Prevalence and correlates of mitral valve prolapse in a population-based sample of American Indians: the strong heart study

CLINICAL STUDIES

Prevalence and Correlates of Mitral Valve Prolapse in a Population-based Sample of American Indians: the Strong Heart Study Richard B. Devereux, MD, Erica C. Jones, MD, Mary J. Roman, MD, Barbara V. Howard, PhD, Richard R. Fabsitz, MA, Jennifer E. Liu, MD, Vittorio Palmieri, MD, Thomas K. Welty, MD, MPH, Elisa T. Lee, PhD PURPOSE: Mitral valve prolapse is heritable and occurs frequently in the general population despite associations with mitral regurgitation and infective endocarditis, suggesting that selective advantages might be associated with mitral valve prolapse. SUBJECTS AND METHODS: Clinical examination and 2-dimensional and color Doppler echocardiography were performed in 3340 American Indian participants in the Strong Heart Study. RESULTS: Mitral valve prolapse (clear-cut billowing of one or both mitral leaflets across the mitral anular plane in 2-dimensional parasternal long-axis recordings or ⬎2-mm late systolic posterior displacement of mitral leaflets by M mode) occurred in 37 (1.8%) of 2077 women and 20 (1.6%) of 1263 men (P ⫽ 0.88); 32 (3.5%) of 907 patients with normal glucose tolerance, 11 (2.3%) of 486 patients with impaired glucose tolerance, and 13 (0.7%) of 1735 patients with diabetes (P ⬍0.0001). Participants with mitral valve prolapse had lower mean (⫾ SD) body mass index (28 ⫾ 5 kg/m2 vs. 31 ⫾ 6 kg/m2, P ⫽ 0.001) and blood pressure (124/71 ⫾ 19/10 mm Hg vs. 130/75 ⫾ 21/10 mm Hg, P ⬍0.05), as well as lower levels of fasting glucose, triglycerides, serum creatinine, and log urine albumin/creatinine ratio

(all P ⬍0.001), than did those without mitral valve prolapse, although all subjects were similar in age (60 ⫾ 8 years). Participants with mitral valve prolapse had lower ventricular septal (0.87 ⫾ 0.08 cm vs. 0.93 ⫾ 0.13 cm) and posterior wall thicknesses (0.82 ⫾ 0.08 cm vs. 0.87 ⫾ 0.10 cm), mass (38 ⫾ 7 g/m2.7 vs. 42 ⫾ 11 g/m2.7), and relative wall thickness (0.33 ⫾ 0.04 vs. 0.35 ⫾ 0.05), and increased stress-corrected midwall shortening (all P ⬍0.01). Mitral valve prolapse was associated with a higher prevalence of mild (16 of 57 [28%] vs. 614 of 3283 [19%]) and more severe mitral regurgitation (5 of 57 [9%] vs. 48 of 3283 [1%], P ⬍0.0001). Regression analyses showed prolapse was associated with low ventricular relative wall thickness, high midwall function, and low urine albumin/creatinine ratio, independent of age, sex, body mass index, and diabetes. CONCLUSIONS: Mitral valve prolapse is fairly common and is strongly associated with mitral regurgitation in the general population. However, it is also associated with lower body weight, blood pressure, and prevalence of diabetes; a more favorable metabolic profile and ventricular geometry; and better myocardial and renal function. Am J Med. 2001;111:679 – 685. 䉷2001 by Excerpta Medica, Inc.

M

mal-dominant inheritance (4 –9). Although initial studies disproved the hypothesis that valvular and extravalvular connective tissue manifestations of mitral prolapse were linked to major fibrillar collagen genes (10,11), a recent study has demonstrated linkage to a region on chromosome 16p (12). Another line of research examines associations between mitral valve prolapse and several complications, most notably, severe mitral regurgitation (1,13,14) and infective endocarditis (1,15,16). Although these complications usually occur in middle or older age, some are seen in young adulthood. In view that genetic conditions with even occasional serious complications during reproductive years are low in prevalence, the moderately common occurrence of mitral valve prolapse in various populations superficially constitutes a “Darwinian paradox.” However, as observed by Allison (17), potentially deleterious genetic conditions could be more prevalent if they were associated with a selective advantage. Early observa-

itral valve prolapse is a moderately common condition affecting 2% to 4% of population samples (1–3). Numerous studies have documented its familial aggregation, with evidence of autosoFrom the Department of Medicine (RBD, ECJ, MJR, JEL, VP), New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York; MedStar Research Institute (BVH), Washington, DC; National Heart, Lung, and Blood Institute (RRF), Bethesda, Maryland; Aberdeen Area Tribal Chairmen’s Health Board (TKW), Rapid City, South Dakota; and School of Public Health (ETL), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Supported in part by Grants U01-HL41642, U01-HL41652, and U01HL41654 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; and M10RR0047-34 (GCRC) from the National Institutes of Health, Bethesda, Maryland. Views expressed in this paper are those of the authors and do not necessarily reflect those of the Indian Health Service. Requests for reprints should be addressed to Richard B. Devereux, MD, Division of Cardiology, Box 222, New York Presbyterian Hospital, 525 East 68th Street, New York, New York 10021. Manuscript submitted March 6, 2001, and accepted in revised form September 5, 2001. 䉷2001 by Excerpta Medica, Inc. All rights reserved.

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tions that patients with mitral valve prolapse had low body weight and blood pressure (18,19) suggested that lower rates of diabetes, hypertension, and preeclampsia might constitute such a selective advantage. However, this possibility has not been systematically examined in population-based samples. We therefore sought to assess the prevalence and the clinical and echocardiographic correlates of mitral valve prolapse among American Indians participating in the Strong Heart Study (20 –22).

METHODS The Strong Heart Study is a population-based survey of cardiovascular risk factors and disease in 13 American Indian tribes in Arizona, Oklahoma, and North and South Dakota. Participants aged 45 to 74 years from three tribes in central Arizona, seven tribes in Oklahoma, and three tribes in North and South Dakota were recruited from members living on reservations or in defined geographic areas (overall participation rate ⫽ 62%) for an initial examination during 1989 to 1992 (20 –22). The second examination (1993 to 1995) assessed change over time in baseline body habitus measurements and blood pressure, and added echocardiography readings, among surviving participants. Standardized measurements were obtained for seated brachial pressure; body habitus, including body mass index, waist/hip ratio, and percentage of body fat by bioelectric impedance; levels of fasting glucose, insulin, hemoglobin A1C (HbA1C), and lipid concentrations; and 2-hour glucose tolerance test. Diabetes was diagnosed by World Health Organization criteria (23) if fasting glucose level was ⬎140 mg/dL, 2-hour postchallenge glucose level was ⬎200 mg/dL, or participants received hypoglycemic medication. Normal or impaired glucose tolerance was identified by normal fasting glucose with postchallenge glucose levels ⬍200 or ⬎200 mg/dL. Prevalent myocardial infarction, coronary heart disease, and congestive heart failure were identified by published criteria (24,25).

Echocardiographic Methods Imaging and Doppler echocardiograms were performed using phased-array echocardiographs with M-mode, 2-dimensional and pulsed, continuous wave, and colorflow Doppler capabilities (26,27). A standardized protocol was followed under which the parasternal acoustic window was used to record ⱖ10 consecutive beats of 2-dimensional and M-mode recordings of the left ventricular internal diameter and wall thicknesses at or just below the tips of the mitral leaflets in long- and short-axis views, long-axis views of the mitral valve and color flow recordings for detection of mitral and aortic regurgitation, and M-mode and 2-dimensional short-axis and long-axis views of the aortic root and left atrium. The apical acoustic window was used to record ⱖ10 cycles of 680

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2-chamber and 4-chamber images and color Doppler recordings to assess ventricular wall motion and to identify valvular regurgitation. To keep study time ⬍30 minutes so that total participant burden remained acceptable, systematic M-mode recordings of the mitral valve and apical long-axis 2-dimensional recordings were excluded.

Measurements Correct orientation of planes for imaging and Doppler recordings was verified as previously described (28). Mitral valve prolapse was identified (29,30) by clear-cut billowing of one or both mitral leaflets across the mitral anular plane in 2-dimensional parasternal long-axis recordings. When M-mode recordings of mitral leaflets were available, ⬎2-mm late systolic posterior displacement of mitral leaflets was considered diagnostic of prolapse (29). Mitral regurgitation was assessed by color Doppler, using a modification of the pulsed Doppler method by Miyatake et al. (31). Regurgitation severity was graded on a 4-point system based on the farthest distance reached from the mitral orifice: ⱕ1.5 cm ⫽ mild (1⫹), 1.5 to 3.0 cm ⫽ moderate (2⫹), 3.0 to 4.5 cm ⫽ moderately severe (3⫹), and ⱖ4.5 cm ⫽ severe mitral regurgitation (4⫹). If centrally oriented mitral regurgitant jets were unusually narrow, 2⫹ to 4⫹ regurgitation was reduced by one grade. Higher regurgitation grades were assigned if unusually wide jets had disproportionate areas for length or if eccentric jets hugged the left atrial wall (32). We measured cardiac dimensions and blood flow using a computerized review station equipped with digitizing tablet and monitor screen overlay for calibration and measurements. Left ventricular internal dimension and septal and posterior wall thicknesses were measured at end-diastole and end-systole on up to three cardiac cycles by American Society of Echocardiography recommendations (33,34). End-diastolic ventricular dimensions were used to calculate left ventricular mass by a necropsy-validated formula (35). Relative wall thickness, fractional shortening in percentage of the ventricular internal dimension, and end-systolic wall stress were calculated by standard methods (26,36). End-diastolic and end-systolic left ventricular volumes calculated by the method of Teichholz et al. (37) were used to derive ejection fraction. Volume determinations by this method have been validated by invasive and Doppler reference standards (38 – 40). We estimated arterial stiffness by the pulse pressure/stroke volume ratio measured by an invasively-validated Doppler method (41,42). Myocardial contractile efficiency was assessed by examining midwall systolic shortening in relation to midwall circumferential end-systolic stress (36,43,44). Midwall shortening was calculated, accounting for epicardial migration of the midwall during systole by assuming con-

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stant volumes of the total ventricular wall and of its inner and outer halves during the cardiac cycle. We used a cylindric model to estimate end-systolic stress at the midwall from M-mode tracings (43). Midwall shortening calculated from echocardiographic measurements was expressed as a percentage of the value predicted from endsystolic stress by equations derived in normal subjects (36); this variable is termed stress-corrected midwall shortening (45).

Statistical Analysis Data were analyzed using SPSS 8-9 (Chicago, Illinois) software, and are expressed as mean ⫾ SD. Differences between groups were assessed by unpaired Student t tests. We estimated the independence of differences from effects of covariates using the general linear model with Sidak’s post hoc test. Independent associations of mitral prolapse with potentially beneficial differences in levels of clinical and echocardiographic variables, as the dependent variable, were assessed by multiple linear regression with an indicator variable for prolapse, together with relevant covariates (age, sex, systolic pressure, body mass index, and diabetes) as independent variables using an enter procedure. Because of differences between clinical and echocardiographic variables among Strong Heart Study participants from different regions (22,46), indicator variables comparing Arizona and Oklahoma participants with those from North and South Dakota were also entered. Because of the large number of variables assessed, two-tailed P ⬍0.01 was considered significant in univariate analyses.

RESULTS Of the 3630 participants in the second Strong Heart Study examination, 3501 (97%) aged 47 to 81 years underwent echocardiography, of whom 3340 (96%) had technically adequate visualization of the mitral valve for inclusion in this study. The eligible participants comprised 1137 in Arizona, 1140 in Oklahoma, and 1063 in North and South Dakota; women comprised 2077 (62%) of participants included. Fifty-seven participants (1.7%) had mitral valve prolapse. Mitral valve prolapse was more prevalent in Oklahoma (31 of 1140 [2.6%]) than in Arizona (7 of 1137 [0.6%]) and North and South Dakota (18 of 1063 [1.6%], P ⬍0.003, adjusted for body mass index), but was equally prevalent in women and men (37 of 2077 [1.8%] vs. 20 of 1263 [1.6%]). Participants with normal and impaired glucose tolerance had a higher prevalence of mitral prolapse (32 of 907 [3.5%] and 11 of 486 [2.3%]) than did those with diabetes (13 of 1735 [0.7%], P ⬍0.001). The prevalence of mitral valve prolapse fell from 3% (15 of 502) in subjects with normal weight (body mass index ⬍25 kg/m2) to 2.2% (23 of 1038) in those with body mass

indexes of 25 to 30 kg/m2 and 1% (18 of 1793) in those with body mass indexes of ⬎30 kg/m2 (P ⫽ 0.003). The prevalence of mitral valve prolapse was similar in hypertensive or normotensive participants (20 of 1582 [1.3%] vs. 36 of 1756 [2.1%], P ⫽ 0.08). Participants with mitral valve prolapse had an increased prevalence of mild (1⫹) mitral regurgitation (16 of 57 [28%] vs. 614 of 3283 [19%]), mild-moderate (2⫹) regurgitation (4 of 57 [7%] vs. 41 of 3283 [1.1%]), and severe (3⫹ to 4⫹) regurgitation (1 of 57 [2%] vs. 12 of 3283 [0.4%], P ⫽ 0.001), but were not more likely to have mild or more severe aortic regurgitation. There was no association of mitral valve prolapse with self-reported alcohol use or cigarette smoking. Both groups did not differ in the prevalence of previous myocardial infarction (0% vs. 107 of 3285 [3%]), coronary heart disease (1 of 57 [2%] vs. 165 of 3285 [5%]), or congestive heart failure (1 of 57 [2%] vs. 90 of 3285 [3%], all P ⬎0.14). There was no age difference between participants (Table 1). Mean body weight and measures of adiposity, including waist/hip ratio (0.94 ⫾ 0.07 vs. 0.96 ⫾ 0.06, P ⫽ 0.01), were lower in subjects with mitral valve prolapse, whereas fat-free body mass was similar in both groups. The difference in body weight between groups did not reflect recent weight loss, as there were similar minimal weight losses in both groups during the 3 years since the first examination (mean ⫽ ⫺0.15 vs. ⫺0.35 kg). Diastolic blood pressure was lower in the mitral valve prolapse group, as was systolic blood pressure. Heart rate and the pulse pressure/stroke index (a measure of systemic arterial stiffness) were, on average, slightly lower among subjects with mitral valve prolapse. There was no difference between groups in the use of beta-blockers (2 of 57 [4%] vs. 133 of 2674 [5%]); however, those with mitral valve prolapse were less likely to receive diuretics (3 of 57 [5%] vs. 414 of 2674 [16%]) or angiotensin-converting enzyme inhibitors (3 of 57 [5%] vs. 539 of 2674 [20%]), but more likely to receive calcium channel blockers (10 of 57 [18%] vs. 330 of 2674 [12%], all P ⬍0.01).

Laboratory Findings Subjects with mitral valve prolapse had more normal renal function, as manifested by serum creatinine levels and the urinary albumin/creatinine ratio (Table 2). There were no between-group differences in total, high-density lipoprotein, or low-density lipoprotein cholesterol levels, but triglyceride levels were lower among those with mitral valve prolapse. Mitral valve prolapse was also associated with lower levels of mean fasting and postchallenge glucose, as well as HbA1c, owing to lower adiposity and prevalence of diabetes. Mean plasma fibrinogen concentration was nearly 30 mg/dL lower in this group.

Cardiac Geometry There was no difference between groups in left ventricular chamber diameter, but wall thicknesses were lower in

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Table 1. Characteristics of Participants with or without Mitral Valve Prolapse Without Mitral Valve Prolapse (n ⫽ 3,285)

Variable (Unit)

With Mitral Valve Prolapse (n ⫽ 57)

P Value

Mean ⫾ SD Age (years) Weight (kg) Height (cm) Body mass index (kg/m2) Adipose mass (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Fat-free mass (kg) Heart rate (beats/min) Ankle/arm index Pulse pressure/stroke index (mm Hg/mL/m2)

participants with mitral valve prolapse. These subjects also had lower ventricular mass, a difference that was strengthened by indexation for height2.7 but eliminated in analyses that adjusted for blood pressure and other covariates (Table 3). Absolute aortic root diameter (3.35 ⫾ 0.43 cm vs. 3.44 ⫾ 0.37 cm, P ⫽ 0.11) and aortic diameter/body height (2.04 ⫾ 0.21 cm/m vs. 2.10 ⫾ 0.20 cm/m, P ⫽ 0.05) were slightly lower among those with mitral valve prolapse.

Left Ventricular Function Measures of left ventricular systolic chamber function, including fractional shortening and ejection fraction, were higher in participants with mitral valve prolapse (Table 3). There was no difference between groups in myocardial afterload, as estimated by end-systolic stress, but midwall shortening was higher among subjects with

60 ⫾ 8 84 ⫾ 19 165 ⫾ 9 31 ⫾ 6 32 ⫾ 12 130 ⫾ 21 75 ⫾ 10 55 ⫾ 17 53 ⫾ 11 68 ⫾ 11 1.1 ⫾ 0.2 1.6 ⫾ 0.6

60 ⫾ 8 77 ⫾ 17 164 ⫾ 9 28 ⫾ 5 26 ⫾ 10 124 ⫾ 19 71 ⫾ 10 53 ⫾ 16 52 ⫾ 13 65 ⫾ 10 1.1 ⫾ 0.1 1.4 ⫾ 0.7

0.66 0.006 0.63 0.001 0.001 0.02 0.009 0.24 0.50 0.03 0.99 0.03

mitral valve prolapse. As a result, stress-corrected midwall shortening was nearly 8% higher in these participants. These differences remained after excluding subjects with prior myocardial infarction and adjusting for medication use. Univariate comparisons of measures of left ventricular diastolic filling between groups revealed slightly higher mean early diastolic peak E velocity (62 ⫾ 16 cm/sec vs. 58 ⫾ 18 cm/sec), slightly lower mean late diastolic peak A velocity (69 ⫾ 16 cm/sec vs. 72 ⫾ 17 cm/sec), and higher mean E/A ratio with mitral prolapse (0.93 ⫾ 0.30 vs. 0.84 ⫾ 0.30, P ⫽ 0.02). Atrial filling fraction was lower (37.8% ⫾ 7.4% vs. 40.1% ⫾ 9.1%, P ⫽ 0.05), and the mean deceleration time of early diastolic transmitral flow was minimally shorter (194 ⫾ 70 ms vs. 204 ⫾ 70 ms, P ⫽ 0.24), with mitral prolapse after adjusting for heart rate and age.

Table 2. Laboratory Findings in Participants with or without Mitral Valve Prolapse

Variable (Unit)

Without Mitral Valve Prolapse (n ⫽ 3,285)

With Mitral Valve Prolapse (n ⫽ 57)

P Value

Mean ⫾ SD Serum creatinine (mg/dL) Urine albumin/creatinine ratio (log) Total cholestrol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) Insulin (IU/mL) Fasting glucose (mg/dL) Two-hour glucose (mg/dL) HbA1c (%) Fibrinogen (mg/dL)

1.1 ⫾ 1.0 3.3 ⫾ 2.0 190 ⫾ 40 41 ⫾ 13 118 ⫾ 34 158 ⫾ 113 22 ⫾ 27 155 ⫾ 80 171 ⫾ 96 7⫾2 364 ⫾ 83

0.9 ⫾ 1.9 2.2 ⫾ 1.3 197 ⫾ 43 43 ⫾ 11 127 ⫾ 35 126 ⫾ 56 20 ⫾ 28 123 ⫾ 59 131 ⫾ 52 6⫾2 336 ⫾ 75

Hb ⫽ hemoglobin; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein. 682

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⬍0.001 ⬍0.001 0.20 0.25 0.05 ⬍0.001 0.03 ⬍0.001 ⬍0.001 0.001 0.01

Mitral Valve Prolapse in a Population-based Sample/Devereux et al

Table 3. Left Ventricular Geometry in Participants with or without Mitral Valve Prolapse

Geometric Measures (Unit)

Without Mitral Valve Prolapse (n ⫽ 3,285)

With Mitral Valve Prolapse (n ⫽ 57)

P Value (Univariate)

P Value (Multivariate)*

Mean ⫾ SD Internal diameter (cm) Posterior wall thickness (cm) Septal thickness (cm) Relative wall thickness Mass (g) Mass/body surface area (g/m2) Mass/fat-free mass (g/kg) Mass/height2.7 (g/m2.7) Functional parameters Fractional shortening Ejection fraction (%) Two-dimensional ejection fraction (%) Circumferential ESS (kdyne/cm2) Stress-corrected midwall shortening (%) Stress/volume index (kdyne/cm3 ⫻ 104) Midwall shortening (%)

4.98 ⫾ 0.52 0.87 ⫾ 0.10 0.93 ⫾ 0.13 0.35 ⫾ 0.05 159 ⫾ 41 84 ⫾ 20 3.1 ⫾ 0.8 42 ⫾ 11

5.00 ⫾ 0.52 0.82 ⫾ 0.08 0.87 ⫾ 0.08 0.33 ⫾ 0.04 148 ⫾ 32 80 ⫾ 13 3.0 ⫾ 0.6 38 ⫾ 7

0.74 ⬍0.001 ⬍0.001 0.001 0.04 0.04 0.13 ⬍0.001

0.37 0.042 0.047 0.014 0.95 0.93 0.44 0.16

0.3 ⫾ 0.1 63 ⫾ 9 62 ⫾ 6 154 ⫾ 44 104 ⫾ 14 6.8 ⫾ 1.7 17 ⫾ 3

0.4 ⫾ 0.1 65 ⫾ 6 63 ⫾ 1 145 ⫾ 36 111 ⫾ 11 6.6 ⫾ 1.5 19 ⫾ 2

0.009 0.005 ⬍0.001 0.13 ⬍0.001 0.26 ⬍0.001

0.16 0.15 0.20 0.87 0.001 0.82 0.002

* Adjusted for age, sex, diabetes, and body mass index. ESS ⫽ end-systolic stress.

In analyses that excluded participants with mitral regurgitation (Table 3), mitral valve prolapse was associated with slightly lower relative wall thickness (by a mean of 0.02), independent of age, sex, and diabetes (all P ⬍0.001), as well as body mass index, whereas there was no independent association of prolapse with ventricular mass or its indexations. Among measures of systolic function, mitral valve prolapse was associated independently with higher midwall shortening (by a mean of 0.9%) and stress-corrected midwall shortening (by a mean of 5%), but not measures of chamber function, including systolic fractional shortening or ejection fraction. The log urine albumin/creatinine ratio was lower (by a mean of 0.8 natural log units, P ⫽ 0.007) with mitral prolapse, whereas there was no independent association of prolapse with serum creatinine, glucose, HbA1c, or triglyceride levels.

DISCUSSION The present study provides new evidence on the population prevalence and correlates of mitral valve prolapse. In accord with previous studies, study participants with mitral prolapse were observed to be leaner and to have lower blood pressure, as well as favorable levels of standard risk factors that are influenced by body weight. Most importantly, this study reveals new associations, independent of body mass and other covariates, between mitral valve prolapse and more favorable values for several indexes of preclinical cardiovascular disease that have been shown

to be associated with future cardiovascular events, including higher left ventricular relative wall thickness (47), lower midwall shortening and stress-corrected midwall shortening (36), and albuminuria (48). The more favorable target organ status in adults with mitral valve prolapse may help mediate, and perhaps increase, beneficial effects on prognosis associated with the lower blood pressure, body weight, and prevalence of diabetes found in subjects in the present and previous studies (2,18,19). Nearly 2% of the middle-aged and older adults had mitral valve prolapse, falling toward the lower end of the previously reported range (1–3). However, this may be related in part to our use of parasternal, long-axis, 2-dimensional echocardiographic recordings as the only means of recognizing mitral valve prolapse, as 10% to 20% of instances of anatomic mitral prolapse involve the medial or lateral scallops of the posterior mitral leaflet, but not its central scallop (29), the best-seen segment in long-axis views. We kept examination time to 30 minutes or less, thus necessitating the elimination of systematic apical 3-chamber 2-dimensional, and M-mode T-scan imaging. Our present findings are therefore compatible with true prevalences of ⱖ2% by a more complete evaluation of mitral leaflet motion. Our findings extend previous evidence of low body weight in patients with mitral prolapse (2,18,19) by documenting that mitral valve prolapse is due to lower adipose body mass as assessed by bioelectric impedance, excluding a primary effect of underlying genetic connective

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tissue abnormality on bone or fat-free organ mass. Participants with mitral valve prolapse had lower blood pressure, similar to subjects in earlier studies (18,19), as well as slightly lower systemic arterial stiffness, as manifested by the pulse pressure/stroke index ratio, possibly owing to greater arterial elasticity due to the connective tissue alteration in prolapse or less systemic atherosclerosis, as might be expected from the more favorable cardiovascular risk factor profile. Future research is needed to assess arterial properties directly in patients with or without mitral valve prolapse. In univariate analyses, mitral valve prolapse was associated with a lower mean body mass index; lower serum triglyceride, fasting and postload glucose, and HbA1c levels; a lower prevalence of diabetes; as well as a lower urine albumin/creatinine ratio. In multivariate analyses that accounted for between-group differences in body mass index and diabetes, and which also adjusted for age and sex, a lower albumin/creatinine ratio remained independently associated with mitral prolapse. This observation raises the possibility that the gene or genes responsible for mitral valve prolapse may have direct effects on microvascular structure or function. This study has several limitations. Obesity was prevalent in study participants, resulting in technical difficulty concerning some echocardiograms and left ventricular chamber enlargement due to volume expansion, which could have reduced valvular:ventricular disproportion, thereby masking expression of mitral prolapse. In addition, the number of subjects with mitral valve prolapse was relatively small. Mitral leaflet thickness was also not measured, thus precluding assessment of this aspect of the mitral prolapse phenotype, which has been associated with complications of mitral prolapse (49 –50). Until genetic mutations responsible for mitral valve prolapse are identified, it will be impossible to tell whether those mutations protect against obesity and its consequences, or if obesity-induced volume expansion masks phenotypic expression of genes for mitral prolapse. The present cross-sectional study cannot determine the prognostic importance of mitral valve prolapse.

ACKNOWLEDGMENT We thank the Indian Health Service facilities, the Strong Heart Study participants, and the participating tribal communities for their extraordinary cooperation and involvement that made this study possible; Betty Jarvis, RN, Tauqeer Ali, MD, and Alan Crawford for their coordination of the study centers; Tauqeer Ali, MD, Helen Beaty, Joan Carter, Michael Cyl, and Neil Sikes for their expert performance of echocardiograms; Elizabeth A. Wood for the design and maintenance of the computer databases; and Virginia Burns for her invaluable assistance in manuscript preparation. 684

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