater rate of dementia [11–17]. Of course, this fear is mainly expressed selectively for aged hypertensive patients, the only ones who can substantially have orthostatic hypotension and dementia (nobody searches for these conditions in the young). Once again, these opinions are only rarely based on multivariate population-based studies, mainly deriving from meta-analyses of few studies or being nothing more than mere conjectures based on a supposed reduction of cerebral self-regulation [4–18] (a condition that, instead, is probably limited to patients with ongoing acute cerebrovascular events). Some of these studies even have an inverse approach, that is they put in evidence a greater prevalence of orthostatic hypotension in dements, sometimes devoided of any statistical significance. As a matter of fact, other authors denied any association between orthostatic hypotension and cognitive decline [17,19] and demonstrated that hypertension in middle age, not orthostatic hypotension, leads to cognitive decline or dementia [14–17]. Furthermore, old age is the main determinant of cognitive decline. The relations between arterial hypertension, orthostatic hypotension and age are therefore unclear, including their direction [20], so that the ideas in this field remain confused: perhaps orthostatic hypotension produces the cerebral damage leading to cognitive decline, or the two conditions are simply associated, or – at least in some cases – individuals having cognitive decline become or remain more often hypertensive and finish to have more frequently orthostatic hypotension, because they are less attentive to prevention and care. The echogenetic context [8,21] could also be of particular interest in this respect. The mere evidence that individuals with cognitive decline show orthostatic hypotension is of course of no aid. On the contrary, it is necessary to evaluate whether or not individuals with orthostatic hypotension are more prone to have cognitive decline, using multivariate analyses in a wide and representative sample of a general population. This is not easy, simply because general populations whose cognitive pattern and many biological confounders are known is not within everyone's means. Only a few research centres have this possibility. This is the case of our Laboratory of Epidemiology. The article ‘Orthostatic hypotension in older persons is not associated with cognitive functioning, features of cerebral damage or cerebral blood flow’ in the present issue of the Journal of Hypertension[22] offers us the possibility to express our evidence-based opinion about the relationship between orthostatic hypotension and cognitive decline. Foster-Dingley et al.[22] found that in a community-based sample of older people orthostatic hypotension was not associated with cognitive decline. Not only this, but no association was found between orthostatic hypotension and cerebral vascular damage or decreased cerebral blood flow. In other words, they showed that orthostatic hypotension is not associated with a decrease in any of the cognitive domains, including executive function, memory and psychomotor speed. Although their sample is limited and represents selected elderly individuals, their data are of great interest because the study protocol is rigorous and the results are strongly plausible. To the aims of the present editorial, we analysed data deriving from our population-based study called LEOGRA-GOLDEN (Last Evidences Of Genetic Risk factors in the Aged – Growing Old with Less Disease Enhancing Neurofunctions), whose protocol has been widely described elsewhere [8,10]. This study concerns 1597 unselected men and women aged 51.1 ± 15.4 years (range 18–94), representative of the adult population. The multivariate analysis, performed having as dependent variable, time to time, the Mini-Mental State Examination and many items of the Brief Neuropsychological Exam (Table 1), and as independent covariables many confounders including age, education degree and body mass [8], demonstrated that orthostatic hypotension is not associated with any reduction of cognitive parameters (Table 1). This was true not only when classic orthostatic hypotension (BP fall ≥20 mmHg systolic or ≥10 mmHg diastolic after ≥3 min from standing) was considered, but also taking into account separately systolic and diastolic orthostatic hypotension (Table 1). Furthermore, cognitive decline was not associated in logistic regression to classic orthostatic hypotension [odds ratio (OR) 0.78, standard error (SE) 0.36, confidence intervals 95% (CI) 0.44–1.47, P = 0.6], to systolic (OR 1.21, SE 0.44, CI 0.59–2.49, P = 0.6) or to diastolic orthostatic hypotension (OR 0.82, SE 0.26, CI 0.44–1.52, P = 0.5).TABLE 1: Univariate descriptive analysisThese results complete those by Foster-Dingley et al.[22] and those obtained by Curreri et al.[17] in a cohort of 1409 community-dwelling individuals aged at least 65 years in a geographical area similar to that used by us. The Foster-Dingley's study on selected individuals is therefore confirmed at a general population level, so that orthostatic hypotension should not be considered a good way to stratify people into having or not having cognitive decline. Nevertheless, when in our experience the lying to standing variation of BP as a continuous variable was considered in multiple regression adjusted for confounders, rather than orthostatic hypotension, some cognitive parameters such as memory with interference at 10 s (R2 = –0.009, P < 0.03) and at 30 s (R2 = –0.012, P < 0.02) and the clock test (R2 = –0.016, P < 0.0001) showed a mild inverse association with clino → ortho systolic decrease: the higher the orthostatic systolic fall, the worse the test scores. The praxic proofs test, another relevant index of cognitive pattern, was depressed near to statistical significance (R2 = –0.001, P = 0.053). These results suggest that, although categorical orthostatic hypotension is not a sensitive parameter, SBP fall in lying-to-standing passage is associated with cognitive decline. The systolic lying → standing variation (that was on average –5.5 mmHg in our experience) should always be taken into account when dealing with the relationship between orthostatic hypotension and cognitive decline. Diastolic pressure had, on the contrary, no role in this sense and its association with cognition was constantly non-significant (data not shown). An elegant alternative to SBP and DBP considered separately is the lying → standing variation of pulse pressure (PP) (systolic minus diastolic), an item that takes into account both pressor components. The results we obtained with PP, given the neutrality of diastolic, are similar to those of systolic alone (data not shown). Other authors have highlighted a possible role of postural variations of mean arterial pressure (MAP), an item which today is made more reliable thanks to the availability of devices measuring primary MAP instead of calculating it with an algorithm. Furthermore, MAP tends to be higher in the orthostatic posture, whereas SBP and DBP can have an opposite trend passing from lying to standing, making the results obtained defining orthostatic hypotension from systo-diastolic variations more difficult to analyse and less homogenous because of the ↑ ↓ variability of postural changes. Brain feels the effects of MAP changes, and in individuals with still elastic arteries – the younger ones or those who have a carotid–femoral pulse wave velocity less than 6.9 m/s – the cognitive pattern correlates directly with the orthostatic MAP increase [12,11]. This seems to indicate that having higher MAP when standing is good for the brain. Magnetic resonance shows that in the elderly or in people with stiff arteries an orthostatic increase of MAP is associated with a bigger brain. In the same individuals, the same authors observed no effect of orthostatic hypotension on cognition [11], confirming that probably orthostatic hypotension as a yes/no variable is not ideal to evaluate the effects of pressor postural variation on the central nervous system. In conclusion, the picture of the consequences of orthostatic hypotension on cognitive pattern is far from being defined and any decisions in this field should be postponed. When dealing with postural BP changes, it is a good practice to take into consideration not only orthostatic hypotension, but also the amount of orthostatic BP fall. Apart from patients with acute or subacute stroke, orthostatic hypotension is probably less fearsome than usually believed. Not only this, but it can even be used as a sort of nonpharmacological therapy whilst awaiting a full effect of drugs: to this aim, patients should be simply encouraged to keep the upright position as much as possible during the day and to sleep in a mild head-up tilting posture, so taking advantage of the postural BP fall [23]. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.