IAGS (International Andreas Gruentzig Society) Proceedings

State-of-the-Art Nonvascular Interventions: Mitral Valvuloplasty

Dominique Himbert, MD, Eric Brochet, MD, Bernard Iung, MD, Alec Vahanian, MD
Dominique Himbert, MD, Eric Brochet, MD, Bernard Iung, MD, Alec Vahanian, MD


J INVASIVE CARDIOL 2008;20:E114-E119

Mitral stenosis (MS) is still frequent in many countries where rheumatic fever remains endemic.1–2 In Western countries, since the disappearance of rheumatic fever, it has become infrequent and remains a clinical entity due to immigration and restenosis after surgical commissurotomy. Percutaneous mitral commissurotomy (PMC), which was introduced more than 20 years ago,3 acts similarly to surgical commissurotomy by splitting the closed commissures (Figure 1). Sometimes the fracturing of calcification may play a role in specific circumstances.

Patient Selection
The application of PMC depends on three major factors: the patient’s clinical condition, valve anatomy, and the experience of the institution’s medical and surgical teams. Evaluation of a patient’s clinical condition must take into account the degree of functional disability, the presence of contraindications to transseptal catheterization, and the alternative risk of surgery as a function of the underlying cardiac and noncardiac status.
The first step in the evaluation of valve anatomy is to establish the severity of MS. It is then critical to ensure that there are no anatomic contraindications to the technique. The first contraindication is the presence of left atrial thrombosis, which must be excluded by systematic performance of transesophageal echocardiography (TEE). The second is the degree of mitral regurgitation (MR). Finally, the coexistence of other valve disease on the aortic or tricuspid valve should be looked for.
Echocardiographic assessment allows for the classification of patients into anatomic groups with a view to predicting the results. Most investigators use the Wilkins score,4 although others exist such as that developed by Cormier and colleagues.5 More recently, scores that take into account the uneven distribution of the anatomic deformities of the leaflets or the commissural area have been developed.6 Their preliminary results are promising, but disputed, and further studies are needed to determine their exact value.
The incidence of technical failure and complications, particularly those related to transseptal catheterization, is clearly related to the operator’s experience. In addition to improvements in the management of the interventional procedure, experience improves the selection of patients by means of clinical evaluation and echocardiographic assessment.7,8


The transvenous or antegrade approach is the most widelyused technique. Transseptal catheterization, which allows access to the left atrium, is the first step in the procedure and one of the most crucial (Figure 2).
The Inoue technique (Figure 2), the first to be developed,3,9 is now almost exclusively used. The Inoue balloon is made of nylon and rubber micromesh and is self-positioning and pressure-expandable. The balloon has three distinct parts, each with a specific elasticity, which can be inflated sequentially. The Inoue balloon comes in four sizes, ranging from 24–30 mm, and each is pressure-dependent so that its diameter can be varied by up to 4 mm as required by circumstances. Balloon size is usually chosen according to patient characteristics of height and body surface area.9 The use of a stepwise dilatation technique under echocardiographic guidance is recommended (Figure 2). The first inflation is performed to the minimum diameter of the balloon chosen. If MR has not increased and valve area is insufficient, inflation is repeated with the balloon diameter increased by 1–2 mm.
The use of TEE10 (Figure 4) or intracardiac echocardiography11 is limited to the rare cases where difficulty is encountered during transseptal catheterization or in particularly high-risk circumstances such as severe cardiothoracic deformity or pregnancy. TEE or intracardiac echocardiography may also help in assessing the mitral valve (Figure 4).

Monitoring of the Procedure and Assessment of Immediate Results
Although echocardiography may be difficult to perform in the catheterization laboratory for logistical reasons, it provides essential information on the efficacy of the procedure and also enables early detection of complications. The following criteria have been proposed for the desired endpoint of the procedure: (a) mitral valve area > 1 cm2 per square meter of body surface area; (b) complete opening of at least one commissure (Figure 5); or (c) appearance or increment of regurgitation > 1/4 classification.9 Tailoring the strategy to the individual circumstances is important; clinical factors as well as anatomic factors and the cumulative data of periprocedural monitoring should be taken into account. Immediately after the procedure, the most accurate evaluation of valve area is provided by planimetry using echocardiography. The final assessment of the degree of regurgitation may be made using angiography or Doppler color-flow imaging.

Immediate Results
The technique of mitral valvuloplasty has now been evaluated in several thousand patients with different clinical conditions and valve anatomy.5,8,12–15
Efficacy. PMC usually provides an increase of over 100% in valve area. Overall good immediate results, defined by a final valve area > 1.5 cm2 without MR > 2/4, are observed in over 80% of cases.

Risks. Procedural mortality ranges from 0–3%.5,8,12–17 The main causes of death are left ventricular perforation or the poor general condition of the patient. The incidence of hemopericardium varies from 0.5–12%. Pericardial hemorrhage may be related to transseptal catheterization or to apex perforation by the guidewires or the balloon itself when using the double-balloon technique. Embolism is encountered in 0.5–5% of cases. The frequency of severe MR ranges from 2–19%. Surgical findings5,18–20 have shown that it is mostly related to noncommissural leaflet tearing (Figure 6), which could be associated with chordal rupture. The development of severe MR depends more on the distribution of the morphologic changes of the valve than on their severity.21 Severe MR may be well tolerated, but more often it is not, and surgery on a scheduled basis is necessary. In most cases, valve replacement is required because of the severity of the underlying valve disease.
The frequency of atrial septal defect reported after valvuloplasty varies from 10–90% depending on the technique used for its detection.22 These shunts are usually small and without clinical consequences.
Although urgent surgery (within 24 hours) is seldom needed for complications, it may be required for massive hemopericardium resulting from left ventricular perforation intractable to treatment by pericardiocentesis or, less frequently, for severe MR with poor hemodynamic tolerance.18
Predictors of immediate results. The prediction of results is multifactorial.5,17 Several studies have shown that, in addition to morphologic factors, preoperative variables such as age, history of surgical commissurotomy, functional class, small mitral valve area, presence of MR before valvuloplasty, atrial fibrillation, high pulmonary artery pressure, and presence of severe tricuspid regurgitation, as well as procedural factors such as balloon type and size, are all independent predictors of the immediate results. Predictive models have been developed, which appear to have a high sensitivity of prediction. Nevertheless, specificity is low. This latter finding is particularly true with regard to the lack of accurate prediction of severe MR.

Long-Term Results

Follow-up data of up to 17 years can now be analyzed. In clinical terms, the overall long-term results of valvuloplasty are good.17,23–28 Late outcomes after valvuloplasty differ according to the quality of the immediate results (Figure 3). When the immediate results are unsatisfactory, patients experience only transient or no functional improvement, and delayed surgery is usually performed when the extracardiac conditions allow.
Conversely, if valvuloplasty is initially successful, then survival rates are excellent, functional improvement occurs in the majority of cases, and the need for secondary surgery is infrequent. When clinical deterioration occurs in these patients, it is late and mainly related to mitral restenosis. Determining the incidence of restenosis by echocardiography is compromised by the absence of a uniform definition. It has generally been defined as a loss of > 50% of the initial gain with a valve area becoming < 1.5 cm2. After a successful procedure, the incidence of echocardiographicallyidentified restenosis is usually low, ranging from 2–40% at time intervals of 3–6 years.25,27,28 The possibility of repeating valvuloplasty in cases of recurrent MS is one of the potential advantages of this nonsurgical procedure. Repeat valvuloplasty can be proposed if recurrent stenosis leads to symptoms, occurs several years after an initially successful procedure, and the predominant mechanism of restenosis is commissural refusion.29,30 At the moment, results of only a small number of series on revalvuloplasty are available; these show good immediate- and mid-term outcomes in patients with favorable characteristics. Although the results are less favorable in patients presenting with worse characteristics, repeat valvuloplasty has a palliative role in patients who are not surgical candidates.29–31 These preliminary results are encouraging; however, defining the exact role of revalvuloplasty must await larger series with longer followup periods.
The degree of MR generally remains stable or slightly decreases during follow up. Atrial septal defects are likely to close over time in the majority of cases because of a reduction in the interatrial pressure gradient. Finally, clinical series suggest that intervention reduces markers of the risk of embolism.32,33 No direct evidence exists that valvuloplasty reduces the incidence of atrial fibrillation, even if it has a favorable influence on predictors of atrial fibrillation.34
Predictors of long-term results. The prediction of longterm results is multifactorial17,26,27 and is based on clinical variables such as age, valve anatomy as assessed by different echocardiography scores, factors related to the evolutional stage of the disease, i.e., a higher New York Heart Association class before valvuloplasty, history of previous commissurotomy, severe tricuspid regurgitation, cardiomegaly, atrial fibrillation, high pulmonary vascular resistances, and the results of the procedure. The quality of the late results is generally considered independent of the technique used.28

Indications for Percutaneous Mitral Commissurotomy
An image of the current practice can be derived from the Euro Heart Survey on Valvular Heart Disease,35 which showed that today, PMC has almost replaced surgical commissurotomy. Intervention should be performed only in patients with significant MS (valve area < 1.5 cm2) because below this threshold, the risks probably outweigh the benefits.36,37 There may be rare cases in which the procedure is offered to patients with slightly larger valve areas if they are of large stature, are highly symptomatic, and have favorable presenting characteristics.
Surgery is the only alternative when PMC is contraindicated. The most important contraindication is left atrial thrombosis; the recommendation is self-evident if the thrombus is free-floating or is situated in the left atrial cavity. This also applies when it is located on the interatrial septum. Small series have suggested that PMC can be performed when the thrombus is located in the LAA,38 however, this is considered a contraindication for the technique in the current guidelines.36,37 If the patient is clinically stable, anticoagulant therapy can be given for 2–6 months;39 and if a new transesophageal examination shows that the thrombus has disappeared, PMC can be attempted.36,37
Other contraindications for PMC are: 1) MR that is more than mild; PMC can, however, be considered in selected patients with moderate MR if the risk for surgery is high or even prohibitive; 2) severe calcification; 3) absence of commissural fusion; 4) combined MS and severe aortic disease, where surgery is obviously indicated in the absence of contraindications. On the other hand, the coexistence of moderate aortic valve disease and severe MS is another situation in which PMC is preferable in order to postpone the inevitable subsequent surgical treatment of both valves; 5) combined severe tricuspid stenosis and tricuspid regurgitation with clinical signs of heart failure is an indication for surgery on both valves. The existence of tricuspid regurgitation is not a contraindication to the procedure, even though it represents a negative prognostic factor;40 6) coronary disease requiring bypass surgery.36,37
Regarding indications, no problems are presented in cases in which surgery is contraindicated or for “ideal candidates”. PMC is the only solution when surgery is contraindicated. It is also preferable to surgery, at least as a first attempt, in patients with an increased risk for surgery.
Surgery may be a higher-risk option because of a cardiac condition, as is the case in patients with restenosis after surgical commissurotomy,41,42 previous aortic valve replacement, or severe pulmonary hypertension.43 PMC can be performed as a life-saving procedure in critically ill patients, as the sole treatment in cases of absolute contraindication to surgery, or as a bridge to surgery in the other cases.44 It can also be performed in elderly patients as a palliative procedure,45–47 or in pregnant patients (after the 20th week) who remain symptomatic despite medical treatment.48–50
In patients with favorable characteristics such as young patients with good PMC results are generally excellent.51 In addition, if restenosis occurs, patients treated with valvuloplasty could undergo repeat balloon procedures. Valvuloplasty would thus appear to be the procedure of choice for these patients in whom we may expect to further delay surgery, enabling, for example, pregnancy to occur. Controversy remains as regards the performance of the procedure in asymptomatic patients and in those with unfavorable anatomy.
Truly asymptomatic patients are not usually candidates for the procedure because of the small but definite risk inherent in the technique. For patients in the latter group, balloon commissurotomy may be considered in selected cases: patients at high risk of thromboembolism (previous history of embolism or heavy spontaneous contrast in the left atrium), recurrent atrial arrhythmias, and pulmonary hypertension. PMC can also be performed when systolic pulmonary pressures is > 50 mmHg at rest. The European guidelines do not fix a threshold for systolic pulmonary pressure on exercise, but recommend performing PMC if symptoms appear during exercise.37 Finally, PMC can be considered for asymptomatic patients requiring major extracardiac surgery or to allow for pregnancy.
In asymptomatic patients, valvuloplasty should only be performed by experienced interventionists and when valve anatomy is favorable, in which case a safe and successful procedure can be expected.
Much remains to be done in refining the indications for valvuloplasty in patients with unfavorable anatomy.52–54 For this group, some favor immediate surgery because of the less satisfying results of valvuloplasty, whereas others prefer valvuloplasty as an initial treatment for selected candidates and reserve surgery for cases in which this treatment fails.
An individualistic approach is favored that allows for the multifactorial nature of prediction (Figure 6). Current opinion is that surgery can be considered the treatment of choice in patients with bicommissural or heavy calcification. On the other hand, balloon valvuloplasty can be attempted as a first approach in patients with extensive lesions of the subvalvular apparatus or moderate or unicommissural calcification, the more so because their clinical status argues in favor of this, such as in young patients with the expectation of further delaying valve replacement with its inherent mortality and morbidity. Surgery should be considered reasonably early after unsatisfactory results or secondary deterioration.36,37

The good results that have been obtained with PMC enable us to say that, currently, this technique has an important place in the treatment of MS and has virtually replaced surgical commissurotomy. When treating MS, PMC and valve replacement must be considered not as rivals, but as complementary techniques, each applicable at the appropriate stage of the disease.





1. Carroll JD, Feldman T. Percutaneous mitral balloon valvotomy and the new demographics of mitral stenosis. JAMA 1993;270:1731–1736.
2. Marijon E, Ou P, Celermajer DS, et al. Prevalence of rheumatic heart disease detected by echocardiographic screening. N Engl J Med 2007;357:470–476.
3. Inoue K, Owaki T, Nakamura T, et al. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg 1984;87:394–402.
4. Wilkins GT, Weyman AE, Abascal VM, et al. Percutaneous balloon dilatation of the mitral valve: An analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J 1988;60:299–308.
5. Iung B, Cormier B, Ducimetiere P, et al. Immediate results of percutaneous mitral commissurotomy. Circulation 1996;94:2124–2130.
6. Padial LR, Abascal VM, Moreno PR, et al. Echocardiography can predict the development of severe mitral regurgitation after percutaneous mitral valvulotomy by the Inoue technique. Am J Cardiol 1999;83:1210–1213.
7. Tuzcu EM, Block PC, Palacios IF, et al. Comparison of early versus late experience with percutaneous mitral balloon valvuloplasty. J Am Coll Cardiol 1991;17:1121–1124.
8. Iung B, Nicoud-Houel A, Fondard O, et al. Temporal trends in percutaneous mitral commissurotomy over a 15-year period. Eur Heart J 2004;25:702–708.
9. Vahanian A, Cormier B, Iung B. Percutaneous transvenous mitral commissurotomy using the Inoue balloon: International experience. Cathet Cardiovasc Diagn 1994;2:8–15.
10. Park SH, Kim MA, Hyon MS. The advantages of on-line transesophageal echocardiography guide during percutaneous balloon mitral valvuloplasty. J Am Soc Echocardiogr 2000;13:26–34.
11. Liang KW, Fu YC, Lee WL, et al. Intra-cardiac echocardiography guided trans-septal puncture in patients with dilated left atrium undergoing percutaneous transvenous mitral commissurotomy. Int J Cardiol 2007;117:418–421.
12. Ben Farhat M, Betbout F, Gamra H, et al. Results of percutaneous doubleballoon mitral commissurotomy in one medical center in Tunisia. Am J Cardiol 1995;76:1266–1270.
13. Arora R, Singh Kalra G, Ramachandra Murty GS, et al. Percutaneous transatrial mitral commissurotomy: Immediate and intermediate results. J Am Coll Cardiol 1994;23:1327–1332.
14. Chen CR, Cheng TO. Percutaneous balloon mitral valvuloplasty by the Inoue technique: A multicenter study of 4832 patients in China. Am Heart J 1995;129:1197–1202.
15. Neumayer U, Schmidt HK, Fassbender D, et al. Early (three-month) results of percutaneous mitral valvotomy with the Inoue balloon in 1,123 consecutive patients comparing various age groups. Am J Cardiol 2002;90:190–193.
16. The National Heart, Lung, and Blood Institute Balloon Valvuloplasty Registry. Complications and mortality of percutaneous balloon mitral commissurotomy. Circulation 1992;85:2014–2024.
17. Palacios IF, Sanchez PL, Harrell LC, et al. Which patients benefit from percutaneous mitral balloon valvuloplasty? Pre-valvuloplasty and post-valvuloplasty variables that predict long-term outcome. Circulation 2002;105:1465–1471.
18. Varma PK, Theodore S, Neema PK, et al. Emergency surgery after percutaneous transmitral commissurotomy: Operative versus echocardiographic findings, mechanisms of complications, and outcomes. J Thorac Cardiovasc Surg 2005;130:772–776.
19. Choudhary SK, Talwar S, Venugopal P. Severe mitral regurgitation after percutaneous transmitral commissurotomy: Underestimated subvalvular disease. J Thorac Cardiovasc Surg 2006;131:927.
20. Hernandez R, Macaya C, Benuelos C, et al. Predictors, mechanisms and outcome of severe mitral regurgitation complicating percutaneous mitral valvotomy with the Inoue balloon. Am J Cardiol 1993;70:1169–1174.
21. Iung B, Vahanian A. Echocardiography in the patient undergoing catheter balloon mitral valvuloplasty: Patient selection, hemodynamic results, complications and long-term outcome. In: Otto CM (ed). The Practice of Clinical Echocardiography. 3rd Edition. Saunders Elsevier: Philadelphia, 2007, pp.481–501.
22. Cequier A, Bonan R, Dyrda I, et al. Atrial shunting after percutaneous mitral valvuloplasty. Circulation 1990;81:1190–1197.
23. Orrange S, Kawanishi D, Lopez B, et al. Actuarial outcome after catheter balloon commissurotomy in patients with mitral stenosis. Circulation 1997;95:382–389.
24. Stefanadis C, Stratos C, Lambrou S, et al. Retrograde nontransseptal balloon mitral valvuloplasty: Immediate results and intermediate long-term outcome in 441 cases — A multi-centre experience. J Am Coll Cardiol 1998;32:1009–1016.
25. Wang A, Krasuski RA, Warner JJ, et al. Serial echocardiographic evaluation of restenosis after successful percutaneous mitral commissurotomy. J Am Coll Cardiol 2002;39:328–334.
26. Iung B, Garbarz E, Michaud P, et al. Late results of percutaneous mitral commissurotomy in a series of 1024 patients: Analysis of late clinical deterioration: frequency, anatomic findings, and predictive factors. Circulation 1999;99:3272–3278.
27. Fawzy ME, Shoukri M, Al Buraiki J, et al. Seventeen years’ clinical and echocardiographic follow up of mitral balloon valvuloplasty in 520 patients, and predictors of long-term outcome. J Heart Valve Dis 2007;16:454–460.
28. Kang DH, Park SW, Song JK, et al. Long-term clinical and echocardiographic outcome of percutaneous mitral valvuloplasty: Randomized comparison of Inoue and double-balloon techniques. J Am Coll Cardiol 2000;35:169–175.
29. Iung B, Garbarz E, Michaud P, et al. Immediate and mid-term results of repeat percutaneous mitral commissurotomy for restenosis following earlier percutaneous mitral commissurotomy. Eur Heart J 2000;21:1683–1690.
30. Pathan AZ, Mahdi NA, Leon MN, et al. Is redo percutaneous mitral balloon valvuloplasty (PMV) indicated in patients with post-PMV mitral restenosis? J Am Coll Cardiol 1999;34:49–54.
31. Kim JB, Ha JW, Kim JS, et al. Comparison of long-term outcome after mitral valve replacement or repeated balloon mitral valvotomy in patients with restenosis after previous balloon valvotomy. Am J Cardiol 2007;99:1571–1574.
32. Chiang CW, Lo SK, Ko YS, et al. Predictors of systemic embolism in patients with mitral stenosis. A prospective study. Ann Intern Med 1998;128:885–889.
33. Cormier B, Vahanian A, Iung B, et al. Influence of percutaneous mitral commissurotomy on left atrial spontaneous contrast of mitral stenosis. Am J Cardiol 1993;71:842–847.
34. Langerveld J, van Hemel NM, Kelder JC, et al. Long-term follow-up of cardiac rhythm after percutaneous mitral balloon valvotomy. Does atrial fibrillation persist? Europace 2003;5:47–53.
35. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart survey on valvular heart disease. Eur Heart J 2003;13:1231–1243.
36. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease. J Am Coll Cardiol 2006;48:e1–e148.
37. Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart disease. Eur Heart J 2007;28:230–268.
38. Chen WJ, Chen MF, Liau CS, et al. Safety of percutaneous transvenous balloon mitral commissurotomy in patients with mitral stenosis and thrombus in the left atrial appendage. Am J Cardiol 1992;70:117–119.
39. Silaruks S, Thinkhamrop B, Kiatchoosakun S, et al. Resolution of left atrial thrombus after 6 months of anticoagulation in candidates for percutaneous transvenous mitral commissurotomy. Ann Intern Med 2004;140:101–105.
40. Song H, Kang DH, Kim JH, et al. Percutaneous mitral valvuloplasty versus surgical treatment in mitral stenosis with severe tricuspid regurgitation. Circulation 2007;116(11 Suppl):I246–1250.
41. Iung B, Garbarz E, Michaud P. Percutaneous mitral commissurotomy for restenosis after surgical commissurotomy: Late efficacy and implications for patient selection. J Am Coll Cardiol 2000;35:1295–1302.
42. Jang IK, Block PC, Newell JB, et al. Percutaneous mitral balloon valvotomy for recurrent mitral stenosis after surgical commissurotomy. Am J Cardiol 1995;75:601–605.
43. Maoqin S, Guoxiang H, Zhiyuan S, et al. The clinical and hemodynamic results of mitral balloon valvuloplasty for patients with mitral stenosis complicated by severe pulmonary hypertension. Eur J Intern Med 2005;16:413–418.
44. Vahanian A, Iung B, Nallet O. Percutaneous valvuloplasty in cardiogenic shock. In: Hasdai D, Berger P, Battler A, Holmes D (eds.). Cardiogenic Shock: Diagnosis and Treatment. Humana Press Inc.: New Jersey, 2003, pp. 181–193.
45. Hildick-Smith DJR, Taylor GJ, Shapiro LN. Inoue balloon mitral valvuloplasty: Long-term clinical and echocardiographic follow-up of a predominantly unfavorable population. Eur Heart J 2000;21:1691–1698.
46. Tuzcu EM, Block PC, Griffin BP, et al. Immediate and long-term outcome of percutaneous mitral valvotomy in patients 65 years and older. Circulation 1992;85:963–971.
47. Iung B, Cormier B, Farah B, et al. Percutaneous mitral commissurotomy in the elderly. Eur Heart J 1995;16:1092–1099. 48. Iung B, Cormier B, Elias J, et al. Usefulness of percutaneous balloon commissurotomy for mitral stenosis during pregnancy. Am J Cardiol 1994;73:398–400.
49. de Souza JA, Martinez EE Jr, Ambrose JA, et al. Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy. J Am Coll Cardiol 2001;37:900–903.
50. Sivadasanpillai H, Srinivasan A, Sivasubramoniam S, et al. Long-term outcome of patients undergoing balloon mitral valvotomy in pregnancy. Am J Cardiol 2005;95:1504–1506.
51. Gamra H, Betbout F, Ben Hamda K, et al. Balloon mitral commissurotomy in juvenile rheumatic mitral stenosis: A ten-year clinical and echocardiographic actuarial results. Eur Heart J 2003;24:1349–1356.
52. Tuzcu ME, Block PC, Griffin B, et al. Percutaneous mitral balloon valvotomy in patients with calcific mitral stenosis: Immediate and long-term outcome. J Am Coll Cardiol 1994;23:1604–1609.
53. Post JR, Feldman T, Isner J, et al. Inoue balloon mitral valvotomy in patients with severe valvular and subvalvular deformity. J Am Coll Cardiol 1995;25:1129–1136.
54. Iung B, Garbarz E, Doutrelant L, et al. Late results of percutaneous mitral commissurotomy for calcific mitral stenosis. Am J Cardiol 2000;85:1308–1314.