Antihypertensive treatment in patients with cerebrovascular disease: the lower the better?

Hypertension is the main risk factor for cerebrovascular events, and there is a strong direct relationship between the blood pressure (BP) level and the occurrence of fatal and nonfatal stroke, which is increasing with older age. Therefore, lowering of BP reduces the risk for stroke more than for any other hypertension-related fatal and morbid events. However, apart from stroke there are more subtle hypertension-related cerebral target organ changes in the form of white matter lesions, lacunar infarcts and brain atrophy, which result in impairment of cognitive functions [1,2] such as an impairment of attention and executive functions [3]. This is considered to be because of hypertension-induced atherosclerosis of the cerebral arteries resulting in endothelial dysfunction [4]. Although the degree of reduction of BP relates strongly with the reduction of risk for stroke (‘the lower the better’), there is uncertainty as how low BP should be lowered in patients who already have cerebral lesions and impaired cognitive functions. Some studies showed that antihypertensive treatment reduced white matter lesions and improved cognitive function in hypertensive patients, particularly in those who already demonstrated an impaired cognitive function at baseline. However, it was also recognized that a too low BP could lead to brain damage and worsen cognitive function [5,6]. For quite some time, the mechanism whereby a low BP could lead to brain damage and thus cognitive impairment had remained somewhat enigmatic. It was hypothesized that differences in cerebral blood flow and brain perfusion could be a possible explanation. These earlier studies used clinic BP measurement and it was not until 24-h ambulatory BP monitoring was used and showed that ‘nondipping’ of BP at night was associated with a smaller brain volume and reduced cognitive function [7], whereas on the contrary, an exaggerated fall in nocturnal BP was associated with an increase in cerebral lesions [8,9] and related behavioral changes [10] as well as stroke prediction[11]. In a similar direction, a too great fall in BP during postural hypotension was found to relate to white matter lesions [12]. Even physiological falls in nocturnal BP assessed by 24-h BP monitoring in elderly patients with cerebrovascular disease and with optimally controlled hypertension were found to be associated with increased white matter volume and cognitive dysfunction reflecting the importance of dynamic BP changes on cerebral damage [13]. Hypertension-related white matter changes can occur in different areas of the brain but predominantly in the frontal, parietal and occipital regions [13]. These areas are the ones that are endowed with a lesser vascularization [14] and, therefore, are most affected by hypoperfusion [15]. Cerebral blood flow follows a circadian rhythm, being lowest during the night [16], and hence these brain areas are most vulnerable to BP changes and BP levels during the night. In this issue, Muller et al.[17] investigated the effect of BP and cerebral blood flow on brain atrophy, adding further to the understanding of BP-related cerebrovascular changes. These investigators used magnetic resonance angiography in about one thousand individuals with symptomatic atherosclerotic disease and different BPs. They found an association of systolic BP and pulse pressure with cortical gray matter volume and that a lower BP by itself was not sufficient to induce brain atrophy unless this occurs in combination with a lower parenchymal cerebral blood flow. This combination resulted in an increased risk of reduced gray matter volume and of brain atrophy. On the contrary, individuals with a high (preserved) cerebral blood flow were ‘protected’ against a low BP. Although these results have been obtained in a special group of individuals and therefore may not readily be applied to the population at large, this study shows for the first time so far that failure of the cerebral blood flow autoregulation leads to brain damage in the presence of a low BP. Although autoregulation of cerebral blood flow is intact in normotensive individuals in the presence of a low BP [18], in hypertensive patients, autoregulation, having been set for higher BPs, may fail in the presence of a low BP [19], and as demonstrated in the study of Muller et al., the consequent reduced cerebral blood flow increases the risk for brain damage. Although we have gained some insight into the mechanisms regarding the relationship between levels of BP, cerebral blood flow and cerebrovascular disease, what are the possible practical consequences? First of all, lowering and control of BP remains most important, as it has been shown that the risk for stroke is reduced in direct relation to the degree of BP lowering. However, accumulating evidence suggests that hypertensive patients with cerebrovascular disease, mainly elderly patients, are at an increased risk of a deterioration of their cognitive function when exposed to too low BP. Often, white matter changes and lacunar infarcts occur silent and may not be clinically overt but are vulnerable to further insults and to an increase in the risk for stroke [20]. As it follows from the studies using ambulatory BP monitoring, fluctuations (dynamic changes) in BP rather than a specific level of BP determine a further cerebral damage and deterioration of cognitive function. As it is not possible to perform ambulatory BP monitoring in every elderly patient, some general precautions could be applied such as a cautious lowering of BP to allow cerebral autoregulation to adjust to lower levels of BP. Low trough BP measured before the morning dose of antihypertensive medication may indicate an excessive nighttime BP dipping. Also, postural hypotension should be avoided by the routine inclusion of measurement of BP while standing. Accumulating evidence suggest that antihypertensive treatment with angiotensin converting enzyme inhibitors [21,22] or angiotensin receptor antagonists [23–26] may be protective against the combined effect of low BP and low cerebral blood flow possibly through adaptation of the cerebral autoregulation to lower levels of BP [27] and therefore preserve or improve cognitive function. Considering that there are currently 24.3 million people with dementia worldwide with a projected increase to 81.1 million in 2040 [28], and with the expected increase in the elderly population, every effort should be made to prevent cognitive impairment in hypertensive patients.