Circulating matrix metalloproteinase patterns in association with aortic dilatation in bicuspid aortic valve patients with isolated severe aortic stenosis

Abstract

Bicuspid aortic valve (BAV) exhibits a clinical incline toward aortopathy, in which aberrant tensile and shear stress generated by BAV can induce differential expression of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs). Whether stenotic BAV, which exhibits additional eccentric high-velocity flow jet upon ascending aorta and further worsens circumferential systolic wall shear stress than BAV with echocardiographically normal aortic valve, can lead to unique plasma MMP/TIMP patterns is still unknown. According to their valvulopathy and aortic dilatation status, 93 BAV patients were included in the present study. Group A (n = 37) and B (n = 28) comprised severely stenotic patients with or without ascending aorta dilatation; Group C (n = 12) and D (n = 16) comprised echocardiographically normal BAV patients with or without ascending aorta dilatation. Plasma MMP/TIMP levels (MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4) were determined via a multiplex ELISA detection system in a single procedure. Among patients with isolated severe aortic stenosis, plasma levels of MMP-2 and -9 were significantly elevated when ascending aortic dilatation was present (p = 0.001 and p = 0.002, respectively). MMP-2, however, remained as the single elevated plasma component among echocardiographically normal BAV patients with dilated ascending aorta (p = 0.027). Multivariate analysis revealed that MMP-2 and MMP-9 could both serve as independent risk factor for aortic dilatation in the case of isolated severe stenosis (p = 0.003 and p = 0.001, respectively), and MMP-2 in echocardiographically normal patients (p = 0.002). In conclusion, BAV patients with isolated severe aortic stenosis demonstrated a distinct plasma MMP/TIMP pattern, which might be utilized as circulating biomarkers for early detection of aortic dilatation.

Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?

“…In this study, we attempted to shed light on intrinsic defects of the aortic wall leading to the observed similarities by comparing the ascending aortic wall of both diseases with each other and with patients with TAV without MFS. As recently several publications focused on a difference in dilation progress after aortic valve repair dependent on whether the diseased aortic valve was stenotic or regurgitant with concomitant root dilation [ 25 , 26 ]; in the latter, we also paid additional attention to the underlying aortic valve pathology besides structural histopathologic features in the patient groups. In the literature, it is argued that the aortic dilation in the stenotic type is a functional hemodynamic-induced problem, while the aortic wall problem in the root phenotype is genetically determined.…”

Year in review

“…The critical role of MMP-2 as a key molecular mediator was supported by a recent meta-analysis. Wang and colleagues further showed MMP-2 as a circulating biomarker of aortic dilatation in BAV patients(73). Phillippi with Gleason and Vorp at University of Pittsburgh further characterized the medial matrix remodeling of the BAV aorta and found unique patterns as compared to TAV patients(74).…”

Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease

“…Neither did we find significant relations with aortic dimensions as measured by echocardiography, although a trend was observed for MMP-2 (adjusted p value 0.087). Previous studies have reported altered plasma MMP-2, -9 and TIMP-1 levels in patients with aortic valve stenosis and ascending aorta dilatation, both in bicuspid valves and in chronic thoracic aortic dissection (Ikonomidis et al, 2013;Wang et al, 2016;Zhang et al, 2014). It may therefore be worthwhile to evaluate MMPs in specific patient subgroups with a high risk of aortic dilatation, in combination with more detailed imaging modalities of the aorta, such as CT or MRI.…”

“…More specific, altered MMP-2, MMP-9 and TIMP-1 levels have been associated with left ventricular (LV) hypertrophy, chronic heart failure and diastolic dysfunction in hypertensive heart disease and coronary artery disease (Ahmed et al, 2006;Chu et al, 2013;Kang et al, 2008;Laviades et al, 1998;Martos et al, 2007). In patients with thoracic aortic aneurysms, specific MMP-2, -9 and TIMP-1 profiles have been described; however, the majority of research in this field is based on histology of the aortic wall rather than circulating blood biomarker levels (Ikonomidis et al, 2013;Wang et al, 2016;Zhang et al, 2014).…”