Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome.

OBJECTIVES: The present study examines the incidence of aortic complications (dissection, marked dilation requiring surgery or progressive moderate to severe aortic regurgitation) and their relation to clinical features and aortic root morphology in patients with the Marfan syndrome. BACKGROUND: Considerable phenotypic variability exists in the Marfan syndrome, and the prospective prediction of the risk for aortic complications in individual patients remains elusive. METHODS: One hundred thirteen patients with the Marfan syndrome underwent anthropometric and echocardiographic evaluation and were followed-up for 49 +/- 24 (mean +/- SD) months. Aortic root dilation was defined as localized when confined to the sinuses of Valsalva (based on two-dimensional echocardiographic confidence limits utilizing age and body size) and generalized if dilation additionally involved the supraaortic ridge and proximal ascending aorta. RESULTS: Aortic root dilation was present in 80% of patients and was localized in 28% and generalized in 51%. Aortic complications occurred during follow-up in none of 23 patients with normal initial aortic size, in 2 (6%) of 32 patients with initially localized dilation and in 19 (33%) of 58 patients with generalized dilation (p < 0.0005). Complications were associated with larger initial aortic size (p < 0.00005), higher systolic blood pressure (p < 0.005), height (p < 0.05), aortic growth rate (p < 0.05) and older age (p < 0.01). The only independent predictor of aortic complications was initial aortic root size (p < 0.005). However, when aortic size, one of the indications for surgical referral, was excluded from analyses, the only independent predictor of aortic complications was generalized aortic dilation (p < 0.005). CONCLUSIONS: The present study indicates that generalized aortic root dilation is a potent marker of an increased risk for subsequent aortic complications in Marfan syndrome.

Mitral valve dimensions and motion and familial transmission of mitral valve prolapse with and without mitral leaflet billowing.

To test the hypothesis that mitral valve prolapse may be due either to billowing of mitral leaflets into the left atrium or to dynamic expansion of the mitral anulus, mitral leaflet and annular dimensions and motion were measured by computer-assisted two-dimensional echocardiography in 35 normal adults and 48 subjects with auscultatory and M-mode echocardiographic evidence of mitral prolapse. Among normal subjects, mitral leaflet and annular dimensions tended to be larger compared with body size or left ventricular size in women than in men. Mitral leaflet billowing was observed in 24 (50%) of 48 patients with mitral prolapse and 0 of 35 normal subjects (100% specificity). The 24 patients without leaflet billowing had greater systolic expansion of the mitral anulus (p less than 0.0001) than did normal adults or patients with leaflet billowing (41 +/- 14% versus 27 +/- 12% and 22 +/- 11%, respectively) and a significantly lower body mass index (p less than 0.005 versus normal group). The ratio of anterior plus posterior mitral leaflet length to end-systolic annular diameter was lower in patients with prolapse without leaflet billowing than in normal subjects (1.09 +/- 0.12 versus 1.19 +/- 0.15, respectively, p less than 0.01) or patients with leaflet billowing (1.21 +/- 0.17, p less than 0.05). Among 35 relatives with mitral prolapse in the families of 23 patients with prolapse, the pattern was the same as in the proband in 31 (89%) (p less than 0.000002).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between clinical features of the mitral prolapse syndrome and echocardiographically documented mitral valve prolapse.

Mitral valve prolapse, the most common inherited cardiovascular condition, has been associated with a variety of signs, symptoms and electrocardiographic abnormalities, but the true spectrum of the mitral prolapse syndrome remains in doubt because clinical findings often contribute to patient identification and their prevalence in patient groups may be overstated because of ascertainment bias. Accordingly, clinical findings in 88 patients with echocardiographic mitral prolapse were compared with those in 81 of their adult first degree relatives with mitral prolapse (a group free of ascertainment bias) and in two control groups without mitral prolapse: 172 first degree relatives and 60 spouses. Comparison of relatives with and without mitral prolapse demonstrated true associations between mitral prolapse and clicks or murmurs, or both (67 versus 9%, p less than 0.001), thoracic bony abnormalities (41 versus 16%, p less than 0.001), systolic blood pressure less than 120 mm Hg (53 versus 31%, p less than 0.001), body weight 90% or less of ideal (31 versus 14%, p less than 0.005) and palpitation (40 versus 24%, p less than 0.01). In contrast, relatives with mitral prolapse showed no significant increase over normal relatives or spouses without mitral prolapse in prevalence of chest pain, dyspnea, panic attacks, high anxiety or repolarization abnormalities, but these features were all more common in women than in men (p less than 0.01 to less than 0.001). Thus, the true spectrum of the mitral prolapse syndrome encompasses a midsystolic click and late systolic murmur, thoracic bony abnormalities, low body weight and blood pressure and palpitation. Other suggested clinical features, including nonanginal chest pain, dyspnea, panic attacks and electrocardiographic abnormalities, have appeared to be associated with mitral valve prolapse because of ascertainment bias and an erroneous classification of differences between men and women as being due to mitral valve prolapse.

Arrhythmias in mitral valve prolapse. Effect of selection bias.

To assess the contribution of bias in subject selection to the prevalence of arrhythmias in cases of mitral valve prolapse (MVP), we compared ambulatory arrhythmias in 63 patients with MVP and 28 symptom-matched control subjects. All subjects were in sinus rhythm. Mean 24-hour heart rate of the prolapse population was lower than that of the control group (76 v 82 beats per minute). Mean atrial premature complex (APC) density per 1,000 beats (0.9 v 0.7 for patients with MVP and control subjects, respectively) and mean ventricular premature complex (VPC) density per 1,000 total beats (1.2 v 1.5) did not differ between groups. Small differences between groups in APC and VPC complexity did not reach statistical significance. Our findings suggest that, compared with similarly symptomatic controls, patients with MVP do not have as high an excess prevalence of arrhythmias as previously believed.

Low prevalence of mitral valve prolapse in patients with panic disorder.

In 25 patients with panic attacks the prevalence of mitral valve prolapse was 8%, close to that in the general population. The higher rates in previous reports may be due to differences in prolapse criteria, sampling techniques, or the samples' sex ratios.

Contrasting patterns of autonomic dysfunction in patients with mitral valve prolapse and panic attacks.

Both mitral valve prolapse (MVP) and panic attacks have been reported to be associated with autonomic dysfunction, but previous studies have been limited by the lack of clear separation between patients with MVP and those with panic attacks and the use of noncomparable control subjects. Accordingly, heart rate and blood pressure responses to deep breathing, five minutes' quiet standing, and the Valsalva maneuver were studied in age- and cardiac symptom-matched groups of 33 control subjects, 66 patients with MVP, 20 patients with panic attacks, and 17 patients with both MVP and panic attacks. Compared with control subjects, patients with MVP exhibited more syncope (13 of 66, or 20 percent, versus none of 33, or 0 percent; p less than 0.01), more orthostatic hypotension during quiet standing (11 of 66, or 17 percent, versus one of 33, or 3 percent; p less than 0.01), loss of the normal decrease with age in vagally-mediated heart rate variability during deep breathing (r = 0.13, p = NS versus r = -0.44, p = 0.01), and lower 24-hour epinephrine excretion (6.1 +/- 0.7 versus 11.0 +/- 2.7 micrograms; p less than 0.01). In contrast, patients with panic attacks had greater increases than control subjects or patients with MVP without panic attacks in heart rate, mean blood pressure, and the product of heart rate and mean blood pressure during each minute of quiet standing and during the early strain phase of the Valsalva maneuver. These findings indicate that autonomic dysfunction occurs both in patients with MVP and in those with panic attacks in comparison with symptomatic control subjects, but that the patterns of abnormality differ. Patients with MVP exhibit decreased effectiveness of responses to orthostatic stress, reduced epinephrine excretion, and abnormal vagal tone, whereas patients with panic attacks have heightened cardiovascular responses to postural and positive intrathoracic pressure stresses.

Complications of mitral valve prolapse. Disproportionate occurrence in men and older patients.

To determine factors influencing the strength of association between mitral valve prolapse and mitral regurgitation, ruptured chordae tendineae, and infective endocarditis, the prevalence of mitral prolapse in patients with disease was compared with both clinical and population control groups. The prevalence of mitral valve prolapse was 4 percent among population and clinical control groups (eight of 196 and 84 of 2,146, respectively) and was significantly higher (p less than 0.001) in patients with endocarditis (11 of 67, 16 percent), mitral regurgitation (17 of 31, 55 percent, and ruptured chordae (27 of 43, 63 percent). Odds ratios for complications in persons with mitral valve prolapse ranged from 4.6 for endocarditis to 41.4 for ruptured chordae in overall analyses, and from 6.8 for endocarditis to 53.0 for ruptured chordae based on age- and sex-matched case-control triplets (p less than 0.001 for each). All complications occurred disproportionately in men with mitral valve prolapse, in whom odds ratios ranged from 2.5 to 7.4 compared with an additional control group of unselected subjects with mitral valve prolapse. Compared with this control group, patients with mitral valve prolapse and endocarditis were slightly more likely to have a previously known heart murmur (odds ratio 3.2, difference not significant) but significantly more likely to have murmurs at the time of evaluation (odds ratio 8.5, p less than 0.01). Patients with mitral valve prolapse and mitral regurgitation and ruptured chordae tendineae were also significantly older than the unselected subjects with mitral valve prolapse (48 +/- 14 and 55 +/- 16 versus 38 +/- 14 years, p less than 0.005 for both). The concentration of risk of endocarditis in men with mitral valve prolapse and patients with antecedent murmur suggests that antibiotic prophylaxis is warranted in these groups but not in women without a murmur of mitral regurgitation.

Cost-effectiveness of infective endocarditis prophylaxis for mitral valve prolapse with or without a mitral regurgitant murmur.

To assess the cost-effectiveness of prevention of infective endocarditis (IE) and to calculate cost-effectiveness of currently recommended regimens in patients with mitral valve prolapse (MVP), data on risk of death, complications, and health-care use, and cumulative incremental health-care costs due to the occurrence of IE were combined with data on the prevalence and manifestations of MVP, estimated years of life lost, and efficacy of antibiotic prophylaxis. Effectiveness and costs of standard endocarditis prophylaxis regimens were calculated per IE case prevented and years of life saved. Under the most likely scenario, oral amoxicillin prophylaxis for all MVP patients would prevent 32 cases of IE per million dental procedures at approximate costs of $119,000 per prevented case and $21,000 per year of life saved. Limiting prophylaxis to patients with mitral murmurs would prevent 80 cases of IE per million procedures at costs of about $19,000 per prevented case and $3,000 per year of life saved. Erythromycin prophylaxis was slightly less expensive than amoxicillin per benefit because of lower cost and lack of drug anaphylaxis, whereas intravenous ampicillin was 7 to 30 times more costly. Sensitivity analyses suggested that erythromycin prophylaxis might be cost-saving under some scenarios, whereas intravenous ampicillin use might cause net loss of life. Thus, prevention with oral antibiotics of the cumulative morbidity and incremental health care costs due to IE in MVP patients is reasonably cost-effective for MVP patients with mitral murmurs.

Time-motion reconstruction of mitral leaflet motion from two-dimensional echocardiography in mitral valve prolapse.

To assess the contributions of mitral leaflet billowing and exaggerated systolic mitral anular expansion to posterior motion of mitral leaflets recognized as mitral valve prolapse (MVP) by M-mode echocardiography, time-motion reconstructions of the anteroposterior displacement of points equally spaced along the anterior and posterior mitral leaflets were derived by computer-assisted analysis of 2-dimensional echocardiograms. Late or holosystolic posterior displacement of mitral leaflets, greater than or equal to 2 mm, occurred in the reconstructions from 24 of 24 (100%) patients with MVP with leaflet billowing and in 20 of 24 (83%) patients with MVP without leaflet billowing compared with 4 of 35 (11%) age-sex matched normal adults (both p less than 0.0000002). Posterior motion of the posterior mitral leaflet in time-motion reconstruction was significantly less with respect to the posterior end of the mitral anulus than with respect to the chest wall in patients with nonbillowing MVP (1.6 +/- 1.9 vs 2.7 +/- 1.6, p less than 0.02), but not in those with leaflet billowing (3.6 +/- 1.8 vs 3.9 +/- 1.8, p = not significant), because anular expansion contributed importantly to MVP in the former but not in the latter group. Thus, M-mode echocardiographic patterns of MVP reflect the separate but interacting effects of distinct abnormalities of mitral anular and leaflet dynamics.

Natural history of mitral valve prolapse.

To assess the rate and predictors of complications in patients with mitral valve prolapse (MVP), 316 subjects (mean age 42 +/- 15 years) with echocardiographic MVP were followed prospectively for a mean of 102 months: 220 (70%) were women, 225 (71%) had clinically recognized MVP, and 91 (29%) were detected in family studies. During follow-up, 11 patients (0.4/100 subject-years) required mitral valve surgery, 6 died of cardiac causes (0.2/100 subject-years), 7 developed cerebral ischemia (0.3/100 subject-years), and 2 developed active infective endocarditis (0.1/100 subject-years). The overall rate of fatal and nonfatal complications (1/100 patient-years) was higher in men than in women (odds ratio [OR] 3.2, p < 0.003), in subjects aged > 45 than < or = 45 years (OR 3.4, p = 0.002), in clinically recognized patients than in affected family members (OR 3.8, p < 0.02), and in those with a holosystolic murmur (OR 26.9, p < 0.00005); the overall rate was lower in those with a midsystolic click (OR 0.3, p < 0.002). Echocardiographic left ventricular or atrial diameter > or = 6.0 or > or = 4.0 cm, respectively, was associated with a 16.7- and 15.1-fold higher likelihood, respectively, of subsequent complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of association between dermal arches and mitral valve prolapse: relation to anxiety.

Mitral valve prolapse (MVP) has been reported to be associated with an increased frequency of dermal arches. To determine whether dermal arches are associated with MVP, 42 patients with echocardiographic (echo) MVP (probands) and 140 first-degree relatives in their families, including 48 with and 92 without MVP, were studied. Seventy-five, subjects with neither MVP nor blood relation to probands served as control subjects. Among the female probands, 6.9% had arches and among the males, 3.8% had arches. The proportion of arches was lower among female control subjects (4.0%) but higher among male control subjects (7.9%) (neither difference being significant [NS]). Among the relatives, 7.1% of the women with MPV and 4.6% of the women without MVP had arches (NS). Five percent of the men with MVP and 6.3% without MVP had arches (NS). No association existed between the occurrence of cardiovascular symptoms in patients and family members with MVP and presence of dermal arches, but a high proportion of probands with elevated trait anxiety without panic disorder had 4 or more dermal arches. These findings do not support a direct association of dermal arches with MVP.

Comparison of cardiovascular and skeletal features of primary mitral valve prolapse and Marfan syndrome.

The association of primary mitral valve prolapse (MVP) with thoracic bony abnormalities has led to the suggestion that MVP may be a forme fruste of the Marfan syndrome. Echocardiographic, skeletal and anthropometric findings in 59 subjects with primary MVP and 59 age- and sex-matched patients with Marfan syndrome were compared with those in 59 control subjects. Subjects with mitral prolapse were similar to control subjects and differed (p less than 0.025 to p less than 0.001) from the patients with Marfan syndrome in aortic root dimensions, height, arm span, upper/lower segment ratio and prevalences of arachnodactyly, scoliosis and pectus carinatum. Subjects with mitral prolapse and patients with Marfan syndrome had similar body mass indexes and prevalences of pectus excavatum and straight back. All 3 groups were similar in arm span/height ratio. The 5 subjects with MVP and arachnodactyly had lower weights, smaller body surface areas and smaller aortic root dimensions, and were more likely to have scoliosis than subjects with MVP without arachnodactyly. Thus, primary MVP differs from the Marfan syndrome in all major skeletal and cardiovascular features.

Two-dimensional echocardiographic aortic root dimensions in normal children and adults.

Two-dimensional echocardiography is increasingly used to measure aortic root dimensions, which provide prognostic information in aortic regurgitation and the Marfan syndrome. Aortic root dilatation is currently detected by nomograms based on M-mode echocardiographic data. Aortic root diameters measured by 2-dimensional echocardiography at the anulus, sinuses of Valsalva, supra-aortic ridge and proximal ascending aorta in 135 normal adults and 52 normal children were compared with age, gender, body habitus, blood pressure and stroke volume, and with M-mode findings and normal limits. Two-dimensional measurements at the sinuses of Valsalva were larger than M-mode aortic root values (p less than 0.001), and use of 2-dimensional values with M-mode nomograms falsely diagnosed aortic dilatation in 40% of normal children and 19% of normal adults. Two-dimensional measurements at the sinuses closely correlated with body surface area in children (r = 0.93, p less than 0.0005), moderately in adults younger than 40 years of age (r = 0.71, p less than 0.0005) and weakly in older adults (r = 0.40, p less than 0.0005). In adults, gender influenced aortic root size at all levels (p less than 0.001), but dimensions were similar when indexed for body surface area. Age strongly influenced supraaortic ridge and ascending aortic diameters; blood pressure and stroke volume had no independent effect on aortic size. In conclusion, (1) 2-dimensional echocardiographic aortic root dimensions are influenced by age and body size but not by blood pressure; (2) aortic root dilatation is overdiagnosed when aortic diameter at the sinuses of Valsalva is compared with M-mode nomograms; (3) nomograms comparing aortic diameter with body surface area should be used in children; and (4) although use of nomograms based on body size in adults should maximize sensitivity for aortic dilatation, 98% specificity is attained by use of an upper normal limit of 2.1 cm/m2 for aortic diameter at the sinuses of Valsalva in both men and women.

Clinical and health care cost consequences of infective endocarditis in mitral valve prolapse.

Although mitral valve prolapse (MVP) predisposes to infective endocarditis (IE), both the clinical consequences of IE and the increment in health care costs it imposes on patients with MVP remain uncertain. Accordingly, 21 MVP patients with IE and 41 age- and sex-matched control subjects with initially uncomplicated MVP were followed (95% complete) a mean of 8 years. Outcomes included death, complications, health care use and cumulative incremental costs. More MVP patients with IE died (25 vs 5%, p < 0.05), underwent valve surgery (40 vs 8%, p < 0.01), had heart failure (50 vs 5%, p < 0.01) or embolization (53 vs 11%, p < 0.01), underwent cardiac catheterization (40 vs 13%), and saw their physicians > 2 times per year (88 vs 33%). The cumulative incremental cost of IE (1990 dollars) was $46,132 per case. Thus, IE in patients with MVP causes considerable cumulative morbidity and incremental health care costs.

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

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 = 0.002), had higher systolic (p = 0.0003) and diastolic (p = 0.007) blood pressures, and were more likely to have hypertension (p = 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.

Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome.

Systematic, prospective data regarding phenotypic features, including echocardiographic findings, in pediatric patients with the Marfan syndrome are lacking. In addition, limited and conflicting information exists regarding the impact of pharmacologic therapy on aortic growth rate in children. Fifty-three children and adolescents with the Marfan syndrome underwent physical examination, anthropometric evaluation, and echocardiography. The relation of pharmacologic therapy to aortic growth rate was examined in the 44 subjects in whom serial echocardiograms were recorded. Although boys and girls did not differ in ocular, skeletal, or cardiovascular manifestations, aortic dilatation tended to be more common in boys (86% vs 72%). Children with aortic dilatation at baseline (42 of 53 or 79%) were more likely to also have scoliosis and mitral prolapse (both p <0.005). The medicated patients had slower aortic growth than the unmedicated patients with regard to both absolute aortic growth rate (p <0.01) and aortic growth rate adjusted for age and body size (p <0.005). Nevertheless, major cardiovascular complications developed in 5 patients despite long-term pharmacologic therapy. In conclusion, beta-blocker and calcium antagonist therapy retards aortic growth rate in children and adolescents with the Marfan syndrome.

In vivo mitral valve morphology and motion in mitral valve prolapse.

Mitral leaflet morphology in mitral valve prolapse (MVP) has been suggested to be prognostically important, but in vivo valvular morphology is incompletely described in patients with MVP or in normal subjects. Accordingly, the length of both mitral leaflets and their zone of apposition, the thickness of their rough and clear zones, diastolic and systolic mitral annular diameters, and indexes of abnormal leaflet motion were measured in the parasternal long-axis echocardiographic view in 100 patients with MVP and 100 age- and sex-matched normal subjects. In both groups posterior leaflet thickness was related to age, as were anterior leaflet thickness and posterior leaflet length in patients with MVP. Compared with normal subjects, MVP patients without mitral regurgitation had thickened leaflets, elongated anterior leaflets, and large annular diameters (p < 0.0001). Patients with severe regurgitation had thicker leaflets, longer posterior leaflet and annular dimensions, and more abnormal leaflet motion than MVP patients without regurgitation. Leaflet thicknesses of different zones were supranormal in 60% to 67% and in 49% to 59% of MVP patients with and without severe regurgitation, respectively. MVP patients with regurgitation also had higher prevalences of abnormal mitral annular diameter than those without regurgitation (67% vs 29%) and > 3 mm posterior leaflet billowing into the left atrium (60% vs 34%). Thus, mitral valve size and leaflet thickness are increased in MVP patients without as well as with clinically important mitral regurgitation. The usefulness of leaflet thickening as a marker of severe MVP is limited by its high prevalence in patients with clinically mild MVP.

Complex arrhythmias in mitral regurgitation with and without mitral valve prolapse: contrast to arrhythmias in mitral valve prolapse without mitral regurgitation.

Atrial and ventricular arrhythmias were characterized by ambulatory electrocardiography in 31 patients with nonischemic mitral regurgitation (MR), 17 of whom had echocardiographic evidence of mitral valve prolapse (MVP) and 14 of whom had other causes of MR. Frequent and complex arrhythmias were common and equally prevalent in each MR subgroup, whether or not MVP was present. Multiform ventricular ectopy was found in 77% (24 of 31), ventricular couplets in 61% (19 of 31), and ventricular salvos or ventricular tachycardia in 35% (11 of 31) of patients with MR. Arrhythmias in patients with MR were significantly more prevalent than in 63 patients with MVP who had no evidence of MR. Among patients with MVP, excess arrhythmias associated with MR were most striking with respect to frequent ventricular premature complexes (41% with MR vs 3% without MR), multiform ventricular ectopic activity (88% vs 43%), ventricular couplets (65% vs 6%), and ventricular salvos or ventricular tachycardia (35% vs 5%) (p less than 0.005 for each comparison). These data demonstrate that complex arrhythmias are common in patients with nonischemic MR irrespective of etiology, and that these arrhythmias are more strongly associated with hemodynamically important MR than with MVP alone.

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.

To determine the mitral valve abnormalities associated with hemodynamically important mitral regurgitation (MR) among patients with mitral valve prolapse (MVP), computerized 2-dimensional echocardiographic measurements of mitral leaflet and anular dimensions and motion in 26 patients with MVP and MR were compared to those in 48 subjects with uncomplicated MVP, 16 patients with MR due to etiologies other than MVP (rheumatic in 8) and 35 normal adults. Compared to both uncomplicated MVP and normal subjects, patients with MVP plus MR were older (p less than 0.05), had strikingly large mitral leaflets and anulus (p less than 0.0005) and were more likely to have systolic billowing of mitral leaflets in the parasternal long-axis view (24 of 26 [92%] vs 24 of 48 subjects with uncomplicated MVP [50%], p less than 0.001). Overlap in anular and posterior leaflet dimensions in normal and uncomplicated MVP subjects occurred in the 20 MVP plus MR patients who continue to be followed medically but not in the 6 MVP plus MR patients who underwent mitral valve surgery during 22 +/- 14 months follow-up. Patients with MR due to rheumatic or other non-MVP etiologies had enlargement of mitral leaflets and anulus virtually identical to that in MVP plus MR patients. In conclusion, patients with severe MR due to MVP are older, have striking mitral valve enlargement and more frequently exhibit leaflet billowing compared with subjects with uncomplicated MVP. Similar mitral leaflet enlargement was found in patients with non-MVP etiologies of MR, suggesting that mitral anular and leaflet enlargement may play a more general role in the pathogenesis of MR than is currently appreciated.