点击显示 收起
From the Weill Medical College of Cornell University, New York.
Correspondence to Jeffrey S. Borer, Weill Medical College of Cornell University, 525 East 68th Street, Room F-467, New York, NY 10021. E-mail ero2002@med.cornell.edu
Aortic stenosis (AS) is a relatively common cause of cardiac debility and death, increasing in frequency and severity with age; indeed, AS of at least moderate severity may affect almost 8% of people 75 years of age.1 The natural history of AS is dependent on the myocardial response to the abnormal left ventricular pressure load caused by the stenotic valve, involving cardiomyocyte hypertrophy, hyperproduction of extracellular matrix collagen by cardiac fibroblasts, and other alterations in myocardial biology. When these changes become critically severe, symptoms develop (angina pectoris, syncope, exertional dyspnea, and other manifestations of pulmonary vascular congestion) followed predictably by cardiac death at an annual rate of 25% unless aortic valve replacement surgery is performed.
See page 592
The basis of the lifesaving effect of aortic valve replacement is clear: the ventricular myocardium is unloaded, enabling myocardial remodeling toward normal, generally with recovery of normal myocardial performance.2 A more satisfactory solution than surgery would be prevention of the stenotic process itself. To achieve this goal, the pathophysiology of stenosis development must be known, and effective pharmacological or other countermeasures must be developed and validated clinically.
The first step, elucidation of the pathobiology of AS, began more than a century ago (see, for example, Osler and Gibson3) with the observation at necropsy that the heavily calcified aortic valves of patients with acquired AS of the "degenerative" or "senile calcific" form (now quantitatively the most common) manifest gross and histopathologic characteristics similar to those associated with atherosclerosis. The accretion of calcium in these lesions is pathophysiologically and prognostically important, and is commonly apparent with advancing age. Indeed, some calcification is present in the aortic valves of more than half the population 55 years of age.1 Epidemiologic data now indicate that the risk factors promoting arterial atherosclerosis (including hypercholesterolemia, diabetes mellitus, hypertension, and smoking, as well as supernormal lipoprotein[a] concentration, expression of apolipoprotein E alleles, C-reactive protein concentration, etc.) also are associated with development and progression of AS.4–8 Therefore, it may be inferred that drugs known to modify these risk factors and to minimize atherosclerosis may also diminish progression of AS. The only rigorous test of this hypothesis is an appropriately designed randomized, controlled clinical trial. At least one such trial is now ongoing, assessing the combination of simvastatin and ezetamibe on AS progression; results are not yet available. Support for such clinical trials comes not only from histopathologic and epidemiological data but also from studies in experimental animals9 and from several retrospective nonrandomized observational series suggesting that hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can minimize progression of AS.10–12 The primary pharmacological effect presumed to underlie the inferred (not yet proven) impact of statins on AS is cholesterol lowering, supported not only by epidemiological data but also from evaluations of the cellular pathophysiology of AS.9,13,14 Thus, it is presumed that calcification is induced by hypercholesterolemia.
Calcification is particularly relevant in the pathogenesis of AS because stiffening of the valve is the basis for hemodynamic deterioration, whereas valve calcification is directly related to the degree of stenosis. Prior studies suggest that the process of valve calcification is surprisingly similar to calcification in the bony skeleton: expression of mature lamellar bone and osteopontin have been demonstrated in human calcified stenotic aortic valves.15,16 In the study of Wu et al, in the current issue of this journal, the same group that made these observations now has provided exciting new insights into the cellular pathophysiology of calcification in AS and into its potential prevention.17 Wu et al demonstrate that, in cultures of myofibroblasts isolated from porcine aortic valves, the effects of statins on bone formation can be dissociated from the effect on systemic cholesterol concentration, and that this action is mediated through inhibition of the cholesterol biosynthetic pathway. These observations provide a plausible basis for the earlier findings of Rajamannanet al, which demonstrated statin-mediated inhibition of cellular proliferation and bone matrix production in aortic valves of hypercholesterolemic rabbits.9 The results of Wu et al provide important additional evidence favoring the specific beneficial effects of statins in preventing AS. In addition, these data suggest that the therapeutic target, prevention of calcification/bone formation, may be approachable by inhibiting the relevant pathway without reference to effects on cholesterol, thus widening the range of possible preventive strategies. To be sure, the studies of Wu et al were performed in a highly circumscribed experimental system. Relevance of this particular pharmacological effect of statins to prevention of aortic stenosis cannot be inferred directly from these findings. Nonetheless, this study adds importantly to the already strong mandate for clinical trials of statins to prevent progression of AS and, simultaneously, may stimulate novel approaches to prevention of neo-ossification in the aortic valve.
Acknowledgments
This manuscript was prepared at The Howard Gilman Institute for Valvular Heart Diseases, Weill Medical College of Cornell University, of which Dr Borer is Director. Dr Borer is the Gladys and Roland Harriman Professor of Cardiovascular Medicine at Weill Medical College and is supported in part by an endowment from the Gladys and Roland Harriman Foundation, New York.
References
Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993; 21: 1220–1225.
Borer JS, Jason M, Devereux RB, Fisher J, Green MV, Bacharach SL, Pickering T, Laragh JH. Function of the hypertrophied left ventricle at rest and exercise: hypertension and aortic stenosis. Am J Med. 1983; 75: Suppl III: 34–39.
Osler W, Gibson A. Diseases of the valves of the heart. In: Osler W, McCrae T, eds. Modern Medicine, Its Theory and Practice, Volume 4. Philadelphia, Pa: Lea & Febiger; 1908: 205–269.
Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with calcific aortic valve disease: Cardiovascular Health Study. J Am Coll Cardiol. 1997; 29: 630–634.
Deutscher S, Rockette H, Krishnaswami V. Diabetes and hypercholesterolemia among patients with calcific aortic stenosis. J Chron D. 1984; 37: 407–415.
Peltier M, Trojette F, Sarano ME, Grigioni F, Slama MA, Tribouilloy CM. Relation between cardiovascular risk factors and nonrheumatic severe calcific aortic stenosis among patients with a three-cuspid aortic valve. Am J Cardiol. 2003; 91: 97–99.
Novaro GM, Sachar R, Pearce GL, Sprecher DL, Griffin BP. Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation. 2003; 108: 1804–1808.
Gerber IL, Stewart RA, Hammett CJ, Legget ME, Oxenham H, West TM, French JK, White HD. Effect of aortic valve replacement on C-reactive protein in non-rheumatic aortic stenosis. Am J Cardiol. 2003; 92: 1129–1132.
Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002; 105: 2660–2665.
Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol. 2001; 88: 693–695.
Bellamy MF, Pellikka PA, Klarich KW, Tajik AJ, Enriquez-Sarano M. Association of cholesterol levels, hydroxymethylglutaryl co-enzyme A reductase inhibitor treatment and progression of aortic stenosis. J Am Coll Cardiol. 2002; 40: 1723–1730.
Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, Schemper M, Binder T, Maurer G, Baumgartner H. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation. 2004; 110: 1291–1295.
Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of "degenerative" valvular aortic stenosis: histologic and immunohistochemical studies. Circulation. 1994; 90: 844–853.
Olsson M, Thyberg J, Nilsson J. Presence of oxidized low density lipoprotein in non-rheumatic stenotic aortic valves. Arterioscler Thromb Vasc Biol. 1999; 19: 1218–1222.
Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001; 103: 1522–1528.
Mohler ER 3rd, Adam LP, McClelland P, Graham L, Hathaway DR. Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol. 1997; 17: 547–552.
Wu B, Elmariah S, Kaplan FS, Cheng G, Mohler ER 3rd. Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts. implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol. 2005; 25: 592–597.