A Further Step to Classical Semiology: The Subtle Expression of Structural and Functional Cerebral Changes in Hypertension

For centuries, clinicians have attempted to detect disease manifestations early, in order to administer the appropriate treatment to cure the disease or slow its progression. However, until the second half of the 20th century, disease-induced functional and structural changes were only detectable by means of a careful systematic physical examination through inspection, palpation, and auscultation, meaning that only substantial anatomical or functional changes could be detected through these classical examination techniques. Chronic diseases with a very slow course, such as essential hypertension, promote structural and functional changes in the heart, expressed by left ventricular hypertrophy and systolic/diastolic dysfunction, and in the endothelium, and wall of the large and small vessels, whose function deteriorates over time, with subtle changes, such as increased intima-media thickness (IMT), and atherosclerotic plaque formation that may occlude the arterial lumen, which cannot be detected by a traditional physical examination until they are sufficiently advanced to auscultate a murmur or detect a change in pulse palpation. When this happens, it is very likely that the organs they supply are already affected by the consequences of flow reduction and ischemic lesions. Structural lesions in the heart, coronary, cerebral, and renal arteries evolve to clinical expression including angina, acute myocardial infarction, heart failure, stroke, dementia, and renal failure. Changes in the large elastic arteries are expressed by the signs and symptoms of peripheral artery disease but, at the same time, contribute to small vessel damage. By then, physicians are late to the party. Hypertension is the most frequent modifiable risk factor for cerebrovascular diseases, such as stroke, cognitive decline, and dementia.1 In addition to the well-established relationship between high blood pressure (BP) and ischemic and hemorrhagic stroke,2 the correlation between hypertension and vascular dementia, Alzheimer’s disease, and mixed dementia has been extensively reported2–6: cognitive decline begins in midlife and, over time, gradually becomes more pronounced and less reversible.7 It may coexist with clinical cardiovascular and renal disease induced by hypertension and the commonly associated cardiovascular risk factors, such as central obesity, dyslipidemia, and type 2 diabetes, which appear to play a major role in the development and progress of cognitive decline and dementia.8 The pathophysiological substrate of stroke and cognitive decline in hypertension involves silent and progressive damage to the cerebral small vessels (CSVs).9 The structural and functional changes in the small vessels cannot be detected by classical semiology and it was not until the explosive growth of technology in the second half of the 20th century that we could determine that hypertensive patients developed anatomical lesions detectable by brain tomography and, more recently, by brain magnetic resonance imaging, in the form of white matter hyperintensities (WMHs), cerebral microbleeds (CMB), enlarged perivascular spaces (EPS), and silent lacunar infarcts.10–14 Age is a confounding factor for the detection of these lesions and several studies have demonstrated that the prevalence of WMH and CMB increases with age and may reach as much as 30% in people aged >80 years. However, hypertension increases the risk of silent cerebral lesions irrespective of age, and their evolution is much more advanced in patients with uncontrolled hypertension than in normotensive subjects or controlled hypertensive patients.14 This is very important, because intensive antihypertensive treatment and BP control has been shown to slow the progression of WMH, particularly if treatment achieves BP levels <130/80 mm Hg.15–17 The clinical consequence is a reduction in the incidence of stroke and dementia, which strengthens the recommendation to start treatment very early in hypertension: “The earlier, the better.” The hypertension-induced silent lesions in the CSVs are associated with cerebral hypoperfusion and neuronal hypoxia, which is one of the main factors involved in the pathophysiology of dementia, including Alzheimer disease.18 Simultaneously with changes in the CSVs, ageing and hypertension modify the structure of the large arteries, leading to increased IMT, aortic stiffening, and increased pulse wave velocity (PWV). Aortic stiffening is particularly deleterious to high-flow organs, such as the brain, resulting in greater transmission of potentially harmful pulsatility to the microcirculation, which may promote a spectrum of microstructural and macroscopic brain diseases often associated with cognitive decline and dementia.19 Whether small and large vessel impairment correlates with early functional brain alterations, such as changes in cerebral oxygenation/perfusion, is unclear. In this issue of the American Journal of Hypertension, Triantafyllou et al.20 publish an interesting study aimed at examining potential links between cerebral oxygenation during physical tasks (submaximal isometric handgrip exercise) and known markers of silent arterial organ damage, namely carotid IMT (cIMT), arterial stiffness assessed by the augmentation index (Aix) corrected for a mean heart rate of 75, carotid-femoral PWV, and retinal vessel morphology assessed by measurement of the central retinal arterial diameter (CRAE). These silent markers of hypertension-induced arterial disease have been associated with stroke and dementia. Cerebral prefrontal oxygenation was measured continuously using near-infrared spectroscopy and the average response during exercise in oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total hemoglobin (tHb) was examined. The authors found that mean cIMT and Aix correlated negatively with the average exercise response in cerebral oxygenation, whereas no significant correlation was observed between PWV and cerebral oxygenation indices. In the adjusted analysis, cerebral oxygenation correlated weakly with CRAE. The authors conclude that these novel findings suggest that indices of lower cerebral oxygenation during submaximal physical tasks are associated with markers of early, subclinical target organ damage, such as increased cIMT, arterial stiffness, and arteriolar retinal narrowing in newly diagnosed hypertensive individuals. These findings aid better understanding of the relationship between structural and functional abnormalities in the small cerebral arteries penetrating the white matter, large vessel lesions, and an early reduced capacity of middle-aged hypertensive patients to increase cerebral oxygenation during physical tasks. Individuals with a blunted increase in cerebral oxygenation, assessed by O2Hb during exercise, exhibited more signs of carotid atherosclerotic vascular disease, as shown by the correlation with cIMT, the Aix, and the narrower caliber of the retinal arterioles. The study is important because the data were obtained in a never-treated middle-aged hypertensive population. This a major strength of the study because antihypertensive treatment and BP control, independently of the class of drugs used, reduce the progression of structural and functional silent brain lesions. For this reason, studying a naive sample of subjects with hypertension is imperative in research on silent brain lesions.10,20 The novel findings of Triantafyllou et al.20 suggest that cerebral oxygenation and blood flow are impacted from the very early stages of hypertension, along with impairments in other target organs, similar to the way that WMHs are present in very early stages of hypertension.10 Prospective studies evaluating the progression of changes in cerebral oxygenation and blood flow in parallel with CSV disease, such as WMH, CMB, EPS and silent lacunar infarcts and cIMT, arterial stiffness and hypertensive retinopathy as markers of silent large artery disease, and the effect of antihypertensive treatment on brain oxygenation, could help elucidate the pathogenesis of hypertension-related cerebrovascular disease. The author declared no conflict of interest.