Arterial hypertension and the turbulent ageing of the aortic valve

This editorial refers to ‘Elevated blood pressure and risk of aortic valve disease: a cohort analysis of 5.4 million UK adults’†, by K. Rahimi et al., on page 3596. Aortic valve disease (AVD), including aortic stenosis (AS) and aortic regurgitation (AR), represent common valvulopathies in the general population, with prevalence and severity that progressively increase with age.1 , 2 Due to the increasing life expectancy, the number of patients with severe AVD has been growing steadily over recent years and is likely to become even more important in the future, in light of the ageing population. As the severity of AVD has a relevant impact on an individual’s morbidity and mortality, identification of preventable causes of AVD progression represents a public health priority. A growing number of cross-sectional studies have reported positive associations between elevated blood pressure and risk of AS or AR.3 The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines for the management of arterial hypertension report that the overall prevalence of hypertension ranges between 30% and 45% of the general European population, with a steep increase with ageing.4 Consequently, the identification of a potential causal relationship between elevated blood pressure and the risk of AVD might provide a therapeutic target to prevent or, at least, slow down the evolution of AVD and reduce its associated costs in modern societies. In this issue of the European Heart Journal, Rahimi et al. reported the results of a longitudinal observational study exploring the relationship between AVD and arterial blood pressure using linked electronic health records collected between January 1990 and 31 December 2015 for 5.4 million patients included in the UK Clinical Practice Research Datalink (CPRD).5 To reduce the risk of reverse causation, the authors decided to exclude all individuals who had a history of cardiovascular disease, AS or AR, or taking lipid-lowering or anti-hypertensive medications at baseline. The diagnosis of AS/AR was identified from hospital discharge reports, death registers, or primary care records, and subjects with congenital or mixed AVD with no clear indication of the dominant condition were excluded. The results documented that each 20 mmHg increment in systolic blood pressure was associated with a 41% increased risk of AS and a 38% increased risk of AR. These associations were similar across the whole spectrum of blood pressure values, and a greater impact of blood pressure on the risk of both AS and AR was observed in younger than in older subjects. In sensitivity analyses, performed to explore the validity of the outcome variables and potential effect of valve severity on outcomes, it was found that associations were similar when: (i) an echocardiographically supported diagnosis was compared with reports without information on imaging; (ii) hospital discharges were compared with outpatient diagnoses; and (iii) analyses were performed on patients with a definitive report of valve replacement and those with no clear reports of valve replacement. The results reported in this study accompany a recent report from the same research group that documented a strong association between long-term exposure to elevated blood pressure and increased risk of primary and secondary mitral regurgitation.6 Again, these associations were observed across the whole spectrum of systolic blood pressure values and were more significant in younger than in older subjects. Taken together, these findings suggest that arterial hypertension might increase the risk of aortic and mitral valve diseases by common pathophysiological mechanisms. Local haemodynamic changes imposed by arterial hypertension might increase mechanical stress on the valve leaflets, ultimately promoting endothelial dysfunction,7 activation of the renin–angiotensin system,8 local inflammation,9 and tissue degeneration (Take home figure). While the activation of these pathways has been reported predominantly in AS, a disruption of the endothelial integrity and function might represent a common and initial step also in aortic and mitral valve regurgitation. Indeed, using transmission electron microscopy, Mirzaie et al. revealed that morphological changes in valves with aortic and mitral regurgitation include cellular swelling and loose binding of endothelial cells, together with loss of the endothelial layer over widespread areas of the leaflets. This is accompanied by areas of fibrous hyperplasia surrounded by calcium deposits, similar to what can be observed in calcific AS.10 Another potential explanation of the results presented by Rahimi et al. is the presence of common pathways affecting both the risk of arterial hypertension and the evolution of aortic and mitral valve degenerative disease. Arterial stiffness and AVD can be regarded as age-related diseases characterized by early changes in the composition of interstitial tissues at the levels of the aortic leaflets and aortic arterial wall.11 , 12 Indeed, previous studies reported a relationship between lower aortic or carotid artery distensibility and a higher risk of aortic valve calcification.13–15 Furthermore, Agmon et al. showed that proximal aortic atherosclerosis is independently associated with aortic valve abnormalities in the general population.16 The hypothesis that degenerative changes of the aortic valve might reflect an early ageing process involving the whole cardiovascular system could also explain the relationship between arterial hypertension and AR. Indeed, vascular ageing not only results in increased arterial stiffness but is often associated with a dilation of the aortic root,17 , 18 which is a major risk factor of AR. Hypertensive patients tend to present significant enlargement of the aortic root in comparison with normotensive patients.18–20 Common pathophysiological changes in aortic valve leaflets, aortic vascular wall, and aortic root that might explain the relationship between arterial hypertension and AS/AR. According to the first hypothesis, local haemodynamic stress imposed by arterial hypertension might increase mechanical stress on the valve leaflets, ultimately promoting endothelial dysfunction/disruption. This leads to accumulation of oxidized LDL (oxLDL), production of angiotensin (Ang) II, and inflammation with macrophages within the subendothelial space. The elevated levels of oxidative stress and pro-inflammatory cytokines promote changes in tissue matrix, including loss of elastin fibres and accumulation of collagen. In addition, leaflet fibroblasts undergo phenotypic transformation into osteoblasts, that promote extracellular calcification of the aortic valve. Following the second hypothesis, in individuals with a higher risk of both arterial hypertension and AS/AR, the same changes of tissue matrix might be related to a genetic predisposition to early cardiovascular ageing or other factors initiating the vascular and valve endothelial injury. Independently from their origin, these changes will lead to aortic root dilation (increasing the risk of aortic regurgitation), increased arterial stiffness (with a higher risk of arterial hypertension), and calcification of the aortic valve (with increased risk of aortic stenosis). The study by Rahimi et al. has several strengths. While previous reports have documented associations between arterial hypertension and risk of AS or AR, they often included a small number of participants and/or had a retrospective study design.4 In the study of Rahimi et al.,5 in contrast, the availability of follow-up data spanning >10 years and the meticulous statistical analysis adopted by the authors improve the degree to which causal inferences can be made from the observed associations. The use of data obtained from general practice records on a very large population is likely to provide accurate estimates of the potential risk of AVD associated with hypertension in the general population. Data on a wide range of established cardiovascular disease risk factors were available, providing the authors with the opportunity to show that common cardiovascular risk factors are unlikely to account for the association of blood pressure values with the risk of AS or AR. This is important as cardiovascular risk factors tend to cluster together, and previous studies documented strong associations between risk of AVD and several cardiovascular risk factors.21 For example, while hypercholesterolaemia is often associated with arterial hypertension and degenerative AVD,22 in the paper by Rahimi et al. adjustment for total, HDL-, and LDL-cholesterol did not reduce the strengths of the association between blood pressure and AVD, suggesting that they are unlikely to account for this relationship. Finally, the evidence that arterial hypertension might have a greater impact on the risk of AVD in young than in older individuals is in line with other large-scale epidemiological studies that have examined the relationship between blood pressure and other cardiovascular outcomes.23 Because AVD is often detected in subjects with concomitant coronary or peripheral vascular diseases, this evidence confers robustness to the presented associations. Beyond its merits, the study also has some limitations. While the statistical analysis was carefully planned, it remains unknown whether blood pressure is on the causal pathways for AVD. The use of data obtained from a general practice registry exposes the study to the risk of measurement error. It is well documented that measurement error in explanatory variables reduces our ability to control for confounding in the analysis, leading to residual confounding.24 This matter is further complicated by unmeasured confounders, often heavily represented in large registries.24 For example, inflammation and oxidative stress may be important confounders of the association between high blood pressure and aortic valve degeneration. As recognized by the authors, Mendelian randomization studies might provide more reliable information on causality as they are less prone to reverse causality and confounding. Also, these studies might provide valuable information on the pathways involved in the risk of high blood pressure that can also promote AVD, thus identifying novel therapeutic targets to prevent or treat both diseases. The study by Rahimi et al. provides the first solid evidence supporting the need for a radical shift in the approach to AVD. Indeed, over the last few years, the research on valvular heart disease has been focused on improving treatment rather than prevention strategies. This is confirmed by the very limited number of large, controlled, randomized clinical trials that have attempted to modify the evolution of AVD using anti-hypertensive medications.3 Thus, the findings provided by Rahimi et al. might be considered the first step towards a change in the management of AVD and are likely to influence future clinical trials and guidelines. Current European guidelines for the management of arterial hypertension do not consider AVD as manifestations of heart damage related to hypertension and, consequently, do not suggest accurate assessment of aortic valve function and structure in patients with arterial hypertension.5 Also, they might stimulate new lines of research, particularly imaging studies, with the scope of identifying early alterations of the aortic valve in patients with hypertension that might be highly predictive of future AVD. Conflict of interest: none declared.