Cardiac rupture, though infrequent in humans, remains a devastating complication after myocardial infarction (MI) [1], and the primary cause of mortality post-MI in murine models. Following infarction, necrosis triggers multiple cytokine signaling pathways that result in both acute inflammatory and chronic ventricular remodeling responses [2]. Repairing the acutely infarcted heart involves biomechanical risks, which may, in turn, lead to cardiac rupture within the first two-weeks in both rodents and human [1], [2], [3]. Specifically, as necrotic tissue and extracellular matrix are degraded in the early phase, the infarcted myocardium loses structural integrity and may tear, resulting in hemodynamic collapse and death secondary to acute pericardial tamponade.

Murine models of MI have identified a plethora of factors contributing to cardiac rupture, including infarct size, hemodynamic parameters, age, sex, and mouse strain [3], [4], [5], [6]. Others have also implicated tensile strength of the infarcted myocardium, collagen content, and intensity of the acute inflammatory response [6], [7], [8]; however, few studies have examined the role of signaling molecules, such as bone morphogenetic proteins (BMP), in modulating the pathophysiology of cardiac rupture.

The growth differentiation factor (GDF)/BMP cytokine subfamily regulates embryonic development through effects on cell proliferation and differentiation, and through its effects on the cardiovascular system (see Reviews [9,10]). Specifically, a subset of GDF/BMP are known to serve important roles in the developing, mature, and pathological heart. Genetic deletion of BMP-2 or -4 results in cardiac developmental anomalies, including left-right (LR) cardiac asymmetry [11] and embryonic heart development in the exocoelomic cavity [12]. Mutations in GDF1 lead to severe cardiac defects involving LR patterning [13], and murine embryos lacking BMP-10 exhibit congenital heart defects – stemming from aberrant expression of cardiogenic transcription factors and reduced cardiomyocyte proliferation that ultimately impairs cardiac specification and maturation during development [14]. GDF3 promotes fibroblast proliferation in vitro and is elevated in mouse hearts and human plasma post-MI, where higher plasma GDF3 levels correlate with worse left ventricular (LV) function [15]. Several members of the GDF/BMP subfamily have also been correlated with positive cardiovascular outcomes as increased circulating GDF11 (and its homologue, GDF8) are associated with reduced risk of incident heart failure hospitalization, stroke, and MI [16], and GDF15 is critically involved in suppressing the inflammatory response post-MI; thereby, protecting the host from fatal cardiac rupture [17].

Beyond its role in skeletal development and chondrogenesis, GDF5 expression has been observed in the developing heart [18] and more recently, GDF5 deficiency has been associated with anthracycline-induced cardiotoxicity [19]. We have also shown that GDF5 expression increases post-MI and have implicated GDF5 in the cardiac remodeling process [20], such that GDF5 knockout (KO) mice manifest increased cardiomyocyte apoptosis at 4-d post-MI, as well as decreased vascularity and greater infarct scar expansion at 28-d post-MI – together suggesting that the expression of GDF5 may play an important role in cardiac protection post-MI.

As GDF5 appears to serve cardioprotective roles in the setting of chronic experimental MI, we here aimed to determine whether GDF5 regulates acute (i.e. 3-d post-MI) processes. Such data would be relevant to any proposed targeting of GDF5 for therapeutic purposes.