Background Maladaptive left ventricular hypertrophy (LVH) remains a prevalent and highly morbid condition associated with end-stage heart disease. Originally evaluated in the context of bone development, periostin is important in endocardial cushion formation and has recently been implicated in heart failure. Because of its potential role in cardiovascular development, we sought to establish the role of periostin after relief of pressure overload in animal and human models. Methods Pressure overload induction of LVH was performed by minimally invasive aortic arch banding of C57Bl6 mice. Bands were removed 1 month later to allow regression. Cardiac tissue was procured in paired samples of patients receiving LV assist devices (LVAD), with subsequent reanalysis at the time of explant for transplantation. Results One week after debanding, heart weight/body weight ratios and echocardiography confirmed decreased LV mass relative to hypertrophied animals. Gene and protein expression of periostin was measured by real-time polymerase chain reaction and Western blot, and was similarly decreased compared with LVH mice. Immunohistochemical localization of periostin showed it was exclusively in the extracellular matrix of the myocardium. The decrease in periostin with pressure relief paralleled changes in interstitial fibrosis observed by picrosirius red staining. Corroborating the murine data, periostin expression was significantly reduced after LVAD-afforded pressure relief in patients. Conclusions Periostin is closely associated with pressure overload-induced LVH and LVH regression in both animal and human models. The magnitude of expression changes and the consistent nature of these changes indicate that periostin may be a mediator of cardiac remodeling.

Background Clinical and experimental studies have traditionally focused on understanding the mechanisms for why a heart fails. We hypothesize that the pathways involved with myocardial recovery are not simply the reverse of those that cause heart failure. However, determining when and how a decompensated heart can recover remains unknown. Methods Male C57BL/6 mice underwent minimally invasive aortic banding for 3, 4, or 6 weeks with or without subsequent band removal for one week (debanding). Physiologic and genomic characterization was performed with intracardiac pressure-volume recordings, rt-PCR, and microarray analysis. Results Heart weight/body weight ratios and PV loops demonstrated a transition from compensated left ventricular hypertrophy to decompensated heart failure between 3 and 4 weeks. Pressure-relief afforded by debanding allowed functional recovery and normalization of LVH after both 3 and 4, but not 6 weeks of banding. Whole genome microarrays demonstrated 397 genes differentially expressed in recovered hearts, 250 genes differentially expressed in the nonrecoverable (6 week) hearts, and only 10 genes shared by both processes. In particular, altered expression patterns of apoptotic and metalloproteinase genes correlated with the heart's ability to functionally recover. Conclusions This clinically-relevant model (1) allows us to temporally and mechanistically characterize the failing heart, (2) demonstrates a unique genomic signature that may predict when a failing heart can recover following pressure relief, and (3) will prove useful as a template for testing therapeutic strategies aimed at recovery of the failing heart.

Background Most cardiovascular studies have implicated the central transcription factor nuclear factor kappa B (NF-κB) as contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. Pressure-overload, left ventricular hypertrophy (LVH), and heart failure represent a spectrum of disease that has both adaptive and maladaptive components. As opposed to its known effects related to myocardial ischemia-reperfusion, we hypothesized that NF-κB is necessary for the compensatory phase of cardiac remodeling. Material and Methods C57BL6 mice underwent minimally-invasive transverse aortic constriction (TAC) with or without inhibition of the proximal NF-κB kinase, inhibitory kappa B kinase-β (IKKβ). Isolated cardiomyocytes were cultured. Transthoracic echocardiography was performed on all animals. Results IKK-β inhibition successfully decreased cardiomyocyte expression of phosphorylated p65 NF-κB and decreased expression of hypertrophic markers with stimulation in vitro. Three weeks after TAC, mice treated with IKK-β inhibition more aggressively developed LVH as measured by heart weight/body weight, LV mass, and wall thickness. These animals also demonstrated functional decline as measured by decreased fractional shortening and ejection fraction. These findings were associated with decreased protein expression of p65 NF-κB. Conclusions Whereas short-term pressure-overload results in compensatory LVH with normal cardiac function, NF-κB inhibition resulted in increased LVH that was associated with functional deterioration. These observations suggest that NF-κB is an important part of the adaptive phase of LVH, and its inhibition detrimentally impacts cardiac remodeling.

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