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

Abstract

BackgroundCardiomyopathy 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 ResultsType 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.ConclusionsCollagen 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.

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

“…On the other hand, in a study in which 66% of patients had cardiac fibrosis at the onset of the disease, baseline serum levels of PIIINP, procollagen type I carboxy-terminal propeptide (PIPP) and collagen type I carboxy-terminal telopeptide (CICT) were increased [127]. Finally, in a study that Aguiar et al [128] conducted in a cohort of patients grouped by the severity of cardiomyopathy, serum levels of biomarkers involved in synthesis (PIPP) and degradation (CICT, MMP1, MMP2) of collagen type I adjusted for bone turnover were analyzed and found that adjusted PIPP levels were significantly increased in patients, including the asymptomatic, being higher in those with ventricular hypertrophy. Such increased levels in asymptomatic patients suggested that adjusted PIPP could be used as an early biomarker of cardiac dysfunction.…”

“…Such increased levels in asymptomatic patients suggested that adjusted PIPP could be used as an early biomarker of cardiac dysfunction. Some of the markers mentioned above have been associated with cardiac manifestations, such as endocardial fractional shortening, ventricular hypertrophy, ventricular dysfunction, maximal left-atrial size or degree of cardiac fibrosis [63,78,125,128], suggesting that mediators of inflammation, or ECM remodeling or regulation may contribute to the detection of cardiac injury, and be useful as indicators of left ventricular dysfunction.…”

Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning

“…In this study, there was no correlation between NT-proBNP and our proteomics assay (with the exception of RSU1, r s = 0.21; P = 0.028) suggesting that the majority of our candidate peptides may be tracking myocyte hypertrophy (LV mass and MWT) and fibrosis (native T1 and LGE) rather than myocardial stress. Though results from enzyme-linked immunosorbent assays appraising collagen synthesis biomarkers in venous blood samples of HCM patients have previously been conflicting (40,64), recent data in Fabry disease (a genetic lysosomal storage disorder resulting in pathological cardiac hypertrophy) demonstrated a correlation between levels of type I collagen synthesis and degradation biomarkers in blood, and LV mass and scar by CMR (65). This would fit with our findings where a different set of proteomics plasma markers of fibrosis, similarly correlate with LV wall thickness, mass and scar by CMR in LVH+ HCM.…”

Parkinson’s Disease and Fabry Disease: Clinical, Biochemical and Neuroimaging Analysis of Three Pedigrees

“…As we previously reported, the p.F113L GLA gene mutation is associated with a high burden of cardiac and CNS manifestations [25,26]. Hearing loss was a common manifestation and age-matched hearing thresholds by frequency are worse in FD than in the general population [18,25,26]. One possible explanation is that the vascular peripheral lesioning could correlate with higher CNS microvascular burden (hearing loss was correlated with microalbuminuria).…”