In the past, calicific aortic stenosis (AS) in the elderly was felt to be a degenerative process from wear and tear upon deformed aortic cusps.1'2 However, over the last decade new pathophysiology has been described. Studies have shown infiltration of macrophages and T-lymphocytes, excess tissue adhesion molecules, elevated C-reactive protein and metalloproteinases consistent with an inflammatory process.3,4,5 Additionally lipoprotein deposition and calcification supports a concomitant atherosclerotic process.6 In some cases renal failure will exaggerate the valvular calcification. With so many variables, the rate of progression of AS may vary considerably from patient to patient.
The two following patients both appeared to develop AS after severe renal failure and their progression certainly occurred at an ultra-rapid pace.
Case 1 is a 65 year-old male who presented with polycystic kidneys and a myocardial infarction in 1988. He had no heart murmur. A left heart catheterization revealed normal left ventricular (LV) function, no aortic valve gradient and a right coronary artery (RCA) stenosis that was successfully angioplastied. An interim echocardiogram (2D-ECHO) in 2001 showed only aortic valve sclerosis and no valvular gradient just prior to starting hemodialysis. His cardiac catheterization was repeated in May 2002 after a bout of rapid atrial fibrillation (AF) with a minimal elevation of troponin. He had a 10mm Hg gradient across the aortic valve and no flow-limiting coronary artery disease (CAD). However, he developed congestive heart failure (CHF) in November 2002. His ECHO and cardiac catheterization were repeated, revealing a mean valve gradient of 45 mm Hg by ECHO and a mean valve gradient of 25 mm Hg with a valve area of 1.3 cm^sup 2^ by cardiac catheterization (a discrepancy due to pressure recovery in a narrow aorta). In August 2003, he had recurrent resistant CHF. Cardiac cathetemation at another facility then showed low pressure AS with a 25 mm Hg gradient, an aortic valve area of 0.85 cm^sup 2^, a drop in the ejection fraction (EF) to 40%, and 50% RCA restenosis. A dobutamine ECHO showed adequate contractile reserve. He was referred for aortic valve replacement (AVR) and single vessel coronary artery bypass grafting (CABG) of the RCA with good results. He is much improved now 15 months post-op. Interestingly, the pathology report of the resected aortic valve described acute inflammation within the substance of the valve with focal accumulation of fibrin and no definite bacteria identified by gram stain.
Case 2 is a 63 year-old female with insulin-dependant diabetes mellitus (DM) and chronic renal failure (CRF). She presented with transient asymptomatic 3rd degree av nodal ventricular block in 1998. No murmur was noted. An ECHO revealed normal LV function and mild sclerodegenerative aortic valve disease without a gradient. She returned in June 2002 with resistant CHF and hypotension. Her EKG was now normal. However a diagnostic cardiac catheterization revealed a mean aortic valve gradient of 55 mm Hg with an aortic valve area of 0.43 cm^sup 2^, and a mitral valve gradient of 18 mm Hg with a mitral valve area of 0.8 cm^sup 2^. Her EF and coronaries were normal. She improved after double valve replacement, but expired suddenly the following year.
Both patients had no apparent AS when starting hemodialysis (HD). However, in the span of just a few years (one and four respectively), both patients developed severe symptomatic AS with resistant CHF that improved only after AVR.
In the past, the progression of AS was felt to be a degenerative process related to the physical effects of turbulance on deformed cusps. Pathologists described thickening of valvular collagen and calicification at the base of the cusps, leaving the margins more mobile. Progression was often insidious with the valve area decreasing by an average of 0.04cm^sup 2^/yr to O.1cm^sup 2^/yr in one study.6
Over the past decade, similarities between AS and atherosclerosis have been reported. The initial valve lesion is a deposition of lipids, which are oxidized similarly to atherosclerosis.4'5 In the past few years, statins have been associated with slower progression of AS.7 Animal studies have shown that high cholesterol diets increased macrophage and osteoblast bone markers on the aortic valve.7 Another important component in the pathogcnesis of AS (as in atherosclerosis) is an inflammatory response with T-lymphocyte and macrophage infiltration.
Recent renal literature has cited renal failure with its alterations in calcium and parathyroid homeostasis as another risk factor for AS progression.8 Valvular calcification occurs in areas of lipoprotein deposition and has been identified with more hemodynamic progression in AS.
Our two patients highlight extreme examples for rapid progression when all risk factors are present, and suggest perhaps a synergistic effect in some cases. Both patients had minimal if any evidence of AS upon presentation but in the span of two years progressed to severe AS with resistant CHF responding only to AVR. Clinicians need to be aware of possible ultra-rapid progression in AS, particularly in patients with renal failure.
1. Crawley IS, Morris DC, Silverman DD. Valvular Heart Disease. In: Hurst JW. The Heart, Arteries and Veins. 4th ed. New York: McGraw-Hill, 1978: 1034.
2. Otto CM, Kuusisto J, Reichenbach DD, et al. Characterization of the early lesion of 'degenerative' valvular aortic stenosis: Histological and immunohistochemical studies. Circulation 1994; 90: 844-53.
3. Wallby L, Janerot-Sjoberg B, Steffensen T, Broquist M. T lymphocyte infiltration in non-rheumatic aortic stenosis: A comparative descriptive study between tricuspid and bicuspid aortic valves. Heart 2002; 88:348-51.
4. Schonenberger A, Winkelspecht B, Kohler H, Girndt M. High prevalence of aortic valve alteration in hemodialysis patients is associated with signs of chronic inflammation. Nephron Cli Pract 2004; 96: c48-55.
5. Olsson M, Dalsgaard CJ, Haegerstrand A, ct al. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrhcmatic stenotic aortic valves. JACC 1994; 23: 1162-70.
6. Bellamy MF, Pellikka PA, Klarich KW, et al. Association of cholesterol levels, HMG CoA reductase inhibitor treatment and the progression of AS in the community. JACC 2002; 40: 1723-30.
7. Rajamannan NM, Subramaniam M, Springett M, et al. Atorvastatin inhibitis hypercholesterolemia induced cellular proliferation and bone matrix production in the rabbit aortiv valve. Circulation 2002; 105: 2660-5.
8. Perkovic V, Hunt D, Griffin SV, et al. Accelerated progression of calcific aortic stenosis in dialysis patients. Nephron Clin Pract 2003; 94: c40-45.
ROGER D. RAYMOND, MD, AND EDWARD . CHOI, MD
Roger D. Raymond, MD, is cardiologist, Rhode Island Hospital, and Clinical Associate Professor, Brown Medical School,
Edward J. Choi, MD, is a Cardiology Fellow, Brown Medical School.
Roger D. Raymond, MD
Rhode Island Hospital
University Cardiology Foundation
2 Dudley Street, Suite 360
Providence, RI 02905
Phone: (401) 453-6754
Fax: (401) 444-3327
Copyright Rhode Island Medical Society Feb 2005
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