Clinically, myocardial remodeling is any change in the size, shape, or function of the LV such that cardiovascular survival is altered. Although symptoms and LV ejection fraction are commonly used as surrogates because they are readily quantifiable, both are relatively poor indicators of survival [9
]. Presently, only two classes of medications, namely, β-blockers and angiotensin-converting enzyme inhibitors, have been shown to significantly improve remodeling and survival beyond their effects on symptoms or blood pressure. By studying the remodeling process explicitly, the goal of our laboratory has been to identify additional potential mediators of regression, or beneficial remodeling.
We have shown the expression pattern of periostin in both experimental and clinical progression and regression of ventricular hypertrophy. Is periostin simply a marker of hypertrophy or does it have a formal role in the remodeling process? We recognize the observational limitations of our study and acknowledge that the changes in periostin may be a phenomenon occurring in parallel with changes in hypertrophy.
We believe, however, that periostin is more than an innocent bystander. Indeed, periostin is positioned as a key ECM protein that likely serves several beneficial roles in the development and maintenance of a well-functioning ventricle. We observed significant tissue levels of periostin in all animals. This is consistent with previous data demonstrating periostin is active developmentally in the endocardial cushion formation [5
]. In addition, a recent study showed an increased rate of ventricular rupture after myocardial infarction in periostin knockout (Pn−/−
) mice [10
]. Collectively, these studies and ours demonstrate that periostin is an integral part of a well-functioning myocardium.
Teleologically, as with LVH, some periostin is good, whereas overexpression can allow for maladaptive LVH and heart failure. In pressure overload, periostin is highly over-expressed and is associated with numerous cardiovascular pathologies. Principally, there is an increased volume of collagen deposition and fibrosis within the myocardium and in perivascular tissues. Increased collagen and fibrotic proliferation is believed to impair ventricular compliance and lead to diastolic dysfunction [11
]. This may have contributed to the decreased contractility that we observed in our pressure overload animals [7
]. Correspondingly, the increased perivascular expression of periostin and collagen that we, and others, have observed is believed to impair nutrient and oxygen delivery to the myocardium [12
]. It is likely that this further diminishes the ability of the myocardium to respond to the increased work of pressure overload.
Although we observed a diffuse increase in periostin expression and collagen deposition across the entire LV in our model, there was a significant predominance of expression in the interventricular septum. This may be due to regional differences in strain experienced by the LV component of the septum, a phenomenon well documented in humans but not yet in mice [13
Importantly, in our series of regression experiments, we were able to successfully demonstrate that periostin expression decreased with relief of pressure overload. It is unknown whether the process of regression actively induced metabolism of periostin, or whether the natural tissue half-life of periostin is relatively short and dependent on continued expression. In contrast, collagen is believed to be a more durable product in fibrosis, and yet collagen was similarly less present in hearts that had experienced relief of pressure overload. This suggests that an active process within the ECM of the myocardium contributed to the metabolism of collagen. Previous authors have speculated that fibrosis and collagen deposition significantly lessen the ability of a ventricle to undergo regression of hypertrophy [14
]. We believe our findings demonstrate that collagen-based changes in the ECM of the LV wall associated with LVH are, in fact, reversible.
Our echocardiographic studies demonstrated that 4 weeks of pressure overload resulted in increased chamber dimension and decreased LVEF, both of which contribute to heart failure [7
]. In regression, we observed a reversal of both phenomena, indicating rescue. Although periostin is believed to be important in establishing and maintaining a healthy and functional ECM, it is likely that in the pathophysiology of pressure overload, it contributes to the dysfunction that leads to features of heart failure. Initial studies strongly linked gene expression of periostin with the progression of heart failure [4
]. More recent studies with Pn−/−
mice have demonstrated that if mice survive myocardial infarction, then the absence of periostin is associated with improved long-term myocardial function [10
], suggesting that the presence of periostin may significantly impair recovery from an ischemic event.
In addition, studies of periostin in cancer have shown that periostin is highly associated with tissue invasion and metastasis. It is typically expressed at border zones, and periostin expression by tumor cells has been directly correlated with loss of host tissue integrity and tumor in-growth [6
]. Although the mechanism of action remains to be determined, it is possible that the characteristics that lead to tissue invasion are similar to those that facilitate ventricular susceptibility to wall stress and pressure overload. Importantly, our findings, including those in our heart failure patients with bridge to transplant VADs, indicate that the LV dilatation and wall thickening associated with pressure overload are partly reversible and that this reversal occurs in an environment of decreased periostin expression.
We fully acknowledge several limitations of the study. Our mouse model of pressure overload and relief is most analogous to aortic valve replacement therapy for aortic stenosis. Our human model of pressure overload is necessarily quite different, in that there are no conditions in which heart tissue may be readily removed from healthy individuals. We believe that our current model, using pressure overloaded, failing hearts and then resampling after ventricular assist, is the closest human model available that affords ready access to tissue.
A related limitation is that the fibrosis that occurs in adult hearts from pressure overload is typically the result of longstanding pathology. In the mice, there is an acute onset of pressure overload, with a relatively rapid progression of hypertrophy and even failure. Despite these differences, both groups showed significant decreases in periostin expression with relief of pressure overload, further reinforcing our hypothesis that excessive periostin expression is associated with ventricular dysfunction and that functional improvement is associated with decreased periostin expression.
In summary, periostin is significantly over-expressed in conditions of myocardial pressure overload and significantly under-expressed in relief of pressure overload. These expression changes correspond closely with ventricular function, myocardial hypertrophy, and ventricular fibrosis. Although mechanisms of action are yet to be determined, a variety of reports suggest that periostin, although necessary developmentally, has significant adverse effects during pathologic over-expression. Specifically, ventricular remodeling is associated with greater dysfunction during periostin expression, and pressure offloading and functional improvement are linked with decreased tissue levels of periostin. We believe our data support further studies that target periostin as a means of therapy for fibrotic myocardial disease.