Clinic Hospital San Carlos, Madrid, Spain
See doi:10.1016/S1095-668X(02)00385-8for the article to which this editorial refers.
The decline in the incidence of rheumatic fever and the increasing proportion of the population over age of 65 have together led to a rise in the number of patients with aortic stenosis (AS), which is now a common valvular lesion. The formerly termed senile and now age-related degenerative or dystrophic calcific AS is the most common cause of AS in adults and the most frequent reason for aortic valve replacement in patients with AS.
Calcific AS was described by Mönckeberg in 1904.1 The process observed in elderly individuals without any history of rheumatic fever in whom the mitral valve is normal, suggests a degenerative process. Calcification occurs in the bases of the cusp in the depth of the sinuses of Valsalva, that is, on the aortic surfaces of the cusps.2 Edwards showed that the primary changes in the calcific aortic valve included alterations of valvular collagen with extra cellular droplets of a neutral fat occurring in bundles followed by calcification.3 The mechanical stress of wear and tear of the valve disrupts collagen and leads to calcification. The abnormal blood flow through congenitalbicuspid aortic valves is associated with increased wear and tear on the valve, which predisposes to calcification and critical calcific AS is earlier in bicuspid than in dystrophic AS. However, there is substantial evidence of a link between lipids and tissue calcification.4
Several lines of evidence suggest that degenerative aortic valve disease is not simply a consequence of aging. Aortic valve disease is not seen universally among the elderly, as 25% to 45% of octogenarians have no evidence of aortic valve calcification. In addition, the early lesion of calcific AS appears to involve an active process withsome similarities to atherosclerosis. Among more than 500 elderly subjects in the Helsinki Aging Study, age, hypertension and body mass index were independent predictors of aortic valve calcification.5 A prospective population-based study of the elderly, the Cardiovascular Health Study (CHS) in 5201 men and women showed that clinical factors associated with aortic sclerosis and AS can beidentified and are similar to risk factors for atherosclerosis.6 This study showed that aortic valvesclerosis was present in 26% and AS in 2% of the entire study cohort; in subjects aged 75 years or older, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (two-fold increase in risk for each 10 year increase in age), male gender (twofold excess risk), current smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein (a) and low-density-lipoprotein cholesterol levels.
Thus, there is increasing evidence that calcific degenerative AS simulates atheroma and its progression is related to known atherosclerotic risk factors. Somewhat surprisingly, aortic sclerosis is associated with an increased risk of myocardial infarction and could be a marker for an increased risk of cardiovascular events.7 But calcific AS,like atherosclerosis, is the product of an active inflammatory process and Chlamyda pneumoniae has been found in early lesions of age-relateddegenerative AS.8
The important study by Glader et al. in this issue of European Heart Journal confirms thatC. pneumoniae infection and a high plasma lipoprotein (a) (Lp(a)) level might influence and aggravate aortic valve sclerosis via the formation of circulating immune complexes and the study also suggest, for the first time, an association between high plasma leptin, tissue plasminogen activator (t.PA) concentration and AS. This paper alsoconfirm the relationship between atherosclerosis and degenerative AS. The fact that 67 out of 101 valvular AS are associated with ischaemic heart disease in agreement with previous findings.
In a histological analysis, Mohler et al. found mature lamellar bone formation and osteopontin bone expression in calcified human aortic valves.9 Active bone remodeling and heterotopic ossification is a common finding in the end-stage calcified cardiac valves. The mechanism by which bonematrix production develops in the aortic valvehas been investigated in a rabbit model. Vascular calcification is a well-known complication of late-stage vascular atherosclerotic lesion secondaryto elevated cholesterol levels in patients withfamilial hypercholesterolemia. In a recent study Rajamannan et al.10 showed that hypercholesterolemia causes an atherosclerotic proliferative valve lesion with the expression of an osteoblast-like phenotype in the rabbit. In the hypercholesterolemic aortic valve, there was an increase in osteopontine expression throughout the valve leaflet. Osteopontine is a bone-specific sialoprotein produced by osteoblast in osteoid matrix, involved in cell-matrix attachment and bone mineralization. Specifically there is marked endothelial cell disruption, cellular proliferation and foam cell formation on the aortic valve surface of animals fed a high-cholesterol diet. The atherosclerotic lesion develops primarily at the base of the leaflets and decreases toward the tip of the leaflet similar to what occurs in humans. The hypercholesterolemic rabbit also expressed certain genes that are characteristic of osteoblast differentiation, such as Cbfa-1 osteoblast-specific transcription factor. During embryonic development, Cbfa-1 expression precedes osteoblast differentiation and if this is correct, these data indicate that there is a transformation of the aortic valve fibroblasts in osteoblast cells.
The elevated level of leptin found by Gladeret al. in valvular AS is intriguing.11 Leptin is synthesised by adipocytes and functions as a starvation and adiposity signal by binding to its receptorlocalised in the hypothalamus. Rodents and humans genetically deficient in leptin signaling aremassively obese. Mice deficient in leptin (ob/ob)or its receptor (db/db) exhibit osteosclerosis (threefold higher bone mass).12 Leptin inhibits bone formation through its action on osteoblasts, but the number of osteoblasts are normal; this observation indicates that any possible local mode of action must affect already differentiated osteoblastsand not their progenitors. Intracerebro-ventricular infusion of leptin in wild-type mice causes bone loss. Lastly, obese individuals, who are often leptin resistant, are protected from bone loss. If leptin inhibits bone formation, it is difficult to understand why calcific and probably osificated AS develops elevated plasma leptin-levels. Leptin, like other major hormones such as thyroid hormones orcortisol, has multiple target organs and functions without a hierarchy among them.12 However,elevated leptin could be a vascular risk factor as shown in this paper as well as in stroke, and myocardial infarction, previously identified by the same authors.
The association between C. pneumoniae and atherosclerosis first came from seroepidemiological studies from Finland in 1988.13 The microbe is a common pathogen in respiratory infections but has also been detected in atherosclerotic lesions. It can survive intracellularly in macrophages, which could be important for transporting C. pneumoniae in the human body. C. pneumoniae causes vascular inflammation, but although it does not induce atherosclerosis alone in mice,14 it is associated with the progression of early stages of carotid atherosclerosis in patients >55 years old with prevalent cerebrovascular disease.15
The positive interaction between C. pneumoniae-specific IgG titer in plasma, and Lp(a), with both components present in circulatingimmune complexes, and high t-PA found in the study of Glader et al.11 support the concept that degenerative AS is an active process similar to atherosclerosis mediated by immunological mechanisms. The striking homology between Lp(a) and plasminogen together with the high levels of t-PA support the idea of inhibition of fibrinolysis in the arterial wall and the importance of thrombosis, both in atherosclerosis and in stenosis of the aortic valve.
Finally, this paper reminds us of that calcific AS is the product of an active inflammatory process and not a degenerative age-related condition and that we must adopt an aggressive stance toward the known atherosclerotic risk factors in order to slow down the progression of ischaemic heart disease and AS. The recent retrospective clinical16 and experimental studies10 suggest that treatment with statins (reductase inhibitors) HMG CoA in patients with calcific AS may slow down the rate of disease progression. Such therapy may have a potentialrole in the early stages of this disease processand prolong the time to surgical aortic valvereplacement.
References
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