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The Human Story of Aortic Stenosis: A Time for New Surrogate Markers in Clinical Decision Making

to note that the most recent data in an animal model of progressive LV pressure overload indicates that, more important than simple collagen accumulation, LV stiffness was determined by post-translational control of determinants of increased collagen stability (thereby resistant to MMP degradation) and increased endogenous TIMPs [5, 6] . In addition to an increase in extracellular matrix components/qualities, Zile et al. [7] have demonstrated an increase in cardiomyocyte microtubules which is also associated with myocardial dysfunction and congestive heart failure in patients with AS. In addition, Schaper and coworkers have demonstrated a decrease in the volume fraction of myofibrils in patients with AS [8] . Taken together, these findings explain both the systolic and diastolic dysfunction in AS emanating from the cardiomyocyte that would appear to be independent of the increase in extracellular matrix. Schaper and coworkers have also reported that the quantity and spatial distribution of Cx43 differs markedly between compensated and decompensated LV hypertrophy in human patients with AS [9] . Thus, cardiac fibrosis in combination with the disarray in Cx43 may play a role in the pathophysiology of heart failure and sudden death from ventricular arrhythmias in these patients [10, 11] . The current study by Golia et al. [1] demonstrates that the extent of left ventricular (LV) fibrosis correlates with LV systolic dysfunction and dilatation in patients with aortic stenosis (AS). This study complements and adds to the wealth of data that has been published over the years on the myocardial response to AS in humans, in particular with regard to the extracellular matrix. It is also consistent with previous reports from Schaper and coworkers demonstrating an increase in angiotensin converting enzyme and TGFexpression in patients with AS and that collagen and fibronectin mRNA expression levels are positively correlated with LV end-diastolic pressure and inversely correlated with LV ejection fraction (EF) [2] . Augmented renin-angiotensin system and TGFexpression provide the profibrotic effect. These same investigators have also shed light on the mechanisms of LV dilatation in AS by demonstrating a progression from compensated hypertrophy to heart failure that is characterized by the upregulation of matrix metalloproteinases (MMPs) and inadequate inhibition by tissue inhibitors of MMPs (TIMPs) [3] . The dysregulation of myocardial MMPs and TIMPs in human AS starts at an early disease stage when LV function is still normal with what appears to be a progressive upregulation of TIMPs promoting a pro-fibrotic accumulation of collagen [4] . It is of interest Received: March 2, 2012 Accepted: March 3, 2012 Published online: May 26, 2012