Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease

Figures & data

Figure 1. MMP-2, MMP-3, MMP-9 and TIMP-1 values were comparable among the diagnostic groups.

Table 1. Characteristics of study population (n = 425).

Variable	Mean ± SD, median [IQ^1–IQ^3] or n (%)	Surgical repair/intervention, n (%)
Age, years	33.3 [25.9–42.1]
Sex, male n (%)	244 (57)
Diagnosis, n (%)
Tetralogy of Fallot	167 (39)	167 (100)
Congenital aortic stenosis	112 (26)	80 (71)
Aortic coarctation	40 (10)	39 (98)
TGA corrected by atrial switch	60 (14)	60 (100)
TGA corrected by arterial switch	18 (4)	18 (100)
Congenitally corrected TGA	18 (4)	9 (50)
Univentricular heart (Fontan)	10 (3)	10 (100)
Age at surgical repair/intervention, years	3.9 [0.8–11.9]
Systolic blood pressure, mmHg	125 ± 16
Diastolic blood pressure, mmHg	79 ± 11
Heart rate, beats/min	74 ± 14
Saturation <90%, n (%)	9 (2)
Cardiac medication, n (%)
ACE-inhibitor	61 (14)
Angiotensin receptor blocker	21 (5)
Betablocker	58 (14)
Diuretics	44 (10)
NT-proBNP, pmol/L	16.6 [7.9–34.3]
NYHA functional class, II–III n (%)	40 (9)

TGA: transposition of the great arteries; ACE: angiotensin converting enzyme; NT-proBNP: N-terminal brain natriuretic peptide; NYHA: New York Heart Association.

Figure 2. Scatterplots demonstrating the correlation of MMP-2 with peak workload %, peak oxygen uptake and carbon dioxide equivalent.

Table 2. Univariable associations (Pearson's correlation, n = 425).

Variable	^10log MMP-2	^10log MMP-3	^10log MMP-9	^10log TIMP-1
Patient characteristics
Age, years	0.027	0.093	−0.049	−0.063
Sex, male	0.066	−0.151**	0.086	−0.011
Body Surface Area, m^2	−0.173**	0.073	−0.137**	0.048
Diagnosis: systemic right ventricle	0.009	−0.018	−0.043	0.097*
Surgical repair	0.080	−0.039	−0.069	0.005
Systolic blood pressure, mmHg	−0.083	0.067	−0.022	0.077
Diastolic blood pressure, mmHg	−0.100*	0.017	−0.111*	0.051
Heart rate, beats/min	0.042	−0.018	−0.012	0.003
Saturation <90%	0.136**	0.073	0.104*	0.074
Use of ARB	−0.006	0.054	0.110*	0.038
^10log NT-proBNP	0.147**	0.035	0.081	−0.004
NYHA functional class, II–III	0.102*	0.064	−0.018	−0.034
Exercise testing
Peak heart rate, % of target (n = 126)	−0.205*	−0.024	0.001	−0.088
Peak workload, % of target (n = 126)	−0.233**	0.032	−0.080	−0.047
Peak oxygen uptake, mL/min (n = 40)	−0.411**	0.004	−0.350*	−0.038
Peak oxygen uptake, % of target (n = 40)	−0.230	−0.141	−0.056	−0.119
Carbon dioxide equivalent (n = 40)	0.396*	0.214	0.270	0.148
Echocardiography
LV end-diastolic dimension, mm	−0.100	0.005	−0.072	0.022
Aortic STJ end-diastolic diameter, mm	0.056	0.070	−0.051	−0.085
Aortic valve peak velocity, m/s	−0.110*	−0.001	0.045	−0.040
Interventricular septum, mm (PLAX)	−0.028	0.092	−0.010	−0.020
RV end-diastolic annulus, mm	0.069	0.071	0.003	0.022
RV end-diastolic area, cm^2	0.061	0.065	−0.009	0.087
RV end-systolic area, cm^2	0.096	0.061	0.002	0.078
Systolic function
LV ejection fraction, %	−0.065	−0.027	0.050	−0.057
LV systolic dysfunction, 0–1	0.102*	0.093	−0.073	0.011
RV fractional area change, %	−0.112	−0.017	−0.019	−0.022
RV systolic dysfunction, 0–1	0.115*	0.047	−0.039	0.018
TAPSE, mm	0.017	0.079	0.081	−0.018
LV diastolic function
E/A ratio	0.012	−0.044	0.049	0.019
E' wave <8 cm/s	0.132*	0.050	−0.014	0.002
E/E' ratio ≥13	0.128*	0.103	0.051	−0.033
Deceleration time, ms	−0.137*	−0.085	0.017	−0.061

MMP: matrix metalloproteinase; TIMP: tissue inhibitor of matrix metalloproteinase; ARB: angiotensin receptor blocker; NT-proBNP: N-terminal brain natriuretic peptide; NYHA: New York Heart Association; LV: left ventricular; STJ: sinotubular junction; PLAX: parasternal long-axis view; RV: right ventricular; TAPSE: tricuspid annular plane systolic excursion.

*p < 0.05,

**p < 0.01.

Table 3. Unstandardised B-coefficients of ¹⁰log MMP-2 values; analysed using linear (for continuous outcome) or logistic regression (for categorical outcome), n = 425.

	Adjusted for age, sex, BSA
	β	p Value
NYHA functional class, II–III	0.57	0.152
Exercise testing
Peak heart rate, % of target (n = 126)	−5.08	0.046
Peak workload, % of target (n = 126)	−11.86	0.007
Peak oxygen uptake, mL/min (n = 40)	−238.7	0.175
Peak oxygen uptake, % of target (n = 40)	−12.79	0.046
Carbon dioxide equivalent (n = 40)	3.69	0.117
Echocardiography
LV end-diastolic dimension, mm	−0.78	0.362
Aortic STJ end-diastolic diameter, mm	1.80	0.098
Aortic valve peak velocity, m/s	−0.26	0.074
Interventricular septum, mm (PLAX)	−0.00	0.997
RV end-diastolic annulus, mm	2.24	0.051
RV end-diastolic area, cm^2	3.40	0.025
RV end-systolic area, cm^2	3.49	0.010
Systolic function
LV ejection fraction, %	−1.64	0.410
LV systolic dysfunction, 0–1	1.00	0.040
RV fractional area change, %	−3.99	0.036
RV systolic dysfunction, 0–1	0.67	0.027
TAPSE, mm	0.39	0.627
LV diastolic function
E/A ratio	0.03	0.735
E' wave <8 cm/s	0.56	0.107
E/E' ratio ≥13	0.51	0.129
Deceleration time, ms	−22.33	0.009

MMP: matrix metalloproteinase; TIMP: tissue inhibitor of matrix metalloproteinase; ARB: angiotensin receptor blocker; NT-proBNP: N-terminal brain natriuretic peptide; NYHA: New York Heart Association; LV: left ventricular; STJ: sinotubular junction; PLAX: parasternal long-axis view; RV: right ventricular; TAPSE: tricuspid annular plane systolic excursion.Values in bold indicate p < 0.05.

Figure 3. Conceptual model illustrating the highly complex interactions between MMPs, TIMP-1 and other biologically active substrates (dashed lines indicate enzyme inhibition). ARBs, angiotensin receptor blockers; CTGF, connective tissue growth factor; EGF, epidermal growth factor; ET-1, endothelin-1; IL-1β, interleukin-1beta; PDGF, platelet derived growth factor; TGF-β, transforming growth factor-beta; TNF-α, tumour necrosis factor-alpha; uPA, urokinase-type plasminogen activator.