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Factors Affecting Aortic Stenosis Progression

Ramdas G. Pai, MD

Loma Linda University Medical Center, Loma Linda, CA, USA

   Aortic stenosis (AS) is common in the aging population. Symptomatic AS is associated with a poor prognosis, but the natural progression of less severe degrees is highly variable. The risk factors for the development of AS are the same as that of coronary artery disease (1), and some of these seem to have an effect on AS progression as well (2-7). This review examines the clinical, echocardiographic and biochemical variables that may affect rate of AS progression and hence may potentially serve as targets for retarding disease progression.

MECHANISMS OF AS PROGRESSION
   The average rate of reduction in aortic valve area is about 0.10 cm2 per year (4,7). However, the rate of progression in a given patient can not be predicted because wide variability and in certain patients it can be as much as 1.0 cm2 per year (7). The rate of progression and factors affecting this may depend on the etiology: different pathophysiological mechanisms may be responsible in patients with degenerative versus rheumatic or bicuspid aortic valves.

   Changes in aortic leaflets in patients with degenerative changes are somewhat similar to atherosclerotic lesions with cholesterol deposits, smooth cell proliferation, fibrosis and dystrophic calcification (2). In addition, the atherosclerotic risk factors are also associated with the presence of degenerative AS. This review addresses patients with degenerative or calcific AS. We summarize the available observational data and speculate on their clinical relevance, especially with regard to potential for secondary prevention.

FACTORS ASSOCIATED WITH THE PROGRESSION OF DEGENERATIVE AS
   1. Etiology of aortic stenosis: Bicuspid aortic valve is common and is found in 1-2% of the population and progresses to significant stenosis only in a minority. Hence, it is reasonable to conclude that AS progression in patients with bicuspid aortic valve is slower than degenerative AS in patients with tricuspid valves. However, the rate of progression after AS develops in bicuspid aortic valve is not well known. In rheumatic heart disease, rate of AS progression is highly variable. It may be accelerated in those with active, recurrent carditis.

   2. Age: The rate of progression seems to be faster in the older subjects (6). This is true in patients with or without chronic renal failure (8).

   3. Gender: Multiple studies indicate that the rate of AS progression is faster among men compared to women (8-10). Effect of gender on AS progression has been shown by Nassimiha et al in 290 patients >60 year of age and patients on dialysis by Urena et al (8,9).

   4. Hypertension: This has not been associated with AS progression in any of the published studies.

   5. Diabetes mellitus: Surprisingly, despite being a very powerful risk factor for progression of coronary artery disease, none of the data support this being a risk factor for AS progression.

   6. Smoking: Effect of smoking on AS progression has been described by Palta et al, Mohler et al and Ngo et al, but the effect does not seem to be as impressive as in coronary artery disease (2,7,11).

   7. Obesity: In their follow up of 87 patients with AS, Ngo et al found obesity and smoking to be independent risk factors for AS progression (11).

   8. Presence of CAD: Peter et al found presence of coronary artery disease to be a risk factor for AS progression (6). This was a small study and the effect may be through the coronary risk factors which also have a bearing on AS progression. But this raises important questions on management decisions in patients with coronary artery disease undergoing coronary artery bypass surgery and have only mild incidental AS.

   9. Chronic renal failure: Urena et al in a study of 110 patients on hemodialysis, found significant AS in 16% of the patients (8). The risk factors in this population included older age, male gender, higher calcium-phosphate product and elevated vitamin D3 levels. This emphasizes the possible role of dystrophic as well as metastatic calcification. It is also possible that other factors such as homocysteine levels and humoral may be operative in these patients.

   10. Serum cholesterol: AS progression is rapid in patients with homozygous hypercholesterolemia and this can occur at an early age with concomitant premature coronary artery and other vascular diseases (12). It has also been shown that in patients undergoing aortic valve replacement of aortic stenosis with or without coronary artery bypass surgery have a higher serum cholesterol, triglyceride and LDL levels compared to those undergoing bypass surgery alone (13). Also in our study of 170 patients with AS, the rate of AS progression was twice as much in those with a serum cholesterol level >200 mg/dl (7). Effect of cholesterol on AS progression seems to be greater in patients with tricuspid as compared to bicuspid aortic valves (14).

   11. Serum calcium: Primary hyperparathyroidism causes accelerated AS progression. Even serum calcium level within the normal range seems to influence AS progression (7). And in patients on dialysis there is a definite relationship between calcium-phosphate product (and vitamin D3) and AS progression (8). This raises valid questions on the safety of calcium and vitamin D supplementation for prevention of osteoporosis.

   12. Serum creatinine: We have demonstrated that a higher serum creatinine level even within the normal range accelerates AS progression (7). The mechanism of this is unclear, but raises the possibility that either creatinine or some of the biochemical factors that accumulate in the blood with a fall in glomerular filtration rate may act as catalysts in AS progression.

   13. LV function and mass: There is some suggestion that patients with reduced LV function or increased LV mass may have more rapid AS progression (10). This may either due to changes in mechanical stress on the valve or more likely to changes in biochemical milieu produced by altered hemodynamics or the effect of factors responsible for LV hypertrophy or remodeling in the first place.

   14. Hydrodynamic factors: A higher LV outflow tract velocity which is associated with greater cardiac output is associated with more rapid AS progression raising the possible importance of mechanical factors which may initiate inflammatory processes as in the genesis of coronary artery disease (7). However, it is interesting that the rate of progression is slower in more severe AS (7). This may perhaps be due to the stretching effect of a greater gradient or the nature of valve pathology (e.g. fibrous tissue content, lipid content and inflammatory components) when AS is more severe.

   15. Degree of aortic valve calcification: It has been suggested that AS progression is faster in patients with moderate or severe aortic valve calcification (10). Also patients with severe AS who have more severe valve calcification have a worse prognosis (16).

   16. Mitral annular calcification: There is one study which implicates mitral annular calcification as a marker of AS progression (9). Mitral annular calcification is associated with age, aortic valve calcification and coronary artery disease and may also reflect an abnormal biochemical process involving calcium/phosphorus metabolism or a tendency on part of the patient for dystrophic calcification.

MANAGEMENT IMPLICATIONS
   The rate of AS progression is highly variable. However, evidence points to multiple clinical, biochemical and echocardiographic variables which affect AS progression. Ability to predict AS progression has clinical implications in patients undergoing surgery for coronary artery disease who also have mild AS. Though the pathology and risk factors for AS progression have lot of commonalities with coronary artery disease, there are striking differences. For example, diabetes which has major effect on coronary artery disease does not seem to have any effect on AS progression and smoking has only marginal effect. Age, gender, obesity, serum cholesterol and chronic renal disease have an effect similar to that in coronary disease. And biochemical factors such as creatinine and calcium are uniquely related to AS progression in contrast to coronary disease. These associations also raise the question if AS progression can be retarded by risk factor modification. The following discussion is speculation on some possible targets as there are no studies addressing these issues.

   1. Smoking cessation: As smoking seems to be associated with AS progression, it is tempting to speculate if stopping it would retard progression. There are studies addressing this question. However, smoking is a modifiable risk factor.

   2. Lipid modification: Evidence that cholesterol and triglycerides modify AS progression is quite strong. However, there are no studies evaluating the effect of lipid lowering on AS progression. We feel a randomized study addressing this issue is warranted.

   3. Serum creatinine: It is clear that renal failure accelerates AS progression, but how serum creatinine within normal range does this is unclear. This issue needs further investigation in terms of other biochemical/cytokine mediators which may be associated with high-normal serum creatinine levels.

   4. Serum calcium: This association certainly emphasizes the need to keep the serum calcium-phosphate ratio within normal range. The burning question is if supplements used for osteoporosis prevention could cause AS or accelerate AS progression. This needs careful evaluation.

   5. Management in chronic renal failure: More intense dialysis with normalization of serum phosphate level may be helpful. Vitamin D administration needs to be evaluated with care.

   6. Possible hemodynamic targets: As AS progression is faster in those with higher cardiac output, it is attractive to speculate if beta blockers will have a role in retarding its progression.

   7. Antiinflammatory agents: As it does in coronary artery disease, the potential role of aspirin should be explored because of pathogenetic similarities.

   8. Angiotensin converting enzyme inhibitors: These may potentially have a role through reducing inflammation, plaque stabilization and reduction in the fibrotic process. But this needs further investigation.

ABSTRACT
This review examines the clinical, echocardiographic and biochemical factors that are associated with aortic stenosis progression. Observational data indicate that aortic stenosis progression may be influenced by age, gender, smoking, obesity, hypercholesterolemia, serum creatinine and calcium levels, and possibly mechanical factors. Potential therapeutic targets for retarding its progression are discussed. These are speculative and randomized clinical trials are warranted.

REFERENCES

1. Faggiano P, Auriegemma GP, Rusconi C, Gaasch WH. Progression of Valvular AS in adults:Literature review and clinical implications. Am Heart J 1996; 132: 408-17.

2. Mohler ER, Sheridan MJ, Nichols R, Harvey WP, Waller BF. Development and progression of aortic valve stenosis: atherosclerosis risk factors- a causal relationship? A clinical morphologic study. Clin Cardiol 1991; 14: 995-9.

3. Malergue MC, Urena P, Prieur P, Guedon-Rapoud C, Petrover M. Incidence and development of aortic stenosis in chronic hemodialysis. An ultrasonographic and biological study of 112 patients. Arch Mal Coeur Vaiss 1997; 90:1595-601

4. Brener SJ, Duffy CI, Thomas JD, Stewart WJ. Progression of aortic stenosis in 394 patients: relation to changes in myocardial and mitral valve dysfunction. J Am Coll Cardiol 1995;25:305-10.

5. Roger VL, Tajik AJ, Bailey KR, Oh JK, Taylor CL, Seward JB. Progression of aortic stenosis in adults: new appraisal using Doppler echocardiography. Am Heart J 1990;119:331-8.

6. Peter M, Hoffmann A, Parker C, Luscher T, Burckhardt D. Progression of aortic stenosis. Role of age and concomitant coronary artery disease. Chest 1993;103:1715-9.

7. Palta S, Pai AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: Implications for secondary prevention. Circulation 2000; 101: 2497-2502.

8. Urena P, Malergue MC, Goldfarb B, Prieur P, Guedon-Rapoud C, Petrover M. Evolutive aortic stenosis in hemodialysis patients: analysis of risk factors. Nephrologie 1999; 20: 217-225.

9. Nassimiha D, aronow WS, Ahn C, Goldman ME. Rate of progression of valvular aortic stenosis in patients > or = 60 years of age. Am J Cardiol 2001; 87: 807-809.

10. Bahler RC, Deser DR, Finkelhor RS, Brener SJ, Youssefi M. factors leading to progression of valvular aortic stenosis. Am J Cardiol 1999; 84: 1044-1048.

11. Ngo MV, Gottdiener JS, Fletcher RD, Fernicola DJ, Gersh BJ. Smoking and obesity are associated with the progression of aortic stenosis. A J Geriatr Cardiol 2001; 10: 86-90.+

12. Sprecher DL, Schaefer EJ, Kent KM, Gregg RE, Zech LA, Hoeg JM, McManus B, Roberts WC, Brewer HB Jr. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients. Am J Cardiol July 1,1984; 54: 20-30.

13. Navaro GM, Pearce GL, Sprecher DL, Griffin BP. Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery versus those undergoing coronary artery bypass grafting. J Heart Valve Dis 2001; 10: 19-24.

14. Chui MC, Newby DE, panarelli M, Bloomfield P, Boon NA. Association between calcific aortic stenosis and hypercholesterolemia: is there a need for a randomized controlled trial of cholesterol-lowering therapy? Clin Cardiol 2001; 24: 52-55.

15. Fujise K, Amerling R, Sherman W. Rapid progression of mitral and aortic stenosis in a patient with secondary hyperparathyroidism.Br Heart J 1993;70:282-4.

16. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, Maurer G, Baumgartner H. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000; 343: 611-617.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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President
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