Left ventricular assist device exchange: the Toronto General Hospital experience.

BACKGROUND: As support times for left ventricular assist devices (LVADs) become longer, several complications requiring device exchange may occur. To our knowledge, this is the first Canadian report regarding implantable LVAD exchange. METHODS: We retrospectively reviewed the cases of consecutive, unique patients implanted with an LVAD between June 2006 and October 2015 at Toronto General Hospital. RESULTS: In total, 122 patients were impanted with an LVAD during the study period. Eight patients required LVAD exchange, and 1 patient had 2 replacements (9 of 122, 7.3%). There were 7 HeartMate II (HMII), 1 HVAD and 1 DuraHeart pumps exchanged. Two of these exchanges occurred early at the time of initial implant, whereas 7 occurred late (range 8-623 d). Six exchanges were made owing to pump thrombosis. Of the 3 exchanges made for other causes, 1 HMII exchange was owing to a driveline fracture, 1 DuraHeart patient had early inflow obstruction requiring exchange to HMII at the initial implant, and the third had a suspected inflow obstruction with no evidence of thrombosis at the time of the procedure. The mean support time before exchange was 225 days, and time from exchange to transplant, death or ongoing support was 245 days. Three patients were successfully bridged to transplant, and at the time of data collection 2 were supported awaiting transplant. Three patients died after a mean duration of 394.3 days (range 78-673 d) of support postreplacement. Four cases were successfully performed using a subcostal approach. CONCLUSION: Pump thrombosis is the most common cause for LVAD exchange, which can be performed with acceptable morbidity and mortality. The subcostal approach may be the preferred procedure for an HMII exchange when indicated.

CONTEXTE: À mesure que la durée d'utilisation des dispositifs d'assistance ventriculaire gauche (DAVG) augmente, plusieurs complications nécessitant un remplacement du dispositif peuvent survenir. À notre connaissance, il s'agit du premier rapport canadien concernant le remplacement des DAVG implantables. MÉTHODES: Nous avons passé en revue de manière rétrospective les cas individuels consécutifs de patients à qui on a implanté un DAVG entre juin 2006 et octobre 2015 à l'Hôpital Général de Toronto. RÉSULTATS: En tout, 122 patients ont reçu un DAVG pendant la période de l'étude. Huit patients ont eu besoin d'un remplacement de DAVG et 1 patient a eu besoin de 2 remplacements (9 sur 122, 7,3 %). Sept dispositifs HeartMate II (HMII), 1 dispositif HVAD et 1 dispositif DuraHeart ont été remplacés. Deux de ces remplacements sont survenus peu de temps après la pose initiale du dispositif, tandis que les 7 autres se sont produits plus tardivement (dans les 8 à 623 jours suivants). Six remplacements ont été effectués en raison d'une thrombose de la pompe. Parmi les 3 remplacements effectués pour d'autres raisons, 1 dispositif HMII a été remplacé en raison d'un bris de la ligne d'activation, 1 dispositif DuraHeart a présenté une obstruction précoce du flux entrant nécessitant la pose d'un HMII dès l'implantation initiale, et le troisième présentait une obstruction présumée du flux entrant sans signe de thrombose au moment de l'intervention. La durée moyenne d'utilisation avant le remplacement du dispositif a été de 225 jours, et l'intervalle entre le remplacement et la transplantation, le décès ou la décision de maintenir l'assistance a été de 245 jours. L'appareil a permis une transition réussie jusqu'à la transplantation chez 3 patients, et au moment de la collecte des données, 2 patients porteurs d'un DAVG étaient en attente d'une transplantation. Trois patients sont décédés après une durée moyenne de 394,3 jours (entre 78 et 673 jours) d'assistance post-remplacement. Quatre remplacements ont été effectués avec succès par une approche sous-costale. CONCLUSION: La thrombose de la pompe est la cause la plus fréquente de remplacement d'un DAVG; le remplacement peut être effectué avec des taux de morbidité et de mortalité acceptables. L'approche sous-costale serait à privilégier lorsqu'un remplacement de HMII est indiqué.

Combined Aortic Valve Replacement and Renal Cell Carcinoma Thrombectomy.

Although nephrectomy for renal cell carcinoma with inferior vena cava invasion is a common procedure, it is rare to have level IV invasion necessitating cardiopulmonary bypass (CPB). Furthermore, it is exceptionally rare to perform cardiac surgery concomitantly with this resection. We report a case in which an aortic valve replacement was done in the same surgical setting as a level IV thrombectomy. We have demonstrated that although it can be difficult to manage the coagulopathy post-CPB, this can be successfully accomplished with adequate prior preparation and a coordinated team effort.

Cessation of biomechanical stretch model of C2C12 cells models myocyte atrophy and anaplerotic changes in metabolism using non-targeted metabolomics analysis.

Studies of skeletal muscle disuse, either in patients on bed rest or experimentally in animals (immobilization), have demonstrated that decreased protein synthesis is common, with transient parallel increases in protein degradation. Muscle disuse atrophy involves a process of transition from slow to fast myosin fiber types. A shift toward glycolysis, decreased capacity for fat oxidation, and substrate accumulation in atrophied muscles have been reported, as has accommodation of the liver with an increased gluconeogenic capacity. Recent studies have modeled skeletal muscle disuse by using cyclic stretch of differentiated myotubes (C2C12), which mimics the loading pattern of mature skeletal muscle, followed by cessation of stretch. We utilized this model to determine the metabolic changes using non-targeted metabolomics analysis of the media. We identified increases in amino acids resulting from muscle atrophy-induced protein degradation (largely sarcomere) that occurs with muscle atrophy that are involved in feeding the Kreb's cycle through anaplerosis. Specifically, we identified increased alanine/proline metabolism (significantly elevated proline, alanine, glutamine, and asparagine) and increased α-ketoglutaric acid, the proposed Kreb's cycle intermediate being fed by the alanine/proline metabolic anaplerotic mechanism. Additionally, several unique pathways not clearly delineated in previous studies of muscle unloading were seen, including: (1) elevated keto-acids derived from branched chain amino acids (i.e. 2-ketoleucine and 2-keovaline), which feed into a metabolic pathway supplying acetyl-CoA and 2-hydroxybutyrate (also significantly increased); and (2) elevated guanine, an intermediate of purine metabolism, was seen at 12h unloading. Given the interest in targeting different aspects of the ubiquitin proteasome system to inhibit protein degradation, this C2C12 system may allow the identification of direct and indirect alterations in metabolism due to anaplerosis or through other yet to be identified mechanisms using a non-targeted metabolomics approach.

Tricuspid Valve Annular Dilation as a Predictor of Right Ventricular Failure After Implantation of a Left Ventricular Assist Device.

BACKGROUND: Tricuspid annular (TA) dilation has been suggested as a more reliable marker of concomitant advanced right ventricular failure (RVF) than severity of tricuspid regurgitation (TR). Our objective was to examine the impact of TA dilation on occurrence of RVF and in-hospital mortality following left ventricular assist device (LVAD) implant. METHODS: Consecutive patients undergoing implantation of a continuous-flow LVAD implant were grouped according to the presence or absence of preoperative dilated TA. Clinical characteristics, hemodynamics, and short-term postoperative outcomes were compared between groups. RVF was defined as unplanned right ventricular assist device (RVAD) or postoperative use of inotropes for >14 days. Linear and logistic regressions were used to explore associations of TA with occurrence of RVF and duration of inotrope use. RESULTS: We included 69 patients who had continuous-flow LVAD implanted between 2006 and 2013 (50 ± 13 years old; 69% males; 37% ischemic etiology; 69% bridge-to-transplant LVAD; 18% INTERMACS 1-2; 48% with significant TR). RVF occurred in nine cases, and overall in-hospital mortality rate was 14%. Tricuspid valve repair was performed in ten cases. Dilated TA (OR 4.86; 95% CI 1.05-22.33; p = 0.04) was associated with RVF. In an adjusted multivariable analysis, indexed TA was an independent predictor of increased days of inotrope use (0.8-day increase in inotrope use for every 1 mm/m2 increase; p = 0.04). CONCLUSION: In this cohort, TA dilation was a predictor of RVF after LVAD implant. The potential benefit of concomitant TVR in selected patients with a dilated TA undergoing LVAD implantation remains to be determined.

MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet.

BACKGROUND: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree PPARß and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2-/- hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination. METHODS: MuRF2-/- mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARß, and PPARγ1-regulated mRNA expression. RESULTS: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2-/- hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2-/- hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states. CONCLUSIONS: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation.

Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet.

BACKGROUND: The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM. METHODS: MuRF3-/- mice were challenged with 26 weeks 60% high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARß, and PPARγ1 activities were assayed. RESULTS: MuRF3-/- mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3-/- mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3-/- mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARß. CONCLUSIONS: These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM. MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.

Recovery from decompensated heart failure is associated with a distinct, phase-dependent gene expression profile.

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 wk with or without subsequent band removal for 1 wk (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 wk. Pressure-relief afforded by debanding allowed functional recovery and normalization of LVH after both 3 and 4, but not 6 wk of banding. Whole genome microarrays demonstrated 397 genes differentially expressed in recovered hearts, 250 genes differentially expressed in the nonrecoverable (6 wk) 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.

Periostin is a novel factor in cardiac remodeling after experimental and clinical unloading of the failing heart.

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.

Muscle ring finger 1 mediates cardiac atrophy in vivo.

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1(-/-) mice decreased approximately 70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by beta-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1(-/-) and wild-type hearts after TAC release. In the second model, MuRF1(-/-) mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

Regression of pressure-induced left ventricular hypertrophy is characterized by a distinct gene expression profile.

OBJECTIVE: Left ventricular hypertrophy is a highly prevalent and robust predictor of cardiovascular morbidity and mortality. Existing studies have finely detailed mechanisms involved with its development, yet clinical translation of these findings remains unsatisfactory. We propose an alternative strategy focusing on mechanisms of left ventricular hypertrophy regression rather than its progression and hypothesize that left ventricular hypertrophy regression is associated with a distinct genomic profile. METHODS: Minimally invasive transverse arch banding and debanding (or their respective sham procedures) were performed in C57Bl6 male mice. Left ventricular hypertrophy was assessed physiologically by means of transthoracic echocardiographic analysis, structurally by means of histology, and molecularly by means of real-time polymerase chain reaction. Mouse hearts were genomically analyzed with Agilent (Santa Clara, Calif) mouse 44k developmental gene chips. RESULTS: Compared with control animals, animals banded for 28 days had a robust hypertrophic response, as determined by means of heart weight/body weight ratio, histologic analysis, echocardiographic analysis, and fetal gene expression. These parameters were reversed within 1 week of debanding. Whole-genome arrays on left ventricular tissue revealed 288 genes differentially expressed during progression, 265 genes differentially expressed with regression, and only 23 genes shared by both processes. Signaling-related expression patterns were more prevalent with regression rather than the structure-related patterns associated with left ventricular hypertrophy progression. In addition, regressed hearts showed comparatively more changes in energy metabolism and protein production. CONCLUSIONS: This study demonstrates an effective model for characterizing left ventricular hypertrophy and reveals that regression is genomically distinct from its development. Further examination of these expression profiles will broaden our understanding of left ventricular hypertrophy and provide a novel therapeutic paradigm focused on promoting regression of left ventricular hypertrophy and not just halting its progression.

Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection.

OBJECTIVE: Myocardial ischemia/reperfusion injury remains a vexing problem. Translating experimental strategies that deliver protective agents before the ischemic insult limits clinical applicability. We targeted 2 proteins in the nuclear factor-kappaB pathway, inhibitory kappa B kinase-beta, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion. METHODS: C57BL/6 mice underwent left anterior descending artery occlusion for 30 minutes. An inhibitory kappa B kinase-beta inhibitor (Compound A), a proteasome inhibitor (PS-519), or vehicle was administered at left anterior descending artery release or 2 hours afterward. Infarct size was analyzed 24 hours later. Pressure-volume loops were performed at 72 hours. Serum and left ventricular tissue were collected 1 hour after injury to examine protein expression by enzyme-linked immunosorbent assay and Western blot. RESULTS: Inhibitory kappa B kinase-beta and proteasome inhibition significantly attenuated infarct size and preserved ejection fraction compared with the vehicle groups. When delivered even 2 hours after reperfusion, Compound A, but not PS-519, still decreased infarct size in mice. Finally, when delivered at reperfusion, successful inhibition of phosphorylated-p65 and decreased interleukin-6 and tumor necrosis factor-alpha levels occurred in mice given the inhibitory kappa B kinase-beta inhibitor, but not in mice with proteasome inhibition. CONCLUSION: Although inhibitory kappa B kinase-beta and proteasome inhibition at reperfusion attenuated infarct size after acute ischemia/reperfusion, only inhibitory kappa B kinase-beta inhibition provided cardioprotection through specific suppression of nuclear factor-kappaB signaling. This feature of highly targeted nuclear factor-kappaB inhibition might account for its delayed protective effects, providing a clinically relevant option for treating myocardial ischemia/reperfusion associated with unknown periods of ischemia and reperfusion as seen in cardiac surgery and acute coronary syndromes.

Myocardin inhibits cellular proliferation by inhibiting NF-kappaB(p65)-dependent cell cycle progression.

We previously reported the importance of the serum response factor (SRF) cofactor myocardin in controlling muscle gene expression as well as the fundamental role for the inflammatory transcription factor NF-kappaB in governing cellular fate. Inactivation of myocardin has been implicated in malignant tumor growth. However, the underlying mechanism of myocardin regulation of cellular growth remains unclear. Here we show that NF-kappaB(p65) represses myocardin activation of cardiac and smooth muscle genes in a CArG-box-dependent manner. Consistent with their functional interaction, p65 directly interacts with myocardin and inhibits the formation of the myocardin/SRF/CArG ternary complex in vitro and in vivo. Conversely, myocardin decreases p65-mediated target gene activation by interfering with p65 DNA binding and abrogates LPS-induced TNF-alpha expression. Importantly, myocardin inhibits cellular proliferation by interfering with NF-kappaB-dependent cell-cycle regulation. Cumulatively, these findings identify a function for myocardin as an SRF-independent transcriptional repressor and cell-cycle regulator and provide a molecular mechanism by which interaction between NF-kappaB and myocardin plays a central role in modulating cellular proliferation and differentiation.

Proteasome inhibition promotes regression of left ventricular hypertrophy.

Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-kappaB (NF-kappaB) is an inflammatory transcription factor that has been shown to be involved in LVH development. We hypothesized that proteasome-mediated NF-kappaB inhibition would prevent the development of LVH and promote its regression. A murine model of reversible hypertrophy was employed by administering isoproterenol (Iso) subcutaneously for 7-14 days. The proteasome inhibitor, PS-519, was delivered both concurrently and after Iso treatment. LVH was quantified by heart weight-to-body weight ratios, histology, transthoracic echocardiography, and hypertrophic gene expression. After 7 days of Iso treatment, all measures indicated successful development of LVH. Another group was treated for 7 days and then observed for an additional 7 days. This group experienced normalization of Iso-induced cell size, wall thickness, and beta-myosin heavy chain expression. When administered concurrently, PS-519 prevented Iso-induced LVH at 7 days. Furthermore, when PS-519 was given to animals during the second week of continued Iso treatment, these animals also experienced regression of hypertrophy by several measures. The success of proteasome inhibition in preventing LVH development and in promoting LVH regression, even in the face of continued hypertrophic stimulation, demonstrates its potential use as a clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.

IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury.

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaBalpha, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta. We hypothesized that specific antagonism of the NF-kappaB inflammatory pathway through IKKbeta inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKbeta kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKbeta inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKbeta inhibition. These findings were further associated with decreased expression of phosphorylated IkappaBalpha and phosphorylated p65 in myocardial tissue. In addition, IKKbeta inhibition decreased serum levels of TNF-alpha and IL-6, two prototypical downstream effectors of NF-kappaB activity. These results demonstrate that specific IKKbeta inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.