Baseline characteristics and comparison between Marfan syndrome patients and control subjects
Eighty-six patients with MFS (55.8% female, 36.3±14.3yr -range 13-70yr-) and 40 age- and sex-matched controls (52.5% female, 37.9±14.4yr -range 16-69yr) were included in the study. One of the study patients declined AECG (figure 1).
Twenty-four patients had undergone cardiovascular surgery at baseline (21 AoRR, 2 mitral valve surgery alone and 1 patient both). Eleven patients had moderate to severe valvular disease (5 mitral valve regurgitation, 4 aortic valve regurgitation and 1 both) of whom 7 had not undergone cardiovascular surgery. These 31 patients formed the MFS-2 group. Eight patients had previously been treated or were currently under treatment for atrial arrhythmia (4 atrial fibrillation and 4 with another type of supraventricular tachycardia) and 3 patients had been treated for symptomatic ventricular ectopia (2 medical treatment and 1 ablation). As shown in table 1 patients in the MFS-1 and MFS-2 groups did not differ significantly except for in the incidence of atrial events in their medical history. Afib in particular was more frequent in the MFS-2 group. In the control group, except for one woman of 69yrs old who had undergone coiling for a cerebral aneurysm, no one had a significant medical history. Two controls had smoked in the past, 2 were treated for arterial hypertension and 7 reported to have hyperlipidemia.
Table 1: Baseline characteristics of the patients with Marfan syndrome
Parameter
|
MFS-1 (N=55)
|
MFS_2 (N=31)
|
p-value
|
Female (%)
|
31 (56.4)
|
17 (54.8)
|
0.891
|
Age
|
35.07±14.7
|
38.5±13.7
|
0.295
|
FBN1 variant type (%)
|
|
|
0.296
|
|
Missense
Frameshift
Nonsense
Splice-site
|
29 (53.7)
13 (24.1)
9 (16.7)
2 (28.6)
|
13 (41.9)
7 (35)
6 (19.4)
5 (71.4)
|
|
|
De novo (%)
|
17 (30.9)
|
8 (26.7)
|
0.682
|
Systemic score a
|
8.02±3.3
|
8.7±3
|
0.401
|
EL (%)
|
25 (48.1)
|
21 (70)
|
0.149
|
|
AoRR (%)
|
0
|
22 (71)
|
n.a
|
|
Valve sparing (%)
Valve replacement (%)
|
|
16 (72.7)
6 (27.3)
|
|
|
MVP (%)
|
|
|
0.393
|
|
|
|
Bulging
Prolapse
|
17 (52.8)
8 (15.1)
|
7 (23.3)
8 (26.7)
|
|
|
MV surgery (%)
|
0
|
3 (9.3)
|
n.a
|
|
|
Valvuloplasty and ring (%)
Bioprosthesis (%)
Mechanical valve (%)
|
|
1
1
1
|
|
|
Atrial arrhythmia (%)b
|
|
|
0.016*
|
|
|
Afib (%)
Other SVT (%)
|
0
2 (3.6)
|
4 (12.9)
2 5 (6.4)
|
|
|
Symp. VE (%)b
|
1
|
2
|
0.261
|
Treatment
|
|
|
0.206
|
|
|
None (%)
BB alone (%)
ARB alone(%)
ACEi alone (%)
BB+ARB (%)
BB+ACEi (%)
|
16 (29.1)
19 (34.5)
6 (10.9)
1 (1.8)
13 (23.6)
0
|
3 (9.7)
16 (51.6)
3 (9.7)
0
8 (25.8)
1 (3.2)
|
|
|
BMI≥25kg/m² (%)
|
13 (23.6)
|
7 (23.3)
|
0.365
|
Smoking (%)
|
|
|
0.979
|
|
Never
Ex-smoker
Current
|
38 (69.1)
11 (20)
6 (10.9)
|
22 (71)
6 (19.4)
3 (9.7)
|
|
AHT (%)
|
6 (10.9)
|
2 (6.5)
|
0.494
|
Hyperlipidaemia (%)
|
5 (9.1)
|
3 (9.7)
|
0.844
|
Diabetes (%)
|
3 (5.5)
|
0
|
0.186
|
a Marfan systemic score is a scoring system which takes into consideration several characteristic features of MFS and assigns each of them a value between 1-3, 3 being the most specific for the disease. A score of ≥7 is considered abnormal and in combination with aortic disease and/or ectopia lentis is diagnostic of MFS
b Patients reporting palpitations in the past were not included. Only confirmed atrial and ventricular ectopy for which treatment was implemented were considered
Abbreviations: ACEi: angiotensin converting enzyme inhibitor, Afib: atrial fibrillation, AoRR: aortic root replacement, ARB: angiotensin II receptor blocker antagonist, BB: beta-blocker, BMI: body mass index, EL: ectopia lentis, HTA: arterial hypertension, MV: mitral valve, MVP: mitral valve prolapse, SVT: supraventricular tachycardia, VE: ventricular ectopy.
As shown in table 2, while 7 (8.1%) of the patients with MFS had mildly decreased LVEF (5 in the MFS-2 group), decreased LVEF was no present in control subjects.
Demographic characteristics in the group with decreased LVEF were similar to the rest of the MFS cohort (supplemental table 1). Median LVEF in this group was 53.1% (IQR 47.1-53.7%). As expected, LVEDDi and LVESDi were significantly higher in patients with decreased LVEF (28.2±3.5mm/m² versus 25.3±3.5mm/m², p=0.038 and 21.7±2.6 mm/m² versus 16.6±2.7mm/m², p<0.001, respectively). Nine patients (10.5%) had a TAPSE value ≤16mm (6 in the MFS-2 group).
Table 2: Comparison between control subjects and patients with Marfan syndrome with and without valvular disease and/or cardiovascular surgery
|
Control subjects
|
patients with Marfan syndrome
|
p-value
|
p-value
|
N=40
|
No surgery
No valvular disease
N=55 (MFS-1)
|
Surgery
Valvular disease
N=31 (MFS-2)
|
Control vs
MFS-1
|
MFS-1
vs
MFS-2
|
Female (%)
|
22 (55)
|
31 (56.4)
|
17 (54.8)
|
0.895
|
0.891
|
Age (%)
|
37.9±14.4
|
35.1±14.7
|
38.5±13.7
|
0.370
|
0.295
|
Height (cm)
|
173±10
|
183.2±11
|
183.9±9.5
|
<0.001
|
0.771
|
Weight (kg)
|
68.3±9.2
|
74.2±17.9
|
74.1±18.3
|
0.041
|
0.987
|
BSA (m²)
|
1.8±0.1
|
1.9±0.2
|
1.9±0.2
|
0.001
|
0.923
|
SBP (mmHg)
|
121.1±12.7
|
121±12.6
|
127.3±15.9
|
0.899
|
0.049
|
DBP (mmHg)
|
73.7±9.6
|
71.6±70
|
67±10.1
|
0.361
|
0.067
|
BB Use (%)a
|
0 (0)
|
32 (58.2)
|
25 (80.6)
|
n.a
|
0.034
|
|
Ao sinus (mm)
|
30.5±2.9
|
39.8±5.1
|
41.1±6.6b
|
<0.001
|
0.498
|
z-score sinus
|
-0.8±0.7
|
2.5±1.4
|
3.3±1.1b
|
<0.001
|
0.094
|
LVEDDi (mm/m²)
|
24.7±2.4
|
24.8±3.4
|
26.7±3.5
|
0.795
|
0.020
|
LVEDDi≥30mm/m² (%)
|
0 (0)
|
5 (9.1)
|
4 (12.9)
|
0.050
|
0.717
|
iLVM
|
86.9±20.2
|
81±34.7
|
86.2±23.04
|
0.331
|
0.486
|
LVEF (%)
|
68.3±7.2
|
66±7.2
|
62.5±7.6
|
0.131
|
0.034
|
LVEF<55%
|
0 (0)
|
2 (3.6)
|
5 (16.1)
|
0.507
|
0.093
|
mw-FS (%)
|
21±7
|
21±5
|
16±6
|
0.778
|
0.004
|
RWT
|
0.45 (0.40-0.50)
|
0.37 (0.32-0.45)
|
0.33 (0.29-0.40)
|
<0.001
|
0.060
|
E/A
|
1.5 (1.2-2)
|
1.6 (1.3-2)
|
1.6 (1.2-2.1)
|
0.351
|
0.975
|
E/E’
|
6.4 (5.1-7.6)
|
7.8 (6.6-9.3)
|
8.6 (7-12.8)
|
<0.001
|
0.051
|
LAVi (ml/m²)
|
21.2±5.5
|
21.4±1.3
|
26.4±11.3
|
0.945
|
0.038
|
MVP (%)c
|
1 (2.5)
|
8 (14.5)
|
8 (26.7)
|
0.045
|
0.185
|
TAPSE (mm)
|
24.5±2.8
|
22.1±4.3
|
19.5±3.8
|
0.003
|
0.010
|
TAPSE ≤16mm (%)
|
0 (0)
|
3 (6.4)
|
6 (20.7)
|
0.250
|
0.077
|
|
NT-ProBNP (pg/ml)
|
30 (19-44.5)
|
53.5 (30-74.2)
|
129 (82-235.2)
|
0.001
|
<0.001
|
|
Min HR (bpm)
|
50.5 (44-55.5)
|
45 (41.5-49)
|
48 (44-55)
|
0.004
|
0.026
|
Average HR (bpm)
|
74.2±8.3
|
64 (56.5-71.5)
|
67 (58.5-73)
|
<0.001
|
0.205
|
QRS width (ms)
|
80 (80-90)
|
96 (86-104)
|
98 (86-106)
|
<0.001
|
0.639
|
QTc (ms)
|
380.2±24.5
|
414 (388-433.5)
|
426 (407-445)
|
<0.001
|
0.028
|
QTc>460ms (%)
|
0 (0)
|
0 (0)
|
4 (12.9)
|
n.a
|
n.a
|
SVES/24h
|
2 (0.25-4.7)
|
7 (2-37.5)
|
17 (1-56)
|
<0.001
|
0.560
|
Atrial runs (%)
|
2 (5)
|
14 (26.4)
|
12 (41.4)
|
0.015
|
0.318
|
VES/24h
|
0 (0-5.7)
|
6 (1-69.5)
|
14 (1.5-373.5)
|
<0.001
|
0.312
|
VE (%)
|
5 (12.5)
|
14 (26.4)
|
13 (41.9)
|
0.099
|
0.090
|
Vent couplets (%)
|
2 (5)
|
9 (17)
|
8 (25.8)
|
0.077
|
0.270
|
NSVT (%)
|
0 (0)
|
5 (9.1)
|
5 (17.2)
|
0.050
|
0.273
|
SDNN (ms)
|
147 (116-185.2)
|
185 (156.2-219.2)
|
132 (95.4-191)
|
0.001
|
0.003
|
RMSDD (ms)
|
53 (36.2-84)
|
82.5 (66.2-82.5)
|
59.3 (42.7-112)
|
<0.001
|
0.040
|
Values are given as mean ±SD, median (IQR) or number (%)
a Beta-blocker alone or in combination
bOnly those patients with valvular pathology without aortic root replacement are considered for the mean value of the sinus and the z-score.
c Only those patients with true mitral valve prolapse considered here. Those with mitral valve bulging were not included in this calculation.
Abbreviations: Ao: aortic, BB: beta-blocker, BSA: Body surface area, DBP: Diastolic blood pressure, Dec Time: Deceleration time, HR: Heart Rate, LAVi: left atrium volume index, LVEDDi: Left ventricular end diastolic diameter index, LVEF: Left ventricular ejection fraction, MFS: Marfan syndrome, MVP: mitral valve prolapse, mw-FS: Mid-wall fractional shortening, NSVT: Non-sustained ventricular, RMSDD: mean squared difference of successive NN intervals, RWT: Relative wall thickness, SBP: Systolic blood pressure, SDNN: Standard deviation of the NN interval, SVES: Supraventricular extrasystoles, VES: Ventricular extrasystoles, TAPSE: Tricuspid annular plane systolic excursion, VE: ventricular ectopy.
To assess whether myocardial involvement in MFS has a primary component, we compared control subjects with those MFS-1 patients without previous surgery or valvular disease. As shown in table 2, mild biventricular myocardial involvement in MFS-1 was evidenced by significantly higher NT-proBNP, left ventricular dimension, E/Em ratio and lower RWT and TAPSE. Furthermore, MFS-1 patients showed longer QRS-duration and QTc time at rest ECG. NSVT only occurred in patients with MFS. SDNN and RMSDD were significantly higher in MFS-1 even after adjusting for beta-blocker use (p=0.008 and p=0.027, respectively).
In comparison to MFS-1 patients, MFS-2 patients showed significantly larger left ventricular dimensions, lower left ventricular ejection fraction, mw-FS and TAPSE, higher NT-proBNP and longer QTc time. QTc time was abnormal (>460ms) in 4 patients in the MFS-2 group. Systolic blood pressure was also slightly but significantly higher in MFS-2 patients (table 2). SDNN and RMSDD were significantly lower in MFS-2 and similar to the control population.
Events during follow-up and AECG characteristics in subsequent examinations
All patients except 4 completed the study (one patient died and 2 patients declined further participation after visit 1 and one patient could not attend the last visit -figure 1-).
During a follow-up period of 30±7months 3 patients died from (suspected) aortic dissection or rupture (2 type A and 1 type B). Two of them died just after completing the 3rd visit (figure 1). Four other patients survived a dissection (1 coronary dissection, 1 type B dissection and 2 type A dissections). Prophylactic AoRR was performed in 6 patients and aortic valve replacement with mechanical prosthesis in an additional patient who had previous AoRR.
As shown in supplemental table 2, LVEDD and LVEF remained stable during the study follow-up. There were no patients showing heart failure symptoms during follow-up.The overall amount of VES on 24h AECG in patients with MFS at baseline was low (7.5 VES/24h IQR 1-98). However, 20 patients (23.3%) showed NSVT on one or more of the 24h AECG (10 at the 1st exam, 10 additionally during the 2 consecutive exams). 80% of these patients was under treatment with a beta-blocker (table 3). Only one patient in this group, showed sustained VT during follow-up. He was 30yrs old at the time of the first sustained VT episode and had had AoRR and MV surgery 4 months earlier. An ICD was implanted and showed recurrent episodes of VT under beta-blocker therapy. VT was only controlled with amiodarone therapy. No patients in the study developed SCD or arrhythmogenic syncope during the study period.
To identify factors associated with NSVT we compared the 20 patients having NSVT with the rest of the MFS cohort. Univariate analysis showed that LVEDDi, LVESDi, NT-proBNP and the amount of VES/24h were significantly higher in the group with NSVT (Table 3). Furthermore, NSVT during follow-up occurred more frequently in the MFS-2 group than in the MFS-1 group (40% versus 14.5%, p=0.008). In multivariate analysis, however, only LVEDDi and VES/24h were independently associated with NSVT (figure 2). These 2 variables were associated with NSVT independently from each other.
Table 3: Comparison between patients with and without non-sustained ventricular tachycardia
|
Non-sustained ventricular tachycardia
|
|
Present (n=20)
|
Absent (n=65b)
|
p-value
|
Female (%)
|
10 (50)
|
37 (59.7)
|
0.604
|
Age (yrs)
|
40.3±15.7
|
35.2±13.8
|
0.170
|
BSA (kg/m²)
|
21.3 (19-25.5)
|
21.4 (18.6-24.8)
|
0.821
|
SBP (mmHg)
|
124.3±12.8
|
122.1±14.5
|
0.549
|
DBP (mmHg)
|
67.7±5.7
|
70.1±10.9
|
0.365
|
BB Use (%)
|
16 (80)
|
39 (62.9)
|
0.157
|
MFS systemic scorea
|
8 (4-11)
|
8 (6-10)
|
0.657
|
MFS group
|
|
|
0.008
|
|
MFS-1 (N=55) (%)
|
8 (40)
|
47 (72.3)
|
|
|
MFS-2 (N=30b) (%)
|
12 (60)
|
18 (27.7)
|
|
Cardiac ultrasound
|
Ao sinus (mm)
|
39.9±4.3
|
40.1±5.6
|
0.906
|
MVP (%)
|
7 (35)
|
9 (15.3)
|
0.058
|
LVEDDi (mm/m²)
|
27.9±3.6
|
24.8±3.2
|
<0.001
|
LVESDi (mm/m²)
|
18.4±3.
|
16.7±2.7
|
0.028
|
LVEF (%)
|
63.6±8.2
|
65.2±7.4
|
0.419
|
Mw-FS (%)
|
21±9
|
19±6
|
0.344
|
RWT
|
0.36 (0.31-0.44)
|
0.35 (0.29-0.40)
|
0.354
|
RVOTi (mm/m²)
|
15.9±2.4
|
15.4±2.7
|
0.476
|
TAPSE (mm)
|
20.8±3.7
|
21.7±4.2
|
0.448
|
LAVi (mm/m²)
|
24.2 (14-29.2)
|
21.2 (15.2-28.6)
|
0.854
|
E/A ratio
|
1.6±0.6
|
1.7±0.6
|
0.723
|
E/Em ratio
|
9.5 (7.1-11.7)
|
7.8 (6.6-9.7)
|
0.100
|
Serologic test
|
NT-ProBNP (pg/ml)
|
112 (78.5-216.5)
|
60 (31-129)
|
0.017
|
Ambulatory ECG
|
Min HR (bpm)
|
47 (42-51)
|
46 (42.2-50)
|
0.792
|
Average HR (bpm)
|
67 (58-72)
|
65.5 (57.2-72.7)
|
0.991
|
Max HR (bpm)
|
122 (100-133)
|
120.5 (101-142)
|
0.684
|
QRS width (ms)
|
100 (90.5-109.5)
|
96 (82.5-101.5)
|
0.075
|
Qtc time (ms)
|
426 (403-443.2)
|
413 (385.2-432)
|
0.199
|
VES/24h
|
345 (9-3727)
|
4 (1-35)
|
0.001
|
SDNN (ms)
|
177 (126.1-264.6)
|
176 (140-203.5)
|
0.620
|
RMSDD (ms)
|
74 (58-159.9)
|
79.5 (57.9-109)
|
0.790
|
Values are given as mean ±SD, median (IQR) or number (%)
a MFS systemic score is a scoring system which takes into consideration several characteristic features of MFS and assigns each of them a value between 1-3, 3 being the most specific for the disease. A score of ≥7 is considered abnormal and in combination with aortic disease and/or ectopia lentis is diagnostic of MFS.
b One patient declined 24h AECG
Abbreviations: Ao: aortic, AoRR: Aortic root replacement, AR: Aortic regurgitation, BB: Beta-blocker, BSA: Body surface area, DBP: Diastolic blood pressure, ECG: Electrocardiogram, HR: Heart Rate, LAVi: left atrium volume index, LVEDDi: Left ventricular end diastolic diameter index, LVESDi: Left ventricular end systolic diameter index, LVEF: Left ventricular ejection fraction, LVMi: Left ventricular mass index, MFS: Marfan syndrome, MR: Mitral regurgitation, MV: Mitral valve, MVP: Mitral valve prolapse, mw-FS: Mid-wall fractional shortening, NSVT: Non-sustained ventricular, RAVi: Right atrium volume index, RMSDD: mean squared difference of successive NN intervals, RVOT: Right ventricular outflow track, RWT: relative wall thickness, SBP: Systolic blood pressure, SDNN: Standard deviation of the NN interval, SVES: Supraventricular extrasystoles, TAPSE: Tricuspid, annular, plane systolic excursion, VES: Ventricular extrasystoles.
Other factors such as the presence of MVP or increased E/Em ratio tended to be higher in the group with NSVT but was not statistically significant. We could not identify variables on the resting ECG or parameters of HRV associated with the presence of NSVT.
At baseline patients in the MFS-2 group had significantly higher amounts of atrial events (SVT or Afib) in their medical history compared to patients in the MFS-1 group. Although baseline AECG showed higher amounts of supraventricular extrasystoles and atrial runs in the MFS-1 group compared to controls, the prevalence of these events was similar between both MFS groups, as shown in table 1. During follow-up 4 patients presented Afib, 2 in the MFS-1 group and 2 in the MFS-2 group. A description of clinical characteristics of these patients can be found in the supplemental table 3’.
Seven patients were under treatment for thyroid disease during the study period (6 women for hypothyroidism with levothyroxine and 1 male for hyperthyroidism with thiamazole). Within the patients with hypothyroidism, one had NSVT during FU and one a history of Afib. All other patients, except for 1 with slightly elevated TSH (5.4mU/l), had normal values (reference value in our institution 0.4-4mU/l). This patient showed no arrhythmic events on his three AECGs.
Genotype-phenotype correlations
As shown in table 4, the presence of NSVT was not associated with a specific type of FBN1 variant. We observed, however, that those patients carrying a missense variant tended to have less arrhythmia. Four out of the 7 patients (57.1%) with decreased LVEF carried a frameshift variant. This was significantly higher than in the group with normal LVEF (20.5%, p=0.050). No other genotype-phenotype correlations were found.
Table 4: Comparison of the genotype between patients with and without arrhythmia and with normal or decreased ejection fraction
|
Non-sustained ventricular tachycardia
|
Left-ventricular ejection fraction
|
Present
(n=20)
|
Absent
(n=64)a
|
p-value
|
<55%
(n=7)
|
|
p-value
|
Type of variant
|
|
|
Missense (%)
|
7 (35)
|
35 (54.7)
|
0.100
|
1 (14.3)
|
41 (52.6)
|
0.058
|
Inframe (%)
|
1 (5)
|
0 (0)
|
0.238
|
0 (0)
|
1 (10.3)
|
0.918
|
Frameshift (%)
|
5 (25)
|
14 (21.9)
|
0.494
|
4 (57.1)
|
16 (20.5)
|
0.050
|
Nonsense (%)
|
4 (20)
|
11 (17.2)
|
0.747
|
0 (0)
|
15 (19.2)
|
0.243
|
Splice-site (%)
|
3 (15)
|
4 (6.3)
|
0.349
|
2 (28.6)
|
5 (6.4)
|
0.100
|
Effect on the protein
|
|
|
Haploinsufficiency (%)
|
9 (45)
|
24 (37.5)
|
0.128
|
4 (57.1)
|
30 (38.5)
|
0.283
|
Localization: exon
|
|
|
Exon 24-32 (%)
|
2 (10)
|
8 (12.5)
|
0.559
|
0 (0)
|
10 (12.8)
|
0.402
|
Values are given as number (%)
a Variant details were lacking in one patient. Another patient declined ambulatory ECG