The association of hypertension and aortic valve sclerosis

Abstract

Background. Aortic valve sclerosis (AVS), a condition of thickening and calcification of the normal trileaflet aortic valve without the obstruction to left ventricular outflow, is likely the initial stage in the development of aortic stenosis and is associated with an increased incidence of cardiovascular events. The objective of this study is to critically review the data on the association of blood pressure and hypertension with AVS. Methods. A systematic search of MEDLINE and EMBASE (to June 2004) was conducted using the keywords hypertension and aortic valve. All English language papers were examined if they dealt with hypertension and AVS. All studies were included for analysis if they had a control group. Results. Three population‐based, cross‐sectional studies with a total sample size of 6450 individuals showed a consistent and significant relationship between hypertension and AVS with an odds ratio (OR) ranging from 1.23 to 1.74. Smaller case–control studies with a total sample size of 1609 individuals did not show consistent results but the OR ranged from 1.75 to 2.38. Only one small study (n = 188) showed fewer cases with hypertension and AVS than in the control group. Hypertension was a significant factor remaining in multivariate analysis after consideration of age and other risk factors in several cross‐sectional studies. In contrast, other studies with blood pressure measurements consistently showed no increased blood pressures in the presence of AVS. However, these studies did not examine the prevalence of AVS within age‐adjusted blood pressure levels. Conclusions. Cross‐sectional population‐based studies present evidence of an association between hypertension and AVS with an OR between 1.23 and 1.74. The major limitation in establishing a causal relationship is the failure to demonstrate a gradient of risk between increasing blood pressure and increasing incidence of AVS. In addition, the literature is confounded by the wide variety of definitions for AVS as well as hypertension. At this time, further data is required to conclude that there is a causal relationship between AVS and elevated blood pressure.

• Aortic valve sclerosis
• hypertension

Introduction

Aortic valve sclerosis (AVS), a condition of thickening and calcification of the normal trileaflet aortic valve without the obstruction to left ventricular outflow, is no longer considered a benign accompaniment of the aging process but rather it is appreciated to be a marker of cardiovascular disease, as it is associated with an increased incidence of coronary events [1], [2]. Indeed, compared with individuals without this condition, AVS is associated with a 50% increase in death from all cardiovascular causes and AVS increases the risk of myocardial infarction, heart failure and stroke [1]. AVS is more common with increasing age. The prevalence increases from 20–28% in those aged 55–74 years, 35–55% in the 75–84‐year age group to 48–75% in those over 85 years of age [3], [4]. Demographic changes in many countries with a greater number of individuals in the older age groups leads to the expectation of an increased prevalence of AVS. Data suggest that AVS is an early stage of and a precursor for aortic valve stenosis [4]. The pathogenesis of aortic valve stenosis has been speculated to involve a continuum beginning with an initial thickening of the aortic valve, which may involve the elements that produce atherosclerosis, and progressing through to narrowing of the valve. As the prevalence of rheumatic valvular heart disease decreases, aortic valve disease is becoming an increasingly greater proportion of valvular heart disease cases [5]. While population data show a decline in mortality from rheumatic valve heart disease, this is not the case for aortic valve disease [5], highlighting the necessity to understand the pathogenesis of AVS and the necessity to develop strategies to prevent aortic stenosis [6].

While age does play an important role in the production of AVS, not all individuals at the same age have AVS; other pathophysiological mechanisms responsible for AVS remain poorly defined. The hypothesis that AVS and atherosclerosis share common mechanisms led to an examination of common risk factors. Hypertension is an obvious candidate, as it shares along with AVS an increasing prevalence with increasing age [7], [8]. Furthermore, the prevalence of early indicators of AVS, namely aortic valve calcification, identified by spiral computerized tomography (CT scan) was 20% in those aged 55–79 years [9], which is strikingly similar to the proportion of AVS in the same age group [3], [4]. The question arises whether the two conditions are associated and, more importantly, whether there is a casual link between hypertension and AVS, such that AVS is another of the consequences of sustained elevations in systemic arterial pressure. This has importance not only for patient management but also because it raises intriguing questions concerning common pathophysiological mechanisms that might provide new insights into the development of both conditions. Evidence to support a causal relationship between a factor and a disease needs to encompass a broad set of criteria that include experimentation, strength of association, gradient of risk, biological sense, consistency, specificity, temporality and coherence [10]. Awaiting clinical proof of causation by the experimental induction of hypertension and the development of AVS is not a reasonable expectation. Thus other criteria such as gradient of risk, biological sense and consistency need to be examined. The objective of this study is the critical analysis of the data on the association of blood pressure or hypertension with AVS focusing on the possibility of a causal relationship.

Materials and methods

Search strategy, selection criteria and data analysis

Studies were identified using a systematic search of MEDLINE (1966 to June 2004) and EMBASE (1980 to June 2004) conducted using the keywords hypertension and aortic valve. All English language papers were examined if they dealt with hypertension and AVS. Papers on the subject of aortic stenosis, aortic regurgitation or prosthetic aortic valves were not excluded from analysis. These valvular lesions when significant produce meaningful alterations of systolic blood pressure, thereby confounding the investigation of a causal relationship between blood pressure and the production of aortic valve disease. Titles and abstracts were evaluated to identify papers that dealt with the associated of hypertension and AVS. Additional relevant papers were searched by examining the reference list of publications. All papers were included for analysis if they had a control group, regardless of definition of AVS or hypertension.

Data analysis to determine the odds ratio (OR) and the 95% confidence intervals (CIs) were calculated if they had not been presented in the paper. If the OR and CIs were presented in the papers, then they were documented in this report. ORs provide an estimate of the association between two variables, thus assessing whether the probability of an event or condition is the same in two groups. An OR of 1 indicates that the event is equally likely in both groups.

Results

Hypertension and AVS

The first question examined was whether hypertension was associated with AVS and what was the strength of the association specifically whether the prevalence of AVS is greater in the hypertensive population than the normotensive population. The literature search identified seven relevant studies. The data linking hypertension and AVS are from a variety of studies, which used markedly different definitions of hypertension, conditions for the measurement of blood pressure and definitions of AVS (Table I). Only studies with echocardiographic evaluation of the aortic valve were considered but the definition of AVS varied considerably between studies. Although some studies including cases of aortic stenosis, the numbers of such cases were small and were unlikely to influence the results. Unfortunately, several studies included cases with calcification in the aortic root in the group, inferred echocardiographically, along with cases of AVS. There was consistency between studies in the age group with AVS as the mean age was between 71 and 80 years of age. The mean age of the comparison group, however, varied and was always slightly younger than the AVS group. The sex distribution between AVS cases and controls was not always matched and ranged from 30% to 61% men. There was consistency but not total uniformity in the data, which indicates a significant association between hypertension and AVS (Figure 1).

Table I. Studies examining the relationship between hypertension and aortic valve sclerosis (AVS).

Author	Name	Type	Method BP assessment	Definition of hypertension	Definition of AVS on echocardiogram
Aronow et al. [11]	None	Case/control	Medical records	BP>160/90 on 3 occasions	Aortic leaflet calcification or leaflet thickening
Pasierski et al. [12]	SHEP	Case/control	SHEP Protocol	SBP 160–219 and DBP<90	Aortic leaflet or aortic root ‘calcification’
Lindroos et al. [13])	Helsinki	Cross‐section	Survey protocol	BP>160/95 or medications	Aortic leaflet thickening and ‘calcification’ includes some cases of aortic stenosis
Boon et al. [14]	None	Case/control	Not stated	BP>160/90 or medications	Aortic leaflets with focal areas of echogenicity decreased valve mobility without obstruction
Stewart et al. [4]	CV Health Study	Cross‐section	Survey protocol	Self‐reported history of hypertension	Aortic leaflets with focal areas of echogenicity included few cases of aortic stenosis
Otto et al. [1]	CV Health Study	Cross‐section	Survey protocol	Self‐reported history of hypertension	Aortic leaflets with focal areas of echogenicity plus thickened leaflets with not restriction
Adler et al. [17]	None	Case/control	Not stated	>140/90 or antihypertensive drug use	Aortic leaflets with focal areas of echogenicity plus thickened leaflets with not restriction
Agmon et al. [16]	SPARC	Cross‐section	Office BP	antihypertensive drug use	Aortic leaflets with irregular thickening included a few cases of aortic stenosis

Table

Author/study name	Type	Age (year), AVS vs control	Sex (% men), AVS vs control	Setting	Sample size
Aronow et al. [11]	Case/control	NA	NA	Hospital	570
Pasierski et al. [12], SHEP	Case/control	69 vs 71	50 vs 49	SHEP substudy	117
Lindroos et al. [13], Helsinki	Cross‐section	75 vs 80	30 vs 28	Helsinki	540
Boon et al. [14]	Case/control	53 vs 74	35 vs 60	Hospital	862
Stewart et al. [4], CV Health	Cross‐section	72 vs 75	40 vs 52		5114
Otto et al. [1], CV Health	Cross‐section	72 vs 75	40 vs 49	Community, USA	5529
Adler et al. [17]	Case/control	72 vs 71	56 vs 55	Hospital	188
Agmon et al. [16], SPARC	Cross‐section	63 vs 76	61 vs 47	Community, USA	381

Figure 1 The odds ratio(OR) and confidence intervals (CI) for studies relating hypertension to aortic valve sclerosis (AVS). The precise definitions encompassing AVS are provided in Table I. The OR was calculated from the data provided for Aronow et al. [16]; Pasierski et al. [17], Otto et al. [1] and Adler et al. [20]. These were univariate (unadjusted) calculations. The OR was plotted from the value stated in the text after multivariate analysis adjusting for age and different variables for the other studies and are indicated by +. The sample sizes for each study are indicated.

In a case–control study of patients with a mean age of 82 years, hypertension was significantly associated with calcified or thickened aortic cusps or calcification of the aortic root with an OR of 1.75 [11]. In a small sub‐study of the Systolic Hypertension in the Elderly Program (SHEP), there was no significant difference in the presence of aortic valve calcification or aortic root calcification compared with age‐matched normotensive screened subjects [12]. However, the OR was 2.17 so that a larger study population would likely have shown a significant relationship. Hypertension was associated with a significant 1.74‐fold increase in aortic valve calcification, which included some cases of aortic stenosis, in a Helsinki community‐based cross‐sectional epidemiological study [13]. Hypertension was a significant factor remaining in multivariate analysis after consideration of age, gender, cigarette smoking, serum ionized calcium or phosphate, serum cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, triglycerides, serum creatinine, diabetes mellitus or serum parathyroid hormone [13]. In a large case–control study based in a University Hospital echocardiography laboratory, hypertension was more common in patients with AVS compared with controls [14]. In multivariate analysis after adjusting for age, diabetes mellitus, dyslipidemia, ischemic heart disease and other valvular lesions, there was a significant relationship between hypertension and AVS with an OR of 2.38 [14]. The Cardiovascular Health Study is a cohort of 5888 men and women 65 years of age and older who were randomly selected from households on Medicare‐eligibility lists in four communities across the USA and who had blood pressure measured at entry [15]. In that cohort, a history of self‐reported hypertension was significantly associated with aortic sclerosis in univariate analysis with an OR of 1.36 [1]. In the same cohort, multivariate analysis that combined cases of AVS with aortic stenosis found that hypertension was significantly related to aortic valve disease after adjusting for over 20 other variables including age [4]. Hypertension defined as the use of antihypertensive drugs was associated with a significant greater occurrence of aortic sclerosis in the cross‐sectional population‐based SPARC study, after multivariate analysis adjusting for age, gender, body mass index and serum lipids [16]. In contrast to these data, a small case–control study of patients (n = 188), with a mean age of 72 years and echocardiographically well‐defined AVS had more cases of hypertension in the control group than in the group with AVS [17]. Perhaps the requirement that all patients have transoesophageal echocardiography (TEE) [17] incorporated a bias in patient selection.

In summary, six of seven studies with a total sample size of almost 8000 persons favoured an association between hypertension and AVS. A formal meta‐analysis combining all the studies was, unfortunately, not possible because several of the studies have a control group that were not matched for age and other studies only reported their multivariate analysis data. The OR from the cross‐sectional epidemiological studies ranged from 1.23 to 1.74.

Blood pressure in AVS

The second question reviewed was whether there was a significant biological gradient of risk between systemic arterial blood pressure and the presence of AVS, i.e. are higher blood pressures more likely to be associated with AVS than lower blood pressures or, phrased in another way, are blood pressures different in those with or without AVS? The literature search identified five relevant papers with three additional studies (Table II). Blood pressure was measurement in a standardized manner following accepted protocols in three of these studies and echocardiographic end assessment was the criteria for diagnosis of AVS in three studies. There were no significant differences in blood pressure between those with and those without AVS in these studies. In an elderly patient group, mean age 80 years, admitted to a geriatric ward of a hospital, there was no difference between admission systolic or diastolic blood pressure and the presence or absence of calcification in the aortic valve observed at subsequent autopsy [18]. In a cross‐sectional population‐based epidemiological investigation of men and women, mean age 62 years, in a Japanese community, there was no difference between those with or without aortic sclerosis according to blood pressure measured using a standardized protocol and with an automated device [19].

Table II. Studies examining the relationship between blood pressure and aortic valve sclerosis (AVS).

Author	Study name	Type	Setting	Sample size	Method BP assessment	Definition of AVS
Pomerance et al. [18]	None	Case/control	Hospital, Wara, Japan	186	Hospital records	Autopsy: aortic valve calcium
Gotoh et al. [19]	JMS Study	Cross‐sectional		784	Automated BP machine	Echo: aortic valve thickening or calcification and mild restriction of mobility
Stewart et al. [4]	CV Health Study	Cross‐sectional	Communities, USA	5114	Survey protocol	Echo: Aortic valve‐ focal increase echogenicity included few cases of aortic stenosis
Agmon et al. [16]	SPARC	Cross‐sectional	Community, USA	381	Office BP	Echo: Aortic leaflets with irregular thickening included a few cases of aortic stenosis
Wong et al. [20]	None	Cross‐sectional	San Francisco, USA	2739	Not stated	CT scan for aortic valve calcification

In the Cardiovascular Health Study, Stewart et al. [4] found that although systolic blood pressure but not diastolic blood pressure was slightly higher in subjects with aortic valve disease, aortic sclerosis plus aortic stenosis, compared with those with normal aortic valves, this was attributed to the older age of subjects with aortic valve disease because blood pressure was not significantly different after multivariate analysis considering subjects age [4]. A similar observation was made in the SPARC study, a cohort in Olmsted County, Minnesota (USA), aged 57–85 years [16]. After age adjustment, Agmon et al. [16] found that there was no significant difference in blood pressure between those with or without AVS. Although echocardiography is the standard or the diagnosis of AVS, this valvular disease can be associated with calcification of the aortic valve. It is noteworthy that in a study of 2739 men and women who underwent cardiac CT scan, Wong et al. [20] reported that there was a marginal positive relationship between systolic blood pressure and the presence of calcification in the aortic valve (OR = 1.11, CI = 0.997–1.23; p = 0.06) in multivariate analysis, including age, but a significant negative relationship between diastolic blood pressure and aortic valve calcification (OR = 0.6, CI = 0.62–0.92; p = 0.006). It is difficult, however, to compare CT evidence of aortic valve calcification and echocardiographically visualized AVS, as sclerosis can occur without the presence of calcification. Thus the data from four separate populations were consistent and showed no relationship between blood pressure and the presence of AVS. These studies, however, did not examine the prevalence of AVS within the different levels of blood pressure for individuals of the same age.

Discussion

This is the first report, to my knowledge, to review critically the association of hypertension and AVS. Studies examined included all case–control and cross‐sectional epidemiological cohort analysis, and none was excluded from evaluation. Case–control studies are faced with the problems of the appropriate selection of controls such as precisely matching age and other variables. Cross‐sectional epidemiological studies can sometimes be more reliable. The OR from the cross‐sectional epidemiological studies ranged from 1.23 to 1.74 indicating a modest but significant association between hypertension and AVS.

Data from studies of aortic stenosis are conflicting [21], [22] and were excluded on the grounds of relevance, because such studied are done at the time of cardiac catheterization or surgery and aortic valve stenosis severe enough to consider surgical replacement has impairment in LV outflow that reduces blood pressure. Studies of aortic regurgitation were excluded because the attendant increase in stroke volume increases systolic blood pressure and would erroneously be included as cases of hypertension.

The absence of a relationship between blood pressure and AVS is perplexing, as one might anticipate a positive association. However, these studies included subjects with hypertension who were on antihypertensive drugs, which would clearly affect blood pressure. In addition, they did not examine the relationship within blood pressure levels (tertiles or quartiles), which would differentiate those with elevated blood pressure from normotensive subjects in whom there may not be a relationship between blood pressure and AVS.

Potential pathophysiological link(s) between hypertension and aortic sclerosis

A cogent pathophysiological link must exist if the connection between hypertension and AVS is to make biological sense. There are a number of potential pathophysiological mechanisms that might causally link hypertension and aortic sclerosis. These can generally be considered in the following categories: (i) a direct effect solely related to hypertension such as tissue trauma to the aortic valve from elevated arterial pressure; (ii) a multifactorial process, in which hypertension plays a facilitatory role; analogous to the theory of hypertension‐induced atherosclerosis, which occurs more readily in conjunction with other risk factors such as dyslipidemia; (iii) a common set of factors produce hypertension and AVS, which may be common vascular or circulating neurohormonal factors; (iv) systemic and local factors induced by hypertension that in turn produce AVS. Of course, these explanations are not mutually exclusive and several may coexist.

The proposal that AVS is the result of mechanical stress on the aortic valve was summarized in 1962 by Edwards: “the normal aortic valve functioning over many years maybe traumatized … as a result of trauma, it may undergo the same changes in its collagen that … have histological counterparts in the supraspinatus tendon of traumatic bursitis” [23]. This concept was further promoted by Roberts [24], who concluded that because calcific deposits are located on the aortic aspects of the aortic valve cusps and because hypertension increases the closing pressure of the aortic valve, hypertension accelerates the development of aortic valve calcification. The normal aortic valve is subject to considerable mechanical stress. During the cycle of opening and closing, the cusps rotate along the line of attachment bending and unbending along the line of co‐aptation [25]. Thus it is not unreasonable to believe that increased stress of valve closure in patients with elevated blood pressure induces thickening of the aortic valve leaflets. However, hypertension per se is an unlikely explanation as one would anticipate that the majority of patients with hypertension would develop AVS and this is not the case.

Hypertension may play a facilitatory role in producing AVS in concert with the other factors that produce atherosclerosis. AVS has been likened to atherosclerosis because of the commonality of histopathological features, namely the occurrence in both conditions of inflammatory cells – macrophages and T cell infiltration as well as lipid deposition [26]. The accumulation of apolipoproteins in the AVS may be analogous to the role of apolipoproteins in atherosclerosis [27]. Familial hypercholesterolemia, which is associated with premature atherosclerosis of the coronary arteries, is also associated with aortic valve disease, which can progress to aortic stenosis [28]. Similarly, the role of platelets and fibrin thrombi in atherosclerosis may be mirrored in their putative role in progressive thickening of the aortic valve [29]. The animal model of atherosclerosis rabbits, fed cholesterol‐enriched diets, manifest with atherosclerotic lesions on the aortic valve [30], [31]. The occurrence of these lesions initially only in areas of maximum intramural stress of the valve [30] is consistent with a pressure‐driven filtration hypothesis of aortic valve disease [32]. This is analogous to the proposed mechanism whereby hypertension accelerates atherosclerosis. Retrospective clinical studies suggest a beneficial effect on aortic stenosis progression by statin drugs that lower serum cholesterol similarly to the favourable outcomes on atherosclerosis from this class of agent [33–35] but prospective clinical trials are necessary to determine whether these agents blunt the progression of AVS to aortic valve stenosis. There are, however, some pertinent dissimilarity between AVS and atherosclerotic lesions such as prominent mineralization and infrequent smooth muscle cells in AVS, which is the opposite of the findings in atherosclerosis [26]. The foam cell, a sign of atherosclerosis, has been said to be absent from calcific aortic valve disease [36], although others disagree [28]. In contrast to the strong association between atherosclerosis and serum lipids or diabetes mellitus, a number of studies refute a relationship between high LDL cholesterol or low HDL cholesterol or diabetes mellitus and AVS [4], [13], [14].

The intriguing possibility that a common set of factors is operative to produce hypertension and AVS is difficult to prove, as the cause of hypertension as well as AVS remains elusive. Nevertheless, there are several potential linkages between these two conditions. Endothelial dysfunction has been noted in hypertension and has been causally linked to hypertension [37]. Patients with aortic sclerosis demonstrate impairment in flow‐mediated dilatation in the brachial artery consistent with endothelial dysfunction [38]. Another attractive potential explanation is changes in compliance of the aorta because of the growing evidence that implicates reduced aortic wall compliance in hypertension [39]. If the changes in aortic compliance extend to the sinuses of Valsalva, then it could produce a stress‐overload on the aortic leaflets leading to changes in their microstructure that culminate in sclerosis and calcification of the cusps [40]. There are theoretical arguments for shared pathophysiological mechanisms with neurohumeral factors. Angiotensin II initially appeared to be an attractive potential link between hypertension and aortic sclerosis because angiotensin‐converting enzyme, a key enzyme in the generation of the potent vasopressor peptide angiotensin II, is present in human aortic valves manifesting aortic sclerosis [41]. In addition, angiotensin II and the AT1 receptor are present on myofibroblasts of stenotic aortic valves [41]. Clinical trial data, however, do not support a role for angiotensin II in aortic sclerosis, as the AT1 receptor blocker losartan did not alter the progression of aortic sclerosis during hypertension treatment any more that the beta‐blocker atenolol [42].

Hypertension may activate or induce the expression of local factors involved in the process of AVS. A variety of factors are involved in the production of collagen, tissue calcification and the other valve components that characterize AVS. Extracellular bone matrix proteins such as osteopontin, osteocalcin and osteonectin are expressed in human aortic valve and in aortic stenosis [21], [43–46]. Although osteopontin expression correlated with cellular accumulation and calcification in aortic valves [45], osteopontin inhibits mineral deposition and promotes regression of ectopic calcification [47]. The role of extracellular bone matrix proteins in hypertension is not well defined. Some data suggests that hypertension is associated with increased expression of osteopontin in the kidney [48]. Thus this factor would not be a likely mediator of hypertension‐induced AVS if the directional changes in the kidney prove to be the same as those in the aortic valve in patients with hypertension and if osteopontin were to inhibit mineral deposition in the aortic valve. A more likely candidate is tenascin‐C. This extracellular matrix glycoprotein has an increased expression in aortic stenosis [49]. Interestingly, there is increased focal tenascin expression by vascular smooth muscle cells in spontaneously hypertensive rats compared with Wistar controls [50]. A causal link between hypertension and tenascin‐C expression in AVS, however, needs to be defined.

Conclusions

Critical evaluation of the evidence suggests that there are data to support an association between hypertension and AVS. Data from case–control and cross‐sectional epidemiological studies have consistently, with one exception, found that hypertension is associated with AVS. There are several highly credible potential biological explanations to link hypertension and AVS. The major limitation in establishing a causal relationship is the data from other studies that fail to demonstrate a gradient of risk between increasing blood pressure and increasing incidence of AVS. The weaknesses of the studies in this field, specifically the differing definitions of AVS as well as hypertension and in some studies the failure to take into account the effects of age, seriously limit the ability to arrive at a consensus. Randomized placebo‐controlled clinical trials of hypertension treatment monitoring the effect on the development AVS are not likely to be performed so this kind of data will not likely be available. At this time, further data is required to conclude that there is a causal relationship between AVS and elevated blood pressure. Further investigation on the biological basis for the development of AVS is necessary to establish whether there is indeed a link between hypertension and AVS, so that the adverse outcome of patients with AVS can be mitigated by specific blood pressure therapeutic regimes.