Biomarkers of Myocardial Fibrosis: Revealing the Natural History of Fibrogenesis in Fabry Disease Cardiomyopathy

Abstract

Background: Cardiomyopathy is a major determinant of overall Fabry disease (FD) prognosis, with the worst outcomes in patients with myocardial fibrosis. Late gadolinium enhancement is currently the gold standard for evaluation of replacement myocardial fibrosis; however, this event is irreversible, thus identification of biomarkers of earlier diffuse fibrosis is paramount.

Methods and results: Type I collagen synthesis and degradation biomarkers (PICP [carboxyterminal propeptide of procollagen type I], ICTP [carboxyterminal telopeptide of type I collagen], and MMP1 [matrix metalloproteinase 1] and MMP2) and markers of bone synthesis and degradation were evaluated (to adjust type I collagen metabolism to bone turnover) in FD patients and controls. FD patients were grouped by cardiomyopathy severity, according to echocardiogram: (1) normal, (2) tissue Doppler abnormalities, (3) left ventricular hypertrophy. A significant increase in PICP and a significant decrease in matrix metalloproteinases were observed in FD patients; even the group with normal echocardiogram had a significant increase in PICP. We also found a significant correlation between left ventricular mass and PICP (ρ=0.378, P=0.003) and MMP1 (ρ=-0.484, P<0.001). PICP (adjusted for bone turnover) was the better predictor of left ventricular mass in multivariable regression, and its diagnostic accuracy to predict late gadolinium enhancement was also significant.

Conclusions: Collagen type I synthesis is increased in FD cardiomyopathy, even in the earlier stages of the disease, and this profibrotic state has good predictive value for and is likely to be critical to the development of overt left ventricular hypertrophy. Moreover, inhibition of enzymes involved in collagen type I cleavage also seems crucial to myocardial collagen deposition.

Keywords: Fabry disease cardiomyopathy; biomarkers; carboxyterminal propeptide of procollagen type I; cardiac fibrosis; matrix metalloproteinases.

Figure 1

Study flow diagram. ICTP indicates carboxyterminal telopeptide of type I collagen; LGE, late gadolinium enhancement; LV, left ventricular; MMP, matrix metalloproteinase; PICP, carboxyterminal propeptide of procollagen type I; TDI, tissue Doppler imaging.

Figure 2

Diagnostic accuracy of several biomarkers for presence of LGE in cardiac MRI. Minus S′ average, E′ average, and eGFR have been used to identify the presence of LGE; lower values of these variables are associated with the presence of LGE. *P<0.05 for true area=0.5. B‐AP indicates bone‐specific alkaline phosphatase; E′, early diastolic myocardial velocity measured at the mitral annulus; eGFR, estimated glomerular filtration rate; ICTP, carboxyterminal telopeptide of type I collagen; LV, left ventricular; MMP, matrix metalloproteinase; NT‐proBNP, N‐terminal probrain natriuretic peptide; PICP, carboxyterminal propeptide of procollagen type I; S′, systolic myocardial velocity measured at the mitral annulus; TRAP5b, tartrate‐resistant acid phosphatase type 5b.