Methods

From January 1, 1997 to June 30, 2009, 549 patients presented to our joint pediatric and adult Marfan clinic with varying clinical features of the Marfan syndrome. All patients underwent our standardized diagnostic program, with a complete evaluation of the clinical criteria as listed in the Ghent nosology. For inclusion in our study, we only considered those who fulfilled the criteria of classic Marfan syndrome. Of the 549 consecutive outpatients, 101 were not residents within the 180-km area around the Hamburg University Clinic and another 244 did not fulfill the criteria for classic Marfan syndrome. The remaining 204 patients constituted our study group ( Table 1 ).

We used our previously described routines to establish the diagnosis of Marfan syndrome according to the Ghent criteria. In 78 patients, we identified FBN1 mutations to corroborate the clinical diagnosis of Marfan syndrome. We did not consider those with neonatal Marfan syndrome (defined as the diagnosis of type I fibrillinopathy with severe valvular involvement before 4 weeks of age ) because the natural history is different from that of classic Marfan syndrome. We used 2-dimensional echocardiography to measure the diameters of the aortic root from cross-sectional echocardiographic images in the parasternal long-axis orientation, and we documented aortic root dilation with measurements >95% confidence interval (CI) for the sinus of Valsalva diameter versus the body surface area. We also considered aortic root dilation in the presence of previously performed surgery of the aortic root. We performed magnetic resonance imaging to establish dural ectasia, and we considered ectopia lentis with any displacement of the lenses on slit-lamp examination under full pupillary dilation or with documentation of previously performed surgery for ectopia lentis. We considered skeletal involvement with ≥4 manifestations of the major criteria for skeletal involvement listed in the Ghent nosology. Sporadic Marfan syndrome was considered present in the absence of a family history for all patients without a parent, child, or sibling independently fulfilling the Ghent criteria. We could not obtain the family history for 2 patients. We identified persons who were relatives of our index patients as family members ( Table 1 ).

Standard M-mode, 2-dimensional, and color-coded transthoracic echocardiography was performed by board-certified cardiologists with ≥6 years of experience in echocardiography to assess MV dysfunction in all patients. We documented the imaging results at baseline and during follow-up with assessment of all data by those who were unaware of the clinical information and final diagnoses and with an averaging of all measurements for 5 cardiac cycles. We diagnosed tricuspid valve prolapse on 2-dimensional echocardiography, and MVP in the presence of any late systolic prolapse >2 mm on M-mode echocardiography or on 2-dimensional echocardiography from the parasternal long-axis view and the apical 4-chamber view as leaflet displacement >2 mm, irrespective of a leaflet thickness of ≥5 mm. We used ≥2 of the following 3 validated methods to quantify MVR. First, we measured the vena contracta at the narrowest central flow region of the regurgitant jet to classify MVR as mild (<0.3 cm), moderate (0.3 to 0.69 cm), or severe (≥0.7 cm). Second, we used the proximal isovelocity surface area method to measure the effective regurgitant orifice area to grade MVR as mild at <0.20 cm ² , moderate at 0.20 to 0.39 cm ² , and severe at ≥0.4 cm ² . Finally, we assessed the regurgitant volume to grade MVR as mild at <30 ml/beat, moderate at 30 to 59 ml/beat, and severe at ≥60 ml/beat. We resolved incongruent grading by both assessing additional supportive signs and quantitative parameters of MVR and re-evaluating our measurements jointly with 2 additional echocardiographers using a consensus method. We performed transesophageal echocardiography to confirm all findings of severe MVR. We applied current clinical and echocardiographic criteria to diagnose infective endocarditis of the native MV ( Table 2 ).

We documented the age of each patient at which the criteria of MV dysfunction were initially fulfilled. In addition to baseline echocardiography at our institution, we evaluated the original reports and, when available, the original recordings of the echocardiographic examinations for the presence of these criteria in all patients who had undergone echocardiography ≥3 months before the first evaluation at our center. In all 14 patients, these investigations complied with our standards, and we considered the findings from these echocardiograms to be the baseline examination findings. For follow-up, we derived the criteria of MV dysfunction from the echocardiographic findings, which we performed routinely at 6- or 12-month intervals. In addition, we performed a standardized telephone interview to identify those who had undergone surgery for severe MV regurgitation or with endocarditis who had been treated outside our center. A total of 30 patients did not undergo follow-up echocardiography, because they presented to our center exclusively for corroboration of the Marfan syndrome (n = 14), they did not complete the interval for their next follow-up echocardiogram (n = 6), they died of causes unrelated to MV dysfunction (n = 3), or they did not respond to our letters or telephone calls (n = 7).

We used the survival analysis technique to assess the cumulative distribution [1 − S(t)] of MV dysfunction. Cases were left-censored for the presence of MV dysfunction on the initial echocardiogram. Cases were right-censored for the absence of MV dysfunction on both the initial and follow-up echocardiograms. All subjects who developed MV dysfunction during follow-up were interval-censored, because we assumed that MV dysfunction had developed in the middle of the interval. We assessed MV dysfunction as the presence of (1) MVP, (2) MVR of any degree (mild to severe), (3) severe MVR, or (4) MV endocarditis. We documented all 4 criteria in all patients separately during the whole follow-up period. We assessed the event time as the age at which we observed the criteria for MV dysfunction, and we considered the end point as the estimated cumulative distribution of having fulfilled the criteria for MV dysfunction. Because we used no covariates, we fitted an intercept-only parametric model, assuming the outcome followed a Weibull distribution. The estimated cumulative distribution of events was 1 − S(t) = 1 − (e ^−λ*tb ), where S(t) is the survival time distribution, t corresponds to the patient’s age, with an event, λ, to a scale parameter, and b to a shape parameter. A b >1 indicated that the event rate increased and b <1 that the event rate decreased with age. All p values were 2-sided, and we considered p <0.05 as statistically significant. Unless otherwise specified, quantitative data are presented as the mean ± SD and qualitative data as numbers (percentage). We compared groups using Fisher’s exact test. We used the KM-Explorer software, release 02.82.04 (Trinovis GmbH, Hannover, Germany), to assess the number of residents within the 180-km area around our center using data derived from the Statistisches Bundesamt 2009. We used Stata, version 9 (StataCorp, College Station, Texas) to fit the Weibull model and the Statistical Package for Social Sciences software, release 17.0.0 (SPSS Statistics for Windows, SPSS, Chicago, Illinois), for all other tests.

Results

We identified 448 subjects with Marfan-like features from 9,399,322 inhabitants within a 180-km area around our center, corresponding to a prevalence of 0.48 in 10,000. We diagnosed the Marfan syndrome in 204 of the 448 subjects. We performed echocardiographic follow-up for 174 patients during a mean of 4.4 ± 4.3 years. The mean patient age was 31.2 ± 16.4 years (range 0 to 77.4) at the initial echocardiographic examination and 35.5 ± 16.7 years (range 3.4 to 78.3) at the final echocardiographic examination ( Table 1 ). Table 2 lists the presence of MVP, grade of MVR, and presence of endocarditis of the native MV for all 204 study patients at the initial echocardiographic study and for the 174 patients with follow-up echocardiographic studies. On the initial or final echocardiographic study, MVP was present in 82 patients (40%), severe MVR in 25 (12%), and MV endocarditis in 5 patients (2.5%). At 30 years of age, the estimated cumulative distribution was 42.6% for MVP (95% CI 36% to 50%), 56.5% (95% CI 49.3% to 64%) for MVR of any degree (mild to severe), 6.7% (95% CI 3.9% to 11.3%) for severe MVR, and 0.92% (95% CI 0.21% to 3.91%) for MV endocarditis. Figures 1 and 2 show and Table 3 lists the estimated cumulative distribution [1 − S(t)] for MV dysfunction for all ages 1 to 80 years. MVP was associated with dural ectasia (p = 0.01), ectopia lentis (p = 0.02), and skeletal involvement (p <0.001). In contrast, severe MVR was related to tricuspid valve prolapse (p = 0.002; Table 4 ) and the sporadic form of the Marfan syndrome (p = 0.006).

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