ABSTRACT
This study assessed the regional changes in myocardial geometry, microstructure, mechanical behavior, and properties that occur in response to progressive left ventricular pressure overload (LVPO) in a large animal model. Using an index of local biomechanical function at early onset of LVPO allowed for prediction of the magnitude of left ventricular chamber stiffness (Kc) and left atrial area at LVPO late timepoints. Our study found that LV myocardial collagen content alone was insufficient to identify mechanisms for LV myocardial stiffness with progression to heart failure with preserved ejection fraction (HFpEF). Serial assessment of regional biomechanical function might hold value in monitoring the natural history and progression of HFpEF, which would allow evaluation of novel therapeutic approaches.
ABSTRACT
BACKGROUND: Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloproteinases (MMPs). Sacubitril/valsartan (Sac/Val) exerts additive cardioprotective actions over renin-angiotensin-aldosterone inhibitors in preclinical models of myocardial infarction and in heart failure patients. We hypothesized that Sac/Val would be more cardioprotective than Val in a rodent model of progressive DOX-induced cardiotoxicity, and this benefit would be associated with modulation of MMP activation. OBJECTIVES: We sought to investigate the efficacy of Sac/Val for the treatment of anthracycline-induced cardiotoxicity. METHODS: Male Wistar rats received DOX intraperitoneally (15 mg/kg cumulative) or saline over 3 weeks. Following the first treatment, control animals were gavaged daily with water (n = 25), while DOX-treated animals were gavaged daily with water (n = 25), Val (31 mg/kg; n = 25) or Sac/Val (68 mg/kg; n = 25) for either 4 or 6 weeks. Echocardiography was performed at baseline, and 4 and 6 weeks after DOX initiation. In addition, myocardial MMP activity was assessed with 99mTc-RP805, and cardiotoxicity severity was assessed by histology at these time points in a subgroup of animals. RESULTS: Left ventricular ejection fraction decreased by 10% at 6 weeks in DOX and DOX + Val rats (both p < 0.05), while this reduction was attenuated in DOX + Sac/Val rats. MMP activity was increased at 6 weeks by 76% in DOX-alone rats, and tended to increase in DOX + Val rats (36%; p = 0.051) but was similar in DOX + Sac/Val rats as compared with time-matched control animals. Both therapies attenuated histological evidence of cellular toxicity and fibrosis (p < 0.05). CONCLUSIONS: Sac/Val offers greater protection against left ventricular remodeling and dysfunction compared with standard angiotensin receptor blocker therapy in a rodent model of progressive DOX-induced cardiotoxicity.
ABSTRACT
Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-µl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-µl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-µg/100-µl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.
