Table 1. Baseline Patient Demographic and Cardiovascular Imaging Data
Factor
|
N
|
Statistic
|
Demographics
|
|
|
Age at first scan (years)
|
30
|
21 (19 – 33)
|
Male Gender (%)
|
30
|
19 (63%)
|
White British (%)
|
30
|
20 (67%)
|
BMI (kg/m2)
|
30
|
29 (26 – 32)
|
Systolic BP (mmHg)
|
30
|
130 ± 19
|
Diastolic BP (mmHg)
|
30
|
82 ± 12
|
Heart rate (beats/min)
|
30
|
86 + 17
|
CMR
|
|
|
T1 Basal (ms)
|
30
|
937 (913-1030)
|
T1 SAX Basal ECV
|
30
|
0.27 (0.22-0.33)
|
LVEDVi (mL/m2)
|
30
|
58 ± 12
|
LVEF (%)
|
30
|
64 ± 9
|
LV mass index (g/m2)
|
30
|
55 (51 - 61)
|
LAV index (mL/m2)
|
30
|
34 (25 - 43)
|
GLS (%)
|
30
|
16 ± 3
|
Echocardiogram
|
|
|
E/A ratio
|
29
|
1.5 (1.3 - 1.6)
|
Average E/e' ratio
|
30
|
7.4 ± 2.1
|
e’ ave (cm/s)
|
27
|
9.1 (7.7 - 11.0)
|
Blood markers
|
|
|
Haemoglobin (g/L)
|
30
|
140 ± 23
|
HbA1c (mmol/mol)
|
29
|
49 (39 - 71)
|
C-peptide (pmol/L)
|
30
|
3136 (1516 - 4113)
|
Cholesterol (mmol/L)
|
30
|
4.8 ± 1.3
|
Triglycerides (mmol/L)
|
30
|
2.5 (1.7 - 4.2)
|
NT-proBNP (ng/L)
|
30
|
51 (25 - 93)
|
eGFR (mL/min/1.73 m2)
|
30
|
108 (62 - 123)
|
Comorbidities
|
|
|
Hypertension
|
30
|
17 (57%)
|
Dyslipidaemia
|
30
|
18 (60%)
|
Infantile cardiomyopathy
|
30
|
12 (40%)
|
Diabetes
|
30
|
18 (60%)
|
CKD
|
30
|
18 (60%)
|
BMI indicates body mass index; BP, blood pressure; CMR, cardiovascular magnetic resonance; E/A ratio, mitral early filling (E)/atrial filling (A) ratio; E/e’, mitral early filling (E)/early myocardial relaxation velocity (e’); ECV, extracellular volume; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; HbA1c, glycated haemoglobin A1c; IQR = interquartile range; LAV, left atrial volume; LV, left ventricular; LVEDVi, left ventricular end-diastolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end-systolic volume indexed; NT-proBNP, serum Nterminal pro B natriuretic peptide; RV, right ventricle; SAX, short axis; CKD chronic kidney disease.
Data are reported as N (%), mean±SD, or median (IQR), as applicable.
Table 2: Mutations in ALMS gene in study participants.
Mutation 1
|
Exome 1
|
Allele 1 nucleotide change
|
Allele_1 amino acid change
|
Homo/ Hetero/CH
|
Mutation 2
|
Exome 2
|
Allele 2 nucleotide change
|
Allele_2 amino acid change
|
Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Homo
|
?Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Nonsense
|
8
|
c.6823C>T
|
p.Arg2275X
|
CH
|
Nonsense
|
10
|
c.9535C>T
|
p.Arg3179X
|
Nonsense
|
8
|
c.2822T>A
|
p.Leu941X
|
CH
|
Frameshift
|
16
|
c.10775delC
|
p.Thr3592Lysfs*6
|
Frameshift
|
8
|
c.6584delA
|
p.Lys2195SerfX10
|
CH
|
Nonsense
|
5
|
c.1008_1009delTG
|
p.Cys336fsX1
|
Nonsense
|
10
|
c.8002C>T
|
p.Arg2668X
|
CH
|
Nonsense
|
16
|
c.10879C>T
|
pArg3627x
|
Nonsense
|
10
|
c.9001C>T
|
p.Gln3001X
|
Hetero
|
|
|
|
|
Frameshift
|
8
|
c.6895delG
|
p.val2299TrpsX43
|
CH
|
Frameshift
|
16
|
c.11443C>T
|
p.Gln3815X
|
Nonsense
|
16
|
11107C>T
|
p.Arg3703X
|
Hetero
|
|
|
|
|
Nonsense
|
16
|
11107C>T
|
p.Arg3703X
|
Homo
|
Nonsense
|
16
|
11107C>T
|
p.Arg3703X
|
Frameshift
|
16
|
c.10579_1580delAT
|
p.Met3527Valfs*13
|
CH
|
Frameshift
|
18
|
c.11856delC
|
p.Asn3952Lysfs*41
|
Frameshift
|
16
|
c.10769delC
|
p.Thr3590LysfsX6
|
CH
|
Missense
|
8
|
c.5356A>G
|
p.Asn1786Asp
|
Nonsense
|
16
|
c.11107C>T
|
p.Arg3703
|
Hetero
|
|
|
|
|
Nonsense
|
8
|
c.6823C>T
|
p.Arg2275X
|
CH
|
Nonsense
|
10
|
c.9535C>T
|
p.Arg3179X
|
Frameshift
|
8
|
c.1729delA
|
p.Arg577Glyfsx17
|
CH
|
Nonsense
|
16
|
c.10477C>T
|
p.Gln3493X
|
|
8
|
c6526C>T
|
p.Gln217X
|
Hetero
|
|
|
|
|
Nonsense
|
10
|
c.8932C>T
|
p.Gln2978X
|
CH
|
Missense
|
8
|
c.5356A>G
|
p.Asn1786Asp
|
Nonsense
|
8
|
c.4937C>A
|
p.Ser1646X
|
Homo
|
Nonsense
|
8
|
c.4937C>A
|
p.Ser1646X
|
Nonsense
|
8
|
c.4937C>A
|
p.Ser1646X
|
Homo
|
Nonsense
|
8
|
c.4937C>A
|
p.Ser1646X
|
Exon
|
9
|
c.7544-
|
|
Homo
|
Exon
|
9
|
c.7544-
|
|
deletion
|
200_7677+1110del
|
deletion
|
200_7677+1110del
|
Nonsense
|
8
|
c.4937C>A
|
p.Ser2646X
|
Hetero
|
Nonsense
|
8
|
c.6526C>T
|
p.Gln2176X
|
Nonsense
|
8
|
c.6299C>A
|
p.Ser2100X
|
CH
|
Nonsense
|
16
|
c.10477C>T
|
p.GIn3493X
|
Nonsense
|
8
|
c.6299C>A
|
p.Ser2100X
|
CH
|
Nonsense
|
16
|
c.10477C>T
|
p.GIn3493X
|
Stop Codon
|
16
|
c.10769delC
|
p.Thr3590LysfsX6
|
CH
|
Missense
|
16
|
c.11410C>T
|
p.Arg38404X
|
Exon
|
9
|
c.7544-
|
|
Homo
|
Exon
|
9
|
c.7544-
|
|
deletion
|
200_7677+1110del
|
deletion
|
200_7677+1110del
|
Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Homo
|
Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Homo
|
?Nonsense
|
8
|
c.2041C>T
|
p.Arg681X
|
Exon deletion
|
9
|
c.7544- 200_7677+1110del
|
|
Homo
|
Exon deletion
|
9
|
c.7544- 200_7677+1110del
|
|
Nonsense
|
16
|
c.10483C>T
|
p.Gln3495X
|
CH
|
Frameshift
|
16
|
c.10775delC
|
p.Thr3592LysfsX6
|
Nonsense
|
16
|
11107C>T
|
p.Arg3703X
|
Hetero
|
|
|
|
|
Frameshift
|
10
|
c.7911dupC
|
p.Asn2638Glnfs*24
|
Homo
|
Frameshift
|
10
|
c.7911dupC
|
p.Asn2638Glnfs*24
|
CH indicates compound heterozygote; Hetero, Heterozygote; Homo, homozygote.
Table 3. Changes over time in markers
|
No.
Patients
|
No.
Scans
|
Correlation Analysis
|
GEE Analysis
|
|
Rho
|
p-Value
|
Gradient (95% CI)
|
p-Value
|
T1 SAX Basal (ms)
|
30
|
104
|
0.415
|
<0.001
|
25.8 (20.0, 31.7)
|
<0.001
|
T1 SAX Mid (ms)
|
30
|
104
|
0.451
|
<0.001
|
21.8 (17.4, 26.1)
|
<0.001
|
T1 SAX Basal ECV
|
30
|
94
|
0.181
|
0.081
|
0.014 (0.008, 0.020)
|
<0.001
|
T1 SAX Mid ECV
|
30
|
94
|
0.192
|
0.064
|
0.011 (0.006, 0.016)
|
<0.001
|
LVEDV Index (ml/m2)
|
30
|
106
|
-0.113
|
0.247
|
0.04 (-0.60, 0.68)
|
0.909
|
LVESV Index (ml/m2)
|
30
|
106
|
-0.164
|
0.094
|
0.92 (-0.06, 1.90)
|
0.067
|
LVEF (%)
|
30
|
106
|
0.104
|
0.289
|
-0.27 (-1.23, 0.68)
|
0.575
|
LV Mass Index (g/m2)
|
30
|
104
|
0.257
|
0.008
|
2.8 (1.9, 3.7)
|
<0.001
|
LAV Biplane (ml/m2)
|
29
|
60
|
-0.221
|
0.090
|
-2.0 (-6.7, 2.7)
|
0.409
|
GLS
|
30
|
95
|
0.032
|
0.756
|
-0.04 (-0.33, 0.26)
|
0.809
|
GRS
|
28
|
86
|
0.010
|
0.924
|
-0.36 (-1.18, 0.47)
|
0.394
|
E/A
|
29
|
72
|
0.133
|
0.267
|
2.3 (-2.2, 6.9)
|
0.313
|
E/e’ Average
|
30
|
68
|
0.161
|
0.189
|
0.3 (-0.2, 0.8)
|
0.299
|
HBA1c (mmol/mol)
|
29
|
100
|
-0.116
|
0.250
|
-0.9 (-2.5, 0.7)
|
0.284
|
C-Peptide (pmol/L)
|
30
|
94
|
-0.028
|
0.788
|
-90.7 (-364.6, 183.2)
|
0.516
|
Pro NT BNP (ng/L)
|
30
|
105
|
-0.101
|
0.306
|
34.4 (-33.9, 102.8)
|
0.324
|
Correlation analysis – results are from Spearman’s rho correlation coefficients between the marker and the timing of the scan, relative to the baseline scan.
GEE analysis - results are from generalised estimating equation models, as described in the methods. The “gradient” represents the average yearly change in the marker over the period.
Bold p-values are significant at p<0.05.
E/A, mitral early filling (E)/atrial filling (A); E/e’, mitral early filling (E)/early myocardial relaxation velocity (e’); ECV, extracellular volume; HbA1c, glycated haemoglobin A1c; LAV, left atrial volume; LV, left ventricular; LVEDV index, left ventricular end-diastolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVESV index, left ventricular end-systolic volume indexed; NT-proBNP, serum Nterminal pro B natriuretic peptide; SAX, short axis.
Table 4: Associations Between T1/ECV Over Time and Changes in Myocardial Structure and Function
|
T1 SAX Mid Gradient
|
T1 SAX Mid ECV Gradient
|
Gradient in:
|
N
|
Rho
|
p-Value
|
N
|
Rho
|
p-Value
|
LVEDV Index (ml/m2)
|
26
|
0.019
|
0.927
|
24
|
-0.052
|
0.809
|
LVESV Index (ml/m2)
|
26
|
-0.444
|
0.023
|
24
|
-0.188
|
0.379
|
LVEF (%)
|
24
|
0.352
|
0.091
|
22
|
0.088
|
0.699
|
LV Mass Index (g/m2)
|
26
|
-0.056
|
0.784
|
24
|
0.203
|
0.340
|
LAV Biplane (ml/m2)
|
20
|
0.245
|
0.298
|
18
|
-0.377
|
0.123
|
GLS
|
25
|
0.422
|
0.036
|
23
|
0.024
|
0.914
|
GRS
|
23
|
0.268
|
0.217
|
21
|
0.116
|
0.618
|
E/A
|
22
|
-0.292
|
0.187
|
20
|
-0.029
|
0.905
|
E/e’ Average
|
23
|
-0.370
|
0.083
|
21
|
-0.268
|
0.241
|
HBA1c (mmol/mol)
|
24
|
-0.119
|
0.579
|
22
|
0.189
|
0.399
|
C-Peptide (pmol/L)
|
26
|
-0.101
|
0.624
|
24
|
-0.037
|
0.865
|
Pro NT BNP (ng/L)
|
26
|
-0.072
|
0.726
|
24
|
0.023
|
0.913
|
For each of the markers considered, a linear regression model was produced for each patient, with the timing of the scan, relative to the first scan, set as a continuous covariate. Only those patients with at least two valid scans for the stated marker were included in the analysis. Spearman’s (rho) correlation coefficients were then produced between the resulting gradients. Bold p-values are significant at p<0.05.
E/A, mitral early filling (E)/atrial filling (A); E/e’, mitral early filling (E)/early myocardial relaxation velocity (e’); ECV, extracellular volume; HbA1c, glycated haemoglobin A1c; LAV, left atrial volume; LV, left ventricular; LVEDV index, left ventricular end-diastolic volume indexed to body surface area; LVEF, left ventricular ejection fraction; LVESV index, left ventricular end-systolic volume indexed; NT-proBNP, serum Nterminal pro B natriuretic peptide; SAX, short axis.
Table 5 – Association between baseline factors and changes in T1/ECV
|
T1 SAX Mid
Gradient (ms per Year)
|
T1 SAX Mid ECV
Gradient (per Year)
|
|
N
|
Mean±SD
|
p-Value
|
N
|
Mean±SD
|
p-Value
|
Age at First Scan*
|
26
|
-0.137*
|
0.505*
|
24
|
0.169
|
0.430
|
Ethnicity
|
|
|
0.278
|
|
|
0.360
|
White British
|
18
|
26.3 ± 25.2
|
|
17
|
0.018 ± 0.025
|
|
Other
|
8
|
12.7 ± 35.9
|
|
7
|
0.007 ± 0.026
|
|
Gender
|
|
|
0.112
|
|
|
0.864
|
Male
|
17
|
15.5 ± 29.4
|
|
15
|
0.014 ± 0.025
|
|
Female
|
9
|
34.5 ± 24.8
|
|
9
|
0.016 ± 0.028
|
|
ACE/ARB
|
|
|
0.969
|
|
|
0.771
|
No
|
6
|
21.7 ± 56.6
|
|
5
|
0.018 ± 0.029
|
|
Yes
|
20
|
22.2 ± 16.0
|
|
19
|
0.014 ± 0.025
|
|
Statins/Fibrates
|
|
|
0.103
|
|
|
0.121
|
No
|
14
|
30.7 ± 22.5
|
|
14
|
0.021 ± 0.028
|
|
Yes
|
12
|
12.1 ± 33.1
|
|
10
|
0.005 ± 0.017
|
|
Hypertension
|
|
|
0.930
|
|
|
0.117
|
No
|
11
|
21.5 ± 35.6
|
|
10
|
0.005 ± 0.024
|
|
Yes
|
15
|
22.5 ± 24.2
|
|
14
|
0.021 ± 0.024
|
|
Hyperlipidaemia
|
|
|
0.040
|
|
|
0.989
|
No
|
11
|
35.5 ± 21.8
|
|
11
|
0.015 ± 0.022
|
|
Yes
|
15
|
12.3 ± 30.1
|
|
13
|
0.015 ± 0.028
|
|
Infantile cardiomyopathy
|
|
|
0.710
|
|
|
0.904
|
No
|
16
|
20.4 ± 33.0
|
|
15
|
0.015 ± 0.029
|
|
Yes
|
10
|
24.9 ± 22.0
|
|
9
|
0.014 ± 0.019
|
|
Diabetes
|
|
|
0.764
|
|
|
0.132
|
No
|
9
|
19.7 ± 39.3
|
|
9
|
0.005 ± 0.025
|
|
Yes
|
17
|
23.4 ± 23.0
|
|
15
|
0.021 ± 0.024
|
|
Insulin resistance (not diabetes)
|
|
|
0.752
|
|
|
0.870
|
No
|
20
|
21.1 ± 30.2
|
|
18
|
0.015 ± 0.026
|
|
Yes
|
6
|
25.5 ± 26.3
|
|
6
|
0.013 ± 0.024
|
|
CKD
|
|
|
0.889
|
|
|
0.630
|
No
|
12
|
23.0 ± 33.3
|
|
12
|
0.012 ± 0.020
|
|
Yes
|
14
|
21.4 ± 25.8
|
|
12
|
0.017 ± 0.030
|
|
Presence of CAD**
|
|
|
0.622
|
|
|
0.121
|
No
|
20
|
23.5 ± 27.5
|
|
20
|
0.010 ± 0.020
|
|
Yes
|
3
|
32.7 ± 44.7
|
|
3
|
0.034 ± 0.047
|
|
Gradients were calculated on a per-patient basis, as described in the methods, with the resulting values reported as mean±SD, and compared between groups using independent samples t-tests, unless stated otherwise. Only those patients with at least two valid scans for the stated marker were included in the analysis.
*Reported as a Spearman’s rho correlation coefficient and p-value. **Excludes N=3 patients with unknown CAD status
Bold p-values are significant at p<0.05
Table 6: Details of Seven Patients with Coronary Artery Disease or Coronary Artery Atheroma
Patient ID
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
Age
|
38
|
42
|
19
|
48
|
36
|
43
|
19
|
Gender
|
M
|
M
|
M
|
M
|
M
|
F
|
M
|
Agatston
|
PM
|
ICA
|
1
|
48
|
69
|
156
|
209
|
Findings
|
RCA Occlusion
|
PCI to LAD
|
Mild atheroma
|
Mild atheroma
|
Mild atheroma
|
Mild atheroma
|
LAD stenosis
|
LGE Pattern
|
Extensive diffuse
|
Focal epicardial
|
Mid wall LGE
|
Extensive diffuse
|
Mid wall LGE
|
Extensive diffuse
|
Focal epicardial
|
LGE territory
|
Basal infero-lateral segment , basal, mid and apical lateral and inferior RV
|
Basal inferolateral and mid inferolateral walls.
|
Basal infero-lateral segment
|
Basal inferolateral and mid inferolateral transmural in the mid and apical anterior
|
Basal inferolateral
|
Basal and mid LV levels, mid antero-lateral, mid infero-lateral, mid inferior
segments
|
Mid inferior and mid infero-lateral LV segments.
|
HTN
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
N
|
Hyperlipidaemia
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Y
|
Diabetes
|
Y
|
Y
|
IR
|
Y
|
N
|
N
|
Y
|
CKD Stage
|
2
|
5
|
0
|
2
|
1
|
1
|
2
|
Infantile CM
|
N
|
Y
|
N
|
N
|
Y
|
Y
|
Y
|
ICA, invasive coronary angiography; CKD, chronic kidney disease stage; CM, cardiomyopathy; HTN, hypertension; ID, identification number; LAD, left anterior descending; PM, Post mortem finding; N, no; Y, yes.