Polymeric prosthetic heart valves: A review of current technologies and future directions.

Valvular heart disease is an important source of cardiovascular morbidity and mortality. Current prosthetic valve replacement options, such as bioprosthetic and mechanical heart valves are limited by structural valve degeneration requiring reoperation or the need for lifelong anticoagulation. Several new polymer technologies have been developed in recent years in the hope of creating an ideal polymeric heart valve substitute that overcomes these limitations. These compounds and valve devices are in various stages of research and development and have unique strengths and limitations inherent to their properties. This review summarizes the current literature available for the latest polymer heart valve technologies and compares important characteristics necessary for a successful valve replacement therapy, including hydrodynamic performance, thrombogenicity, hemocompatibility, long-term durability, calcification, and transcatheter application. The latter portion of this review summarizes the currently available clinical outcomes data regarding polymeric heart valves and discusses future directions of research.

Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Magnetic susceptibility and R2* of myocardial reperfusion injury at 3T and 7T.

PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.

Altered Responsiveness to TGFß and BMP and Increased CD45+ Cell Presence in Mitral Valves Are Unique Features of Ischemic Mitral Regurgitation.

[Figure: see text].

Iron imaging in myocardial infarction reperfusion injury.

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.

Mitral valve leaflet response to ischaemic mitral regurgitation: from gene expression to tissue remodelling.

Ischaemic mitral regurgitation (IMR), a frequent complication following myocardial infarction (MI), leads to higher mortality and poor clinical prognosis if untreated. Accumulating evidence suggests that mitral valve (MV) leaflets actively remodel post MI, and this remodelling increases both the severity of IMR and the occurrence of MV repair failures. However, the mechanisms of extracellular matrix maintenance and modulation by MV interstitial cells (MVICs) and their impact on MV leaflet tissue integrity and repair failure remain largely unknown. Herein, we sought to elucidate the multiscale behaviour of IMR-induced MV remodelling using an established ovine model. Leaflet tissue at eight weeks post MI exhibited significant permanent plastic radial deformation, eliminating mechanical anisotropy, accompanied by altered leaflet composition. Interestingly, no changes in effective collagen fibre modulus were observed, with MVICs slightly rounder, at eight weeks post MI. RNA sequencing indicated that YAP-induced genes were elevated at four weeks post MI, indicating elevated mechanotransduction. Genes related to extracellular matrix organization were downregulated at four weeks post MI when IMR occurred. Transcriptomic changes returned to baseline by eight weeks post MI. This multiscale study suggests that IMR induces plastic deformation of the MV with no functional damage to the collagen fibres, providing crucial information for computational simulations of the MV in IMR.

Comparative pathology of human and canine myxomatous mitral valve degeneration: 5HT and TGF-ß mechanisms.

Myxomatous mitral valve degeneration (MMVD) is a leading cause of valve repair or replacement secondary to the production of mitral regurgitation, cardiac enlargement, systolic dysfunction, and heart failure. The pathophysiology of myxomatous mitral valve degeneration is complex and incompletely understood, but key features include activation and transformation of mitral valve (MV) valvular interstitial cells (VICs) into an active phenotype leading to remodeling of the extracellular matrix and compromise of the structural components of the mitral valve leaflets. Uncovering the mechanisms behind these events offers the potential for therapies to prevent, delay, or reverse myxomatous mitral valve degeneration. One such mechanism involves the neurotransmitter serotonin (5HT), which has been linked to development of valvulopathy in a variety of settings, including valvulopathy induced by serotonergic drugs, Serotonin-producing carcinoid tumors, and development of valvulopathy in laboratory animals exposed to high levels of serotonin. Similar to humans, the domestic dog also experiences naturally occurring myxomatous mitral valve degeneration, and in some breeds of dogs, the lifetime prevalence of myxomatous mitral valve degeneration reaches 100%. In dogs, myxomatous mitral valve degeneration has been associated with high serum serotonin, increased expression of serotonin-receptors, autocrine production of serotonin within the mitral valve leaflets, and downregulation of serotonin clearance mechanisms. One pathway closely associated with serotonin involves transforming growth factor beta (TGF-ß) and the two pathways share a common ability to activate mitral valve valvular interstitial cells in both humans and dogs. Understanding the role of serotonin and transforming growth factor beta in myxomatous mitral valve degeneration gives rise to potential therapies, such as 5HT receptor (5HT-R) antagonists. The main purposes of this review are to highlight the commonalities between myxomatous mitral valve degeneration in humans and dogs, with specific regards to serotonin and transforming growth factor beta, and to champion the dog as a relevant and particularly valuable model of human disease that can accelerate development of novel therapies.

Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis.

Myostatin (MSTN) is a transforming growth factor (TGF)-ß superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups (n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFß receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFß receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF.NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.

Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery.

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.

MicroRNA-195 Regulates Metabolism in Failing Myocardium Via Alterations in Sirtuin 3 Expression and Mitochondrial Protein Acetylation.

BACKGROUND: Heart failure leads to mitochondrial dysfunction and metabolic abnormalities of the failing myocardium coupled with an energy-depleted state and cardiac remodeling. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function through regulating the mitochondrial acetylome. It is interesting to note that unique cardiac and systemic microRNAs have been shown to play an important role in cardiac remodeling by modulating key signaling elements in the myocardium. METHODS: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells, and acetylation levels in rodent models of SIRT3-/-and transgenic microRNA-195 (miR-195) overexpression were compared with wild type. Luciferase assays, Western blotting, immunoprecipitation assays, and echocardiographic analysis were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. RESULTS: In failing human myocardium, we observed induction of miR-195 along with decreased expression of the mitochondrial deacetylase SIRT3 that was associated with increased global protein acetylation. We further investigated the role of miR-195 in SIRT3-mediated metabolic processes and its impact on regulating enzymes involved in deacetylation. Proteomic analysis of the total acetylome showed increased overall acetylation, and specific lysine acetylation of 2 central mitochondrial metabolic enzymes, PDH and ATP synthase, as well. miR-195 downregulates SIRT3 expression through direct 3'-untranslated region targeting. Treatments with either sirtuin inhibitor nicotinamide, small interfering RNA-mediated SIRT3 knockdown or miR-195 overexpression enhanced acetylation of PDH complex and ATP synthase. This effect diminished PDH and ATP synthase activity and impaired mitochondrial respiration.SIRT3-/- and miR-195 transgenic mice consistently showed enhanced global protein acetylation, including PDH complex and ATP synthase, associated with decreased enzymatic activity. CONCLUSIONS: Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection.

BACKGROUND: Exosomes are cell-derived circulating vesicles that play an important role in cell-cell communication. Exosomes are actively assembled and carry messenger RNAs, microRNAs and proteins. The "gold standard" for cardiac allograft surveillance is endomyocardial biopsy (EMB), an invasive technique with a distinct complication profile. The development of novel, non-invasive methods for the early diagnosis of allograft rejection is warranted. We hypothesized that the exosomal proteome is altered in acute rejection, allowing for a distinction between non-rejection and rejection episodes. METHODS: Serum samples were collected from heart transplant (HTx) recipients with no rejection, acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of serum exosome was performed using a mass spectrometer (Orbitrap Fusion Tribrid). RESULTS: Principal component analysis (PCA) revealed a clustering of 3 groups: (1) control and heart failure (HF); (2) HTx without rejection; and (3) ACR and AMR. A total of 45 proteins were identified that could distinguish between groups (q < 0.05). Comparison of serum exosomal proteins from control, HF and non-rejection HTx revealed 17 differentially expressed proteins in at least 1 group (q < 0.05). Finally, comparisons of non-rejection HTx, ACR and AMR serum exosomes revealed 15 differentially expressed proteins in at least 1 group (q < 0.05). Of these 15 proteins, 8 proteins are known to play a role in the immune response. Of note, the majority of proteins identified were associated with complement activation, adaptive immunity such as immunoglobulin components and coagulation. CONCLUSIONS: Characterizing of circulating exosomal proteome in different cardiac disease states reveals unique protein expression patterns indicative of the respective pathologies. Our data suggest that HTx and allograft rejection alter the circulating exosomal protein content. Exosomal protein analysis could be a novel approach to detect and monitor acute transplant rejection and lead to the development of predictive and prognostic biomarkers.

Increased de novo ceramide synthesis and accumulation in failing myocardium.

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.

Bridging Anticoagulation After Mechanical Aortic Heart Valve Replacement: A Questionable Routine.

BACKGROUND: This retrospective single-center study evaluates differences in bleeding and thrombotic events between a homogenous group of patients undergoing mechanical aortic valve replacement who either received or did not receive intravenous unfractionated heparin or subcutaneous low-molecular weight heparin as bridging strategy to warfarin therapy. METHODS: Clinical data on a total of 158 patients undergoing mechanical aortic valve replacement at our center between 2001 and 2014 were collected. Patients were grouped according to postoperative anticoagulation strategy: warfarin only (n = 53) and warfarin plus heparin bridge (n = 105). The outcomes of interest were bleeding event and thromboembolic event recorded during hospital stay. RESULTS: Patients' baseline characteristics were comparable between the two groups except for preoperative atrial fibrillation, which was more common in the warfarin plus heparin group than the warfarin group (p = 0.04). There were significantly more bleeding complications in the warfarin plus heparin group versus warfarin group as evidenced by higher rates of pericardial effusions (24% versus 8%, p = 0.02) and reoperation for bleeding (8% versus 0%, p = 0.05). All observed thromboembolic events (n = 4) occurred in the warfarin plus heparin group (p = 0.55). Logistic regression analysis identified group assignment (warfarin plus heparin versus warfarin only) to be significantly associated with the odds of bleeding (odds ratio 4.46, 95% confidence interval:1.42 to 14.02, p = 0.01). CONCLUSIONS: Bridging anticoagulation therapy increases the chances of bleeding in the postoperative phase for mechanical aortic valve replacement patients. Owing to low incidence, no statistically significant difference was detected for thromboembolic event rates.

Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy.

Abnormal intracellular calcium (Ca(2+)) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2α), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2α, and XBP1s levels. Apoptosis as reflected by C/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2α/eIF2α and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca(2+) storing protein calsequestrin, Na(+)-Ca(2+) exchanger, sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca(2+) content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca(2+) handling in patients with advanced HF. These changes may impact the potential for myocardial recovery.

Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction.

Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.

Cardiac myostatin upregulation occurs immediately after myocardial ischemia and is involved in skeletal muscle activation of atrophy.

UNLABELLED: Myostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors. METHODS: Coronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total). RESULTS: Cardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN-dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac-derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1. CONCLUSION: Our study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1.

Del Nido Cardioplegia can be safely administered in high-risk coronary artery bypass grafting surgery after acute myocardial infarction: a propensity matched comparison.

OBJECTIVE: Del Nido (DN) cardioplegia solution provides a depolarized hyperkalemic arrest lasting up to 60 minutes, and the addition of lidocaine may limit intracellular calcium influx. Single-dose DN cardioplegia solution may offer an alternative myocardial protection strategy to multi-dose cold whole blood (WB) cardioplegia following acute myocardial infarction (AMI). METHODS: We retrospectively reviewed 88 consecutive patients with AMI undergoing coronary artery bypass (CABG) surgery with cardioplegic arrest between June 2010 to June 2012. Patients exclusively received WB (n = 40, June 2010-July 2011) or DN (n = 48, August 2011-June 2012) cardioplegia. Preoperative and postoperative data were retrospectively reviewed and compared using propensity scoring. RESULTS: No significant difference in age, maximum preoperative serum troponin level, ejection fraction, and STS score was present between DN and WB. A single cardioplegia dose was given in 41 DN vs. 0 WB patients (p < 0.001), and retrograde cardioplegia was used 10 DN vs. 31 WB patients (p < 0.001). Mean cardiopulmonary bypass and cross clamp times were significantly shorter in the DN group versus WB group. Transfusion rate, length of stay, intra-aortic balloon pump requirement, post-operative inotropic support, and 30-day mortality was no different between groups. One patient in the WB group required a mechanical support due to profound cardiogenic shock. CONCLUSIONS: DN cardioplegia may provide equivalent myocardial protection to existing cardioplegia without negative inotropic effects in the setting of acute myocardial infarction.

Suppression of atrogin-1 and MuRF1 prevents dexamethasone-induced atrophy of cultured myotubes.

OBJECTIVE: The mechanistic role of the ubiquitin ligases atrogin-1 and MuRF1 in glucocorticoid-induced muscle wasting is not fully understood. Here, we tested the hypothesis that glucocorticoid-induced muscle atrophy is at least in part linked to atrogin-1 and MuRF1 expression and that the ubiquitin ligases are regulated by compensatory mechanisms. METHODS: The expression of atrogin-1 and MuRF1 was suppressed individually or in combination in cultured L6 myotubes by using siRNA technique. Myotubes were treated with dexamethasone followed by determination of mRNA and protein levels for atrogin-1 and MuRF1, protein synthesis and degradation rates, and myotube morphology. RESULTS: Suppression of atrogin-1 resulted in increased expression of MuRF1 and vice versa, suggesting that the ubiquitin ligases are regulated by compensatory mechanisms. Simultaneous suppression of atrogin-1 and MuRF1 resulted in myotube hypertrophy, mainly reflecting stimulated protein synthesis, and prevented dexamethasone-induced myotube atrophy, mainly reflecting inhibited protein degradation. CONCLUSIONS: The results provide evidence for a link between upregulated atrogin-1 and MuRF1 expression and glucocorticoid-induced muscle atrophy. The study also suggests that atrogin-1 and MuRF1 levels are regulated by compensatory mechanisms and that inhibition of both ubiquitin ligases may be needed to prevent glucocorticoid-induced muscle proteolysis and atrophy.