Severe mitral regurgitation due to mitral valve prolapse: risk factors for development, progression, and need for mitral valve surgery

Severe mitral regurgitation due to mitral valve prolapse: risk factors for development, progression, and need for mitral valve surgery

Severe Mitral Regurgitation Due to Mitral Valve Prolapse: Risk Factors for Development, Progression, and Need for Mitral Valve Surgery Rampaul G. Sing...

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Severe Mitral Regurgitation Due to Mitral Valve Prolapse: Risk Factors for Development, Progression, and Need for Mitral Valve Surgery Rampaul G. Singh, MD, Roger Cappucci, MD, Randi Kramer-Fox, MS,* Mary J. Roman, MD, Paul Kligfield, MD, Jeffrey S. Borer, MD, Clare Hochreiter, O. Wayne Isom, MD, and Richard B. Devereux, MD

MD,

Patients with mitral valve prolapse (MVP) may develop severe mitral regurgitation (MR) and require valve surgery. Preliminary data suggest that high body weight and blood pressure might add to the irreversible factors of older age and male gender in increasing risk of these complications. Fifty-four patients with severe MR due to MVP were compared with 117 control subjects with uncomplicated MVP to elucidate factors independently associated with severe MR: the need for valve surgery and the cumulative risk of requiring mitral valve surgery. Patients with severe MR were older (p <0.00005), more overweight (p ⴝ 0.002), had higher systolic (p ⴝ 0.0003) and diastolic (p ⴝ 0.007) blood pressures, and were more likely to have hypertension (p ⴝ 0.0001) and to be men (p <0.001). In both groups, men had higher blood pressure and relative body weight than women. In multivariate analysis, older age was most strongly associated with MR; higher body mass index, hypertension, and gender were independent predictors of severe

MR in analyses that excluded age. Among the 54 patients with severe MR, the 32 (59%) who underwent mitral valve surgery during 11 years of follow-up were older, more overweight, and more likely to be hypertensive than those not requiring surgery. Among patients undergoing mitral valve surgery in 3 centers, mitral prolapse was the etiology in 25%, 67% of whom were men. Using these data and national statistics, we estimate that the gender-specific cumulative risk for requiring valvular surgery for severe MR in subjects with MVP is 0.8% in women and 2.6% in men before age 65, and 1.4% and 5.5% by age 75. Thus, subjects with MVP who are older, more overweight, and hypertensive are at greater risk for severe MR and valve surgery. Higher blood pressure and relative weight in men with MVP appear to contribute to the gender difference in risk for severe MR. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:193–198)

itral valve prolapse (MVP) is generally a benign disorder that occurs in about 3% of adults. M However, compared with the general population, pa-

Two potentially reversible risk factors for severe MR due to MVP have been suggested by preliminary observations: increased arterial blood pressure and obesity.8,9 To assess whether these factors are associated with the development of severe MR in patients with MVP, independent of the established risk factors of older age and male gender,1– 4 the present casecontrol study was undertaken to compare patients with severe MR due to MVP with relatively unselected adults with MVP. Additional goals of the study were to examine whether these same risk factors predicted progression to need for valvular surgery among MVP patients with severe MR, and to estimate the cumulative likelihood of needing mitral valve surgery among women and men with MVP.

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tients with MVP are at increased risk for infective endocarditis, potentially life-threatening arrhythmias, development of severe mitral regurgitation (MR), and other complications.1– 4 Identification of subgroups of patients with MVP at high risk for complications is important because it may lead to the recognition of potentially preventable or reversible risk factors. Successes in this regard have been the demonstration that the risk of infective endocarditis in patients with MVP is concentrated in those who have MR murmurs2,5,6 and that endocarditis prophylaxis is reasonably costeffective when given to this subgroup of patients.7 From the Departments of Medicine and Surgery, The New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York. This study was supported in part by Grants HL22006 and HL-25604 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received May 21, 1999; revised manuscript received and accepted August 23, 1999. Address for reprints: Richard B. Devereux, MD, Division of Cardiology, Box 222, The New York Presbyterian Hospital-Weill Medical College of Cornell University, 525 East 68th Street, New York, New York 10021. E-mail: [email protected]. *Deceased, June 15, 1999. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 15, 2000

METHODS

Subjects of the primary case-control study: To obtain a control group of subjects with MVP whose characteristics would approximate those of patients with MVP in the general population, we identified consecutive adult relatives or spouses who were found to have MVP in family studies that have been previously described in part.10,11 After obtaining informed consent by a protocol approved by the Committee on Human Rights in Research of Cornell University 0002-9149/00/$–see front matter PII S0002-9149(99)00645-1

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Medical College in 1979 and at regular intervals thereafter, a history was taken and physical examination performed in all subjects that included auscultation in multiple positions, along with standard M-mode and 2-dimensional echocardiography. Mitral prolapse was diagnosed as previously described if M-mode echocardiography demonstrated ⬎2 mm of posterior movement of continuous leaflet interfaces behind the mitral valve C-D line in late systole11 or if 2-dimensional long-axis views demonstrated leaflet billowing beyond the plane of the mitral annulus into the left atrium during systole.11,12 Of a total of 120 family members who met these criteria, 3 (2.5%) had evidence of moderate or severe MR. The remaining 117 subjects with uncomplicated MVP constituted the control group of the present study. Those with the Marfan syndrome or other causes of secondary MVP were excluded from control and case groups. The case group consisted of 54 consecutive patients with isolated, pure, severe MR due to primary MVP enrolled in an ongoing, prospective study of noninvasive predictors of the natural history of MR that has been previously described in part.13,14 Informed consent was obtained under a protocol approved in 1980 and at regular intervals thereafter. All patients had severe (ⱖ3⫹/4⫹) MR by pulsed and/or color flow Doppler echocardiography and/or left ventriculography. The etiology of MR was determined by review of the patient’s medical history, echocardiograms, catheterization, and operative reports, and pathologic anatomic reports in patients who had undergone valvular surgery or necropsy. Patients with angiographically significant coronary artery disease, determined by coronary arteriography, were excluded from further analysis. Patients with primary MVP constituted 54% of the total of 99 patients enrolled in the study of isolated severe MR. Clinical and demographic variables: In patients with severe MR or relatively unselected subjects with primary MVP, age, gender, height, weight, body mass index (weight in kg/[height in m2]), and systolic and diastolic blood pressures determined by use of appropriately sized arm cuffs and mercury manometers were recorded at the time of each evaluation. Data collected on the earliest evaluation when subjects were free of medication that might be cardioactive or affect blood pressure were used in primary analyses. The most commonly held medications were ␤ blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors. Whether or not each patient had a clinical history of hypertension was recorded, and a summary measure was compiled of patients who had either a clinical history of hypertension or unmedicated arterial pressure ⱖ140/90 mm Hg. To determine the proportion of patients undergoing mitral valve replacement or repair at The New York Hospital in whom severe MR due to MVP was the underlying etiology, the cardiac surgery log was reviewed for a 2.5-year period. For the group of patients undergoing isolated mitral valve surgery, age, gender, and etiology diagnosed by surgical inspection and pathologic examination were ascertained. 194 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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Echocardiographic measurements: Left ventricular internal dimension at end-diastole and left atrial diameter were measured by 2-dimensionally guided Mmode echocardiography as previously described.15 Statistical analysis: Group data are presented as mean ⫾ SD. Data were analyzed using Crunch 4 software (Crunch Inc., Oakland, California). Unpaired t tests were used to compare normally distributed continuous variables and 2-tailed Fisher’s exact test was used to compare categorical variables between groups; data were also analyzed separately by gender. A 2-tailed p value ⬍0.05 was considered statistically significant. Multiple logistic regression analysis considered factors significantly associated with severe MR in univariate analyses as independent variables, and the presence or absence of severe MR as the dependent variable. In the primary stepwise analysis, only independent variables that had a p value ⬍0.05 to enter were evaluated, whereas in secondary exploratory analyses, various combinations of predictor variables were “forced” to enter and nonsignificant p values were displayed for information purposes. Estimation of cumulative risk of mitral valve surgery for severe regurgitation in subjects with mitral valve prolapse: To calculate the cumulative risk of requir-

ing mitral valve surgery by a specified age, one needs (1) estimates of the number of operations performed annually for severe MR owing to MVP in women and men within a given age range in a defined population, and (2) estimates of the total number of women and men with MVP in the same population. For the purposes of the present study, the population of interest was adults in the United States aged 15 to 74, the age range within which nearly all operations on prolapsed mitral valves are performed. Data on the total number of mitral valve repairs or replacements for 1985 through 1987 were obtained from the National Center for Health Statistics Summaries of United States Hospital Discharges.16 The proportion of all mitral valve surgery performed for severe MR due to MVP was estimated from published data of Olson et al17 and Hanson et al,18 and from data on all mitral valve repairs or replacements at The New York HospitalCornell Medical Center from January 1985 through June 1987. The number of women and men with MVP undergoing surgery were estimated by combining the total number of operations annually on prolapsed mitral valves, with data on gender distribution of such patients in these 3 series and among MVP patients in other surgical series reported in the 1980s that did not provide a denominator of all mitral operations.19 –22 The final needed information, the total number of women and men with MVP aged 15 to 74 years in the United States, was calculated by combining the total number of such adults in 1985 census data,23 with the estimate that 5% of adult women and 3% of adult men have MVP based on results from published reports and our own experience in echocardiographic surveys of unselected adults.1 JANUARY 15, 2000

TABLE I Comparison of MVP Patients With and Without Severe MR Women Severe MR Due to MVP (n ⫽ 21) Age (yrs) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Left atrial diameter (cm) Left ventricular diastolic diameter (cm)

56 23.5 129 80 4.9 6.1

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

13 3.2 19 9 0.9 0.6

p Value ⬍0.0005 ⬍0.04 ⬍0.01 ⬍0.02 ⬍0.0005 ⬍0.0005

RESULTS

Characteristics of control subjects: The 117 subjects

with uncomplicated MVP ranged in age from 16 to 73 years (mean 35 ⫾ 15). Sixty-six percent were female. Mean body mass index was 21.8 ⫾ 3.4 kg/m2. Mean left atrial diameter and left ventricular internal dimension in diastole were 3.1 ⫾ 0.4 and 4.9 ⫾ 0.5 cm, respectively. The mean unmedicated blood pressure was 121 ⫾ 16/76 ⫾ 9 mm Hg. Univariate comparisons: Compared with control subjects, patients with severe MR were older (56 ⫾ 12 years), more often men (61%), and had higher body mass indexes (23.9 ⫾ 3.0 kg/m2, all p ⬍0.001). As expected, patients with severe MR had larger left ventricular and left atrial dimensions (6.4 ⫾ 0.7 and 5.1 ⫾ 0.8 cm, respectively, both p ⬍0.0001). Unmedicated blood pressure was also higher than in subjects with uncomplicated MVP (133 ⫾ 17/81 ⫾ 10 mm, p ⫽ 0.0003 and p ⫽ 0.007, respectively). When analyses were repeated separately in men and women, differences in age and body mass index remained statistically significant (Table I). Systolic and diastolic blood pressures were significantly higher among women with severe MR than in those with uncomplicated MVP alone, whereas directionally similar trends among men did not attain statistical significance. Body mass index and arterial pressures were higher in men than in women among cases and controls (Table I). When the subset groups were pooled, men with MVP had higher body mass index (23.1 ⫾ 2.9 vs 22.1 ⫾ 3.7 kg/m2, p ⬍0.05), systolic pressure (130 ⫾ 16 vs 121 ⫾ 16 mm Hg, p ⬍0.001), and diastolic pressure (80 ⫾ 10 vs 76 ⫾ 9 mm Hg, p ⬍0.01) than women. A clinical history of hypertension was present in 3% of subjects with uncomplicated MVP and in 15% of patients with MVP and severe MR (p ⫽ 0.002). The average duration of hypertension was approximately 10 years among those with severe MR. As a result of the differences in age and gender distribution between cases and controls, the estimated relative risk of severe MR was higher in men than in women (odds ratio 3.0, 95% confidence interval 1.55 to 5.90) and in subjects aged ⬎45 years (odds ratio 14.5, 95% confidence interval 6.3 to 33.2). The latter partition was previously2 found to be associated with the risk of infective endocarditis. Results of multivariate analyses: Multiple logistic regression analysis considering age, gender, body

Men MVP Without MR (n ⫽ 77) 36 21.6 118 75 3.0 4.8

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

14 3.8 16 9 0.2 0.4

Severe MR Due to MVP (n ⫽ 33) 57 24.0 135 82 5.3 6.7

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

11 3.2 20 11 0.8 0.7

MVP Without MR (n ⫽ 40)

p Value ⬍0.0005 ⬍0.018 NS (0.058) NS ⬍0.0005 ⬍0.0017

35 22.4 127 79 3.6 5.2

⫾ ⫾ ⫾ ⫾ ⫾ ⫾

16 2.4 13 8 0.4 0.6

TABLE II Multiple Logistic Regression Analysis With MR as Dependent Variable p Value

Primary analysis* Gender, age, HTN Secondary analysis Age, gender, BMI Age, gender, BMI, HTN Age, gender, HTN Gender, HTN BMI, HTN Gender BMI, HTN BMI, gender

Age

Gender

0.0000

0.017

0.0000 0.0000 0.0000

0.028 0.029 0.017 0.004 0.009 0.007

BMI

HTN 0.501

0.251 0.339

0.023 0.031 0.002

0.699 0.501 0.001 0.010 0.014

*Including all variables, p ⬍0.05 in univariate analyses. BMI ⫽ body mass index (kg/m2); HTN ⫽ clinical history of hypertension or blood pressure ⱖ140/90 mm Hg.

mass index, and unmedicated systolic and diastolic arterial pressure, and a diagnosis of hypertension based on either current arterial pressure ⱖ140/90 mm Hg or clinical history of hypertension in patients who were either currently receiving hypertensive medication or had stopped them only briefly,1–3 revealed that age and male gender were the only statistically independent predictors of the presence of hemodynamically important MR (Table II). When body mass index and hypertension were forced to enter the multiple logistic regression model, age remained the strongest independent predictor of severe MR (Table II). When age was not considered, hypertension, higher body mass index, and male gender were all independently associated with severe MR (Table II). Risk factors for surgery among mitral prolapse patients with isolated pure severe mitral regurgitation (Table III): During the period of up to 11 years after study

enrollment, 32 of 54 patients (59%) with severe MR underwent mitral valve repair or replacement. At initial evaluation, patients who subsequently were referred for surgery by their personal physician (in almost all cases because of development of New York Heart Association class ⱖII exertional dyspnea) were older (odds ratio 5.6, 95% confidence interval 1.0 to 31.1 for age ⱖ45), more obese (odds ratio 3, 95% confidence interval 0.9 to 9.5, for body mass index ⬎22.5), more likely to have hypertension (odds ratio

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the National Center for Health Statistics16 and analyzed in conjunction with the above information (Table IV). On average, in 1985 through 1987, there were approximately 7,333 mitral valve replacements or reValvular No Valvular pairs annually among patients 15 to 64 years old and Surgery Surgery about 6,333 such procedures/year in those ⱖ65 years Variable (n ⫽ 32) (n ⫽ 22) p Value old.16 Applying the estimate arrived at above, i.e., Duration of follow-up 74 68 NS 25% of all mitral valve operations were due to MVP, (mos) yields a total of 1,833 and 1,583 operations on proAge (yrs) 59.7 ⫾ 10.0 51.6 ⫾ 12.8 0.02 Male gender (%) 56 68 NS lapsed mitral valves, respectively, ⬍65 and ⬎65 years Body mass index 25.6 ⫾ 3.4 22.7 ⫾ 2.3 0.02 of age. Combining these data with the estimate that (kg/m2) about 67% of the operations for severe MR due to Hypertension* 17/32 (53%) 5/22 (23%) 0.02 MVP were in men, Census Bureau data on the number Left ventricular 6.5 ⫾ 0.6 6.5 ⫾ 1.0 NS of women and men aged 15 to 64 and 65 to 74 years diameter (cm) Left atrial size (cm) 5.2 ⫾ 0.8 4.9 ⫾ 0.8 NS (0.10) in the United States in 1985, and the estimated prevalence of MVP of 5% and 3% among women and men *Clinical history of hypertension or blood pressure ⱖ140/90 mm Hg. in the general population, estimates were made of the annual risk for mitral surgery in women and men with MVP. The estimated annual risk of requiring miTABLE IV Estimated Cumulative Risk of Mitral Valve Surgery Among Patients With tral valve surgery for women and MVP men with MVP was about 1 in 6,600 Data for Women Data for Men and 1 in 1,900 for the age range 15 to 64 and about 1 in 1,600 and 1 in 330 Age 15–64 Age 65–74 Age 15–64 Age 65–74 for affected persons aged 65 to 74 Total population, 1985 80,283,000 17,003,000 78,529,000 11,537,000 years. Based on calculations in Table Estimated percentage of 5% 5% 3% 3% IV, we estimate the cumulative risk population with MVP Estimated number with 4,014,150 850,000 2,355,879 346,110 of surgery in women with MVP is MVP, 1985 0.8% through age 64 and 1.4% by Estimated mitral valve 611 528 1,222 1,056 age 75. The cumulative risk of suroperations due to gery is approximately 3 times as high MVP 1/6,570 1/610 1/1,928 1/32 Annual risk of surgery in men (2.6% through age 64, 5.5% for MR due to MVP by age 75). TABLE III Characteristics of Patients With MVP and Severe MR Who Did or Did Not Undergo Mitral Valve Surgery During Follow-Up

in 1985 Estimated cumulative risk by age 64 or 74

1/131

1/72

1/39

3.8, 95% confidence inteval 1.18 to 13.0), and tended to have slightly larger left atria (p ⫽ 0.10). Gender did not predict the need for surgery once severe MR was present. In multivariate analysis, older age (p ⬍0.02) and higher body mass index (p ⬍0.04) were independent predictors of surgery. Cumulative risk of mitral valve surgery for severe mitral regurgitation due to mitral valve prolapse:

Among patients undergoing mitral valve surgery, either replacement or repair, at The New York HospitalCornell Medical Center over a 2.5-year period, the etiology was MVP in 40 of 186 or 22%. Comparable proportions were 32 of 100 (or 32%) in the report by Hanson et al18 and 35 of 136 (or 26%) in the report by Olson et al,17 resulting in an overall estimate indicating that 25% of mitral valve surgery was performed for severely regurgitant prolapsed valves. With respect to surgery for severe MR alone, MVP was the underlying etiology in 51% of cases at The New York Hospital. In these series and others that were restricted to patients with MVP,1,21–22,24 –27 300 of 451 or 67% of all MVP patients with severe MR were men. Data on the number of mitral valve operations from 1985 to 1987 in the United States were obtained from 196 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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DISCUSSION

In the present study we found higher age and body mass index, a greater prevalence of hypertension, and a higher proportion of men in patients with severe MR due to MVP than in control subjects with MVP without significant regurgitation. These findings extend previous studies demonstrating an increased risk of complications of MVP, including MR, among men and older subjects.1 The association between structural abnormalities of the mitral valve and significant MR among patients with MVP has been well established.3,22,28 –30 However, only 1 study has estimated the actual risk of an individual with MVP requiring valve surgery for severe MR,4 and none has examined systematically the role of such potentially reversible risk factors as increased arterial pressure or overweight. The higher systolic and diastolic blood pressures and greater prevalence of hypertension in MVP patients with hemodynamically important MR in the present study are consistent with the hypothesis that this complication is due to a persistent hemodynamic burden placed on an intrinsically abnormal valve.8 A similar line of reasoning may explain the association of severe MR with higher body mass index in the present population, because the deleterious effects of an increased hemodynamic load might summate over JANUARY 15, 2000

time, also contributing to severe MR among older subjects. Our finding that men with MVP had higher systolic and diastolic pressure and body mass index than affected women suggests that greater hemodynamic burden may contribute to the higher incidence of MR among men than among women with MVP. When age was included in the multiple logistic regression analyses, arterial pressure fell short of statistical significance as an independent correlate of the presence of severe MR. However, in secondary analyses that excluded age, higher body mass index, hypertension, and male gender were independently associated with severe MR. However, the strength of the association between higher blood pressure and severe MR in patients with MVP may be underestimated by the known limitations of conventional blood pressure determinations for measuring the impact of pressure load on the heart.31 Unfortunately, 24-hour blood pressure recordings were not available for either the cases or control subjects in the present study. Our conclusions with regard to risk factors for severe MR in patients with MVP are limited by the cross-sectional nature of our primary case-control study and by the limited number of patients with severe MR due to MVP available for multivariate analysis. The inherent limitation of measuring clinical variables at one isolated point in time may be most important for blood pressure because of its known biologic variability, but may also be relevant for body mass index, which varies over time in many patients. Related to this consideration, a potential limitation of our multivariate statistical analyses is that systolic and diastolic blood pressures, as well as body mass index, were positively related to age among MVP patients with severe MR (r ⫽ 0.36, r ⫽ 0.48 and r ⫽ 0.37, respectively). Some wear and tear on the mitral valve, which is biologically caused by less accurately measurable variables such as higher blood pressure and relative body weight, might therefore have been misattributed to the accurately measured variable of age in our multivariate statistical analyses, thereby contributing to the finding that age was the only strong independent correlate of severe MR. Risk factors found to be important in predicting the need for mitral valve surgery in subjects with MVP who had already developed severe regurgitation included older age, higher body mass index, and the presence of hypertension. In multivariate analysis, both older age and body mass index remained statistically independent as predictors of surgery. Once again, these parameters may identify a subset of patients who have had more substantial damage to an intrinsically abnormal mitral valve and hence were at greater risk for surgery. Together with other data, our findings allow estimation of annual and cumulative risks for valve surgery among adult women and men with MVP in the United States. These observations suggest a cumulative risk of 0.8% for surgery for women and 2.6% for men with MVP before age 65, respectively, and a risk of 1.4% for women and 5.5% for men by age 75. Although these estimates help quantitate the overall

level of risk, they do not clarify the extent to which risk may be further stratified accurately in young persons by accounting for the presence or absence of mild MR24 or of prominent mitral valve enlargement,28 –29 thickening,30 or distorted leaflet coaptation. Because of the associations we found between severe MR due to MVP and hypertension, as well as relative body weight, in our primary case-control study, and the predictive value of higher initial body mass index and hypertension for subsequent valvular surgery during prospective follow-up of our MVP patients with severe MR, it may be prudent to correct overweight and treat even very mild systemic hypertension in MVP patients with more than mild MR or with especially prominent valvular deformity. Further study of larger numbers of patients are needed to elucidate fully the relative contribution of potentially reversible risk factors such as overweight and hypertension compared with abnormal mitral leaflet length and thickness, as well as annular dilatation, to the development of severe MR in patients with MVP. 1. Devereux RB, Hawkins I, Kramer-Fox R, Lutas EM, Hammond IW, Spitzer MC, Hochreiter C, Roberts RB, Belkin RN, Kligfield P, Brown WT, Niles N, Alderman MH, Borer JS, Laragh JH. Complications of mitral valve prolapse: disproportionate occurrence among men and older patients. Am J Med 1986;81: 751–758. 2. MacMahon SW, Roberts JK, Kramer-Fox R, Zucker DM, Roberts RB, Devereux RB. Mitral valve prolapse and infective endocarditis. Am Heart J 1987; 113:1291–1298. 3. Kligfield P, Levy D, Devereux RB, Savage DD. Arrhythmias and sudden death in mitral valve prolapse. Am Heart J 1987;113:1298 –1307. 4. Wilcken DE, Hickey AJ. Lifetime risk for patients with mitral valve prolapse of developing severe valve regurgitation requiring surgery. Circulation 1988;78: 10 –14. 5. Hickey AJ, MacMahon SW, Wilcken DE. Mitral valve prolapse and bacterial endocarditis: when is antibiotic prophylaxis necessary? Am Heart J 1985;109: 431– 435. 6. Danchin N, Voirot P, Briancon S, Bairati I, Mathieu P, Deschamps JP, Dureux JB, Cherrier F. Mitral valve prolapse as a risk factor for infective endocarditis. Lancet 1989;1:743–745. 7. Devereux RB, Frary CJ, Kramer-Fox R, Roberts RB, Ruchlin HS. Costeffectiveness of infective endocarditis prophylaxis for mitral valve prolapse with or without a mitral regurgitant murmur. Am J Cardiol 1994;74:1024 –1029. 8. Roberts WC. Mitral valve prolapse and systemic hypertension. Am J Cardiol 1985;56:703. 9. Roberts WC. Morphologic features of the normal and abnormal mitral valve. Am J Cardiol 1983;51:1005–1028. 10. Devereux RB, Brown WT, Kramer-Fox R, Sachs I. Inheritance of mitral valve prolapse: effect of age and sex on gene expression. Ann Intern Med 1982;97:826 – 832. 11. Devereux RB, Kramer-Fox R, Shear MK, Kligfield P, Pini R, Savage DD. Diagnosis and classification of severity of mitral valve prolapse: methodologic, biologic, and prognostic considerations. Am Heart J 1987;113:1265–1280. 12. Levine RA, Triulzi MO, Harrigan P, Weyman AE. The relationship of mitral annular shape to the diagnosis of mitral valve prolapse. Circulation 1987;75: 756 –767. 13. Hochreiter C, Niles N, Devereux RB, Kligfield P, Borer JS. Mitral regurgitation: relationship of non-invasive descriptors of right and left ventricular performance to clinical and hemodynamic findings and to prognosis in medically and surgically treated patients. Circulation 1986;73:900 –912. 14. Kligfield P, Hochreiter C, Niles N, Devereux RB, Borer JS. Relationship of sudden death in pure mitral regurgitation with and without mitral valve prolapse, to repetitive ventricular arrhythmia and right and left ventricular ejection fraction. Am J Cardiol 1987;60:397–399. 15. Ganau A, Devereux RB, Atlas SA, Pecker M, Roman MJ, Vargiu P, Cody RJ, Laragh JH. Plasma atrial natriuretic factor in essential hypertension: Relationship to cardiac size, function, and hemodynamics. J Am Coll Cardiol 1989;14:715– 724. 16. Lawrence L. Detailed diagnoses and procedures for patients discharged from short-stay hospitals, United States, 1985–1988; National Center for Health Statistics. Hyattsville:MD 1986 –1989. (DHHS publication no. (PHS) 86 to 89 – 1747). 17. Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD.

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Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc 1987;62:22–34. 18. Hanson TP, Edwards BS, Edwards JE. Pathology of surgically excised mitral valves. Arch Pathol Lab Med 1985;109:823– 828. 19. Phillips HR, Levine FH, Carter JE, Boucher CA, Osbakken MD, Okeda PD, Akins CW, Daggett WM, Buckley MJ, Pohost GM. Mitral valve replacement for isolated mitral regurgitation: analysis of clinical course and late post-operative left ventricular ejection fraction. Am J Cardiol 1981;48:647– 654. 20. Waller BF, Maron BJ, Del Negro AA, Gottdiener JS, Roberts WC. Frequency and significance of M-mode echocardiographic evidence of mitral valve prolapse in clinically isolated pure mitral regurgitation: analysis of 65 patients having mitral valve replacement. Am J Cardiol 1984;53:139 –147. 21. Danielsen R, Nordrehaug JE, Vik-Mo H. High occurrence of mitral valve prolapse in cardiac catheterization patients with pure isolated mitral regurgitation. Acta Med Scand 1987;221:33–38. 22. Roberts WC, McIntosh CL, Wallace RB. Mechanisms of severe mitral regurgitation in mitral valve prolapse determined from analysis of operatively excised valves. Am Heart J 1987;113:1316 –1323. 23. U.S. Department of Commerce, Statistical Abstract of the United States 1991.111th ed. Washington, DC: 13. 24. Kolibash AJ, Kilman JW, Bush CA, Ryan JM, Fontana ME, Wooley CF. Evidence for progression from mild to severe mitral regurgitation in mitral valve prolapse. Am J Cardiol 1986;58:762–767. 25. Tresch DD, Doyle TP, Boncheck LI, Siegel R, Keelen MH Jr, Olinger GN,

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Brooks HL. Mitral valve prolapse requiring surgery. Clinical and pathologic study. Am J Med 1985;78:245–250. 26. Caidahl K, Larsson S, Sudow G, Wallentin J, Angelhed JE, Olsson BS. Conservative surgery for mitral valve prolapse with regurgitation: clinical follow-up and noninvasive assessment. Eur Heart J 1987;8:384 –394. 27. Jerasaty RM, Edwards JE, Chawla SK. Mitral valve prolapse and ruptured chordae tendinea. Am J Cardiol 1985;55:138 –142. 28. Pini R, Devereux RB, Greppi B, Roman MJ, Hochreiter C, Kramer-Fox R, Niles NW, Kligfield P, Erlebacher JA, Borer JS. Comparison of mitral valve dimensions and motion in mitral valve prolapse with severe mitral regurgitation to uncomplicated mitral valve prolapse and to mitral regurgitation without mitral valve prolapse. Am J Cardiol 1988;62:257–263. 29. Weissman NJ, Pini R, Roman MJ, Kramer-Fox R, Andersen HS, Devereux RB. In vivo mitral valve morphology and motion in mitral valve prolapse. Am J Cardiol 1994;73:1080 –1088. 30. Levine RA, Stathogiannis, Newell JB, Harrigan P, Weyman AE. Reconsideration of echocardiographic standards for mitral valve prolapse: lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality. J Am Coll Cardiol 1988;11:1010 –1019. 31. Devereux RB, Pickering TG, Harshfield GA, Kleinert HD, Denby L, Clark L, Pregibon D, Jason M, Kleiner B, Borer JS, Laragh JH. Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress. Circulation 1983;68:470 – 476.

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