Mitral valve prolapse has a prevalence of 2% to 3% in the general population, with adverse outcomes such as mitral valve regurgitation (MVR), heart failure, and endocarditis. Predictors of outcomes are used in idiopathic mitral valve prolapse for the timing of surgery, but such predictors are unknown in Marfan syndrome. Therefore, a population-based cohort study of 112 patients (49 male, 63 female; mean age 34 ± 15 years) with classic Marfan syndrome and mitral valve prolapse with moderate or less MVR at baseline was conducted. During 4.6 ± 3.6 years of follow-up, progression of MVR was observed in 41 patients and valve-related events, which comprised mitral valve endocarditis (7 events), heart failure (5 events), and mitral valve surgery (25 events), were observed in 31 patients. Multivariate Cox proportional-hazards regression analysis identified a flail mitral leaflet (hazard ratio [HR] 3.262, 95% confidence interval [CI] 1.406 to 7.566, p = 0.006) and increased indexed end-systolic left ventricular diameters (HR 1.113, 95% CI 1.043 to 1.188, p = 0.001) as independent predictors of progression of MVR. Similarly, mitral valve–related events were independently predicted by a flail mitral leaflet (HR 5.343, 95% CI 2.229 to 12.808, p <0.001), and mild (HR 14.336, 95% CI 1.873 to 109.755, p = 0.01) or moderate (HR 16.849, 95% CI 2.205 to 128.76, p = 0.006) degree of MVR. Conversely, aortic dilatation, dural ectasia, and sporadic mode of inheritance were not associated with outcome. In conclusion, the same clinical determinants that predict outcomes in idiopathic mitral valve prolapse also predict outcomes in mitral valve prolapse associated with Marfan syndrome.
Mitral valve (MV) prolapse (MVP) has a prevalence of 2% to 3% in the general population and carries a definitive risk for progression to complications such as severe MV regurgitation (MVR), heart failure, and infective endocarditis. Some patients with MVP fulfill criteria of the Marfan syndrome, an autosomal dominantly inherited disease of the connective tissue that is caused by mutations in the gene coding for fibrillin-1, FBN1. Our recent population-based cohort study of patients with Marfan syndrome documented MVP in 40%, severe MVR in 12%, and endocarditis in 2.5% of affected patients. To date, the clinical characteristics that predict outcomes of MVP in patients with Marfan syndrome are unknown. However, outcome predictors are well characterized in idiopathic MVP, and recommendations for timing of surgery are based on such predictors. To date, there is no evidence for the common practice of applying established guidelines for the timing of surgery in idiopathic MVP to patients with Marfan syndrome. Thus, we recruited residents of all ages from an area of 180 km around the Hamburg University Clinic who fulfilled criteria of classic Marfan syndrome and criteria of MVP but without severe MVR and conducted a population-based cohort study to assess clinical variables that predict the outcomes of MVP in Marfan syndrome.
Methods
From January 1, 1997, to March 30, 2010, a total of 668 patients presented to our joint pediatric and adult Marfan clinic with clinical features of Marfan syndrome. We subjected all patients to a standardized diagnostic program with complete evaluation of clinical criteria listed in the Ghent nosology. For inclusion in our study, we considered only patients who fulfilled criteria of classic Marfan syndrome and echocardiographic criteria of MVP with, moderate or less MVR, as described previously. We did not consider patients with clinical criteria of neonatal Marfan or alternative syndromes of the connective tissue. Among the 668 consecutive outpatients, 113 were not residents within the 180-km area around the Hamburg University Clinic adn 254 did not fulfill criteria for classic Marfan syndrome (252 patients) or exhibited severe MVR at initial presentation (2 patients). Another 45 patients did not undergo echocardiography for follow-up. From the remaining 256 patients with classic Marfan syndrome and echocardiographic follow-up, 112 fulfilled criteria of MVP. These patients constituted our study group (49 male, 63 female; mean age 34 ± 15 years, range 2 to 67). We assessed outcome in all study patients by transthoracic echocardiography, which we performed routinely at 6- or 12-month intervals, and by a standardized phone interview to identify patients with clinical events. Three patients underwent follow-up echocardiography at only 3 months after initial echocardiography.
We assessed outcomes of MVP separately at 2 different end points ( Table 1 ). First, we considered progression of MVR as an increase of ≥1 MVR grade between baseline and follow-up echocardiography. Second, we considered MV-related clinical events with presence of clinical and echocardiographic criteria of infective endocarditis involving the MV, definitive heart failure according to established criteria, and surgery of the MV that was performed as an isolated procedure at our center for severe MVR in all patients with early timing of surgery as recommended. We also assessed other outcomes, comprising death or cerebral ischemic events, according to our previously described protocol. However, we considered for analysis only those events that were attributed unequivocally to the MV ( Table 1 ).
| Outcome | Number of Patients | Time of Event (Years) | Age at Event (Years) |
|---|---|---|---|
| Progression of MVR (study end point 1) | |||
| MVR ≥1 grade | 41 (37%) | 5.3 ± 3.7 (1–14) | 30 ± 14 (15–71) |
| MV-related clinical events (study end point 2) | |||
| MV endocarditis | 7 (6%) | 3.6 ± 2.6 (0.5–6.8) | 36 ± 15 (19–60) |
| Heart failure | 5 (5%) | 3.5 ± 2.2 (1.5–7.1) | 40 ± 7 (31–50) |
| MV replacement | 13 (12%) | 7 ± 4.6 (0.7–14.2) | 38 ± 13 (21–65) |
| MV reconstruction | 12 (11%) | 4.3 ± 3.2 (0.9–10.9) | 34 ± 12 (19–58) |
| Total number of patients with MV-related events ⁎ | 31 (28%) | 3.1 ± 3.6 (0.7–12.5) | 37 ± 12 (19–65) |
| Non-MV-related clinical events (no study end point) | |||
| Cerebral ischemic event | 3 (3%) | 1.5 ± 2.1 (0.3–3.9) | 58 ± 2.3 (56–60) |
| Sudden death | 4 (4%) | 3.3 ± 2.4 (1.2–3.3) | 36 ± 5 (31–41) |
⁎ Total numbers of patients do not add up to 37, because 5 patients experienced >1 clinical event. For analysis of outcome predictors, we considered only the first clinical event in these patients.
We assessed all variables for potential prediction of outcomes at the time of baseline echocardiography, including age, body mass index, and body surface area ( Tables 2 and 3 ). We considered active smoking as any inhaled intake of nicotine ≤7 days before echocardiography lasting ≥1 year, and we measured fasting lipid levels within 24 hours of baseline echocardiography. We estimated glomerular filtration rates according to the Modification of Diet in Renal Disease (MDRD) study. We obtained systolic and diastolic blood pressure after 15 minutes of rest using a standard sphygmomanometer, and we quantified co-morbidities in all patients. We considered previous ischemic neurologic events occurring before baseline echocardiography with documentation of cerebral infarction as defined by the persistence of a focal neurologic deficit for ≥24 hours caused by altered circulation of the cerebral hemispheres, brain stem, or cerebellum as shown on tomographic images or as transient ischemic attack, defined as focal neurologic symptoms of sudden occurrence and resolution ≤24 hours related to altered circulation of the brain. We considered a history of heart failure as documentation of New York Heart Association class III or IV or congestive heart failure according to the Framingham criteria before baseline echocardiography, and we noted atrial fibrillation using criteria on standard 12-lead standard electrocardiography or during ambulatory 24-hour electrocardiography. We performed magnetic resonance imaging to establish dural ectasia, and we considered ectopia lentis as detailed previously. We considered skeletal involvement as ≥4 manifestations of the major criteria for skeletal involvement and sporadic Marfan syndrome as the absence of a family history. We identified patients who were relatives of our index patients as family members. We considered β-blocker use as the intake of β blockers (52 patients) and other medication use as the intake of angiotensin-converting enzyme inhibitors (12 patients) or angiotensin receptor blockers (16 patients) over ≥1 year before baseline echocardiography.
| Variable | All (n = 112) | Progression of MVR | MV-Related Clinical Events | ||||
|---|---|---|---|---|---|---|---|
| Absent (n = 71) | Present (n = 41) | p Value ⁎ | Absent (n = 81) | Present (n = 31) | p Value ⁎ | ||
| Male gender | 49 (44%) | 27 (38%) | 22 (54%) | 0.1 | 30 (37%) | 19 (61%) | 0.03 |
| Age at initial evaluation (years) | 34 ± 15 | 34 ± 15 | 35 ± 15 | 0.8 | 34 ± 15 | 34 ± 14 | 0.8 |
| Body surface area (m 2 ) | 1.94 ± 0.27 | 1.98 ± 0.24 | 1.87 ± 0.3 | 0.06 | 1.92 ± 0.28 | 1.96 ± 0.25 | 0.5 |
| Body mass index (kg/m 2 ) | 20.9 ± 3.6 | 21.2 ± 3.7 | 20.6 ± 3.6 | 0.5 | 21 ± 3.9 | 20.8 ± 0.28 | 0.8 |
| Active smoking | 28 (25%) | 16 (23%) | 12 (30%) | 0.5 | 18 (22%) | 10 (33%) | 0.3 |
| Total cholesterol (mg/dl) | 184 ± 40 | 184 ± 39 | 184 ± 42 | 0.9 | 184 ± 38 | 183 ± 44 | 0.9 |
| High-density lipoprotein cholesterol (mg/dl) | 56 ± 18 | 59 ± 17 | 52 ± 17 | 0.1 | 58 ± 18 | 53 ± 17 | 0.3 |
| Low-density lipoprotein cholesterol (mg/dl) | 103 ± 33 | 101 ± 33 | 107 ± 34 | 0.4 | 103 ± 33 | 104 ± 36 | 0.9 |
| MDRD-estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 103 ± 29 | 105 ± 28 | 99 ± 31 | 0.4 | 106 ± 29 | 94 ± 27 | 0.1 |
| Systolic blood pressure (mm Hg) | 124 ± 15 | 124 ± 15 | 124 ± 16 | 0.9 | 124 ± 16 | 123 ± 15 | 0.7 |
| Diastolic blood pressure (mm Hg) | 73 ± 11 | 73 ± 12 | 72 ± 11 | 0.7 | 73 ± 12 | 73 ± 10 | 0.9 |
| Co-morbidity index | 1.21 ± 0.6 | 1.18 ± 0.5 | 1.24 ± 0.7 | 0.6 | 1.15 ± 0.4 | 1.35 ± 0.8 | 0.2 |
| Previous ischemic neurologic event | 4 (4%) | 3 (4%) | 1 (2%) | 1 | 4 (5%) | 0 | 0.6 |
| History of heart failure | 6 (5%) | 4 (6%) | 2 (5%) | 1 | 2 (3%) | 4 (13%) | 0.05 |
| Atrial fibrillation | 7 (6%) | 4 (6%) | 3 (7%) | 1 | 3 (4%) | 4 (13%) | 0.09 |
| Dural ectasia | 61 (55%) | 36 (51%) | 25 (63%) | 0.3 | 43 (54%) | 18 (58%) | 0.8 |
| Skeletal involvement | 44 (39%) | 26 (37%) | 18 (44%) | 0.5 | 29 (36%) | 15 (48%) | 0.3 |
| Ectopia lentis | 43 (38%) | 24 (34%) | 19 (46%) | 0.2 | 30 (37%) | 13 (42%) | 0.7 |
| Sporadic Marfan syndrome | 55 (49%) | 40 (56%) | 15 (37%) | 0.05 | 36 (44%) | 21 (682%) | 0.04 |
| Family member | 15 (13%) | 9 (13%) | 6 (15%) | 0.8 | 12 (15%) | 3 (10%) | 0.6 |
| β blockers | 52 (46%) | 25 (35%) | 27 (66%) | 0.003 | 32 (40%) | 20 (65%) | 0.02 |
| Other medications | 28 (25%) | 16 (23%) | 12 (29%) | 0.5 | 18 (22%) | 10 (32%) | 0.3 |
| LV ejection fraction (%) | 55 ± 11 | 56 ± 11 | 54 ± 11 | 0.3 | 57 ± 10 | 50 ± 13 | 0.006 |
| Indexed end-systolic LV diameter (mm/m 2 ) | 18 ± 5 | 18 ± 5 | 20 ± 5 | 0.04 | 18 ± 5 | 20 ± 5 | 0.04 |
| Indexed end-diastolic LV diameter (mm/m 2 ) | 29 ± 7 | 27 ± 5 | 31 ± 6 | 0.001 | 28 ± 6 | 31 ± 5 | 0.002 |
| Indexed left atrial diameter (mm/m 2 ) | 20 ± 5 | 19 ± 5 | 22 ± 6 | 0.008 | 19 ± 5 | 22 ± 6 | 0.02 |
| Aortic root ratio | 1.4 ± 0.38 | 1.35 ± 0.3 | 1.48 ± 0.49 | 0.09 | 1.41 ± 0.41 | 1.35 ± 0.3 | 0.4 |
| Ascending aorta diameter (cm) | 3.3 ± 0.9 | 3.2 ± 0.9 | 3.4 ± 0.8 | 0.5 | 3.2 ± 0.9 | 3.3 ± 0.9 | 0.7 |
| Tricuspid valve prolapse | 36 (32%) | 18 (25%) | 18 (44%) | 0.06 | 21 (26%) | 15 (48%) | 0.04 |
| Posterior leaflet prolapse | 72 (64%) | 41 (58%) | 31 (76%) | 0.07 | 45 (57%) | 27 (87%) | 0.002 |
| Anterior leaflet prolapse | 107 (96%) | 67 (94%) | 40 (98%) | 0.7 | 77 (95%) | 30 (97%) | 1 |
| Bileaflet prolapse | 69 (62%) | 38 (54%) | 31 (76%) | 0.03 | 42 (52%) | 27 (87%) | <0.001 |
| MV leaflet thickening | 13 (12%) | 8 (11%) | 5 (12%) | 1 | 7 (9%) | 6 (19%) | 0.2 |
| Flail mitral leaflet | 9 (8%) | 2 (3%) | 7 (17%) | 0.01 | 1 (1%) | 8 (26%) | <0.001 |
| Degree of MVR | 0.004 | <0.001 | |||||
| None or trivial | 38 (34%) | 29 (41%) | 9 (22%) | 36 (44%) | 2 (7%) | ||
| Mild | 47 (42%) | 32 (45%) | 15 (37%) | 32 (40%) | 15 (48%) | ||
| Moderate | 27 (24%) | 10 (14%) | 17 (42%) | 13 (16%) | 14 (45%) | ||
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