Rationale: Metabolic and structural remodeling is a hallmark of heart failure. This remodeling involves activation of the mTOR (mammalian target of rapamycin) signaling pathway, but little is known on how intermediary metabolites are integrated as metabolic signals. Objective: We investigated the metabolic control of cardiac glycolysis and explored the potential of glucose 6-phosphate (G6P) to regulate glycolytic flux and mTOR activation. Methods and Results: We developed a kinetic model of cardiomyocyte carbohydrate metabolism, CardioGlyco , to study the metabolic control of myocardial glycolysis and G6P levels. Metabolic control analysis revealed that G6P concentration is dependent on phosphoglucose isomerase (PGI) activity. Next, we integrated ex vivo tracer studies with mathematical simulations to test how changes in glucose supply and glycolytic flux affect mTOR activation. Nutrient deprivation promoted a tight coupling between glucose uptake and oxidation, G6P reduction, and increased protein-protein interaction between hexokinase II and mTOR. We validated the in silico modeling in cultured adult mouse ventricular cardiomyocytes by modulating PGI activity using erythrose 4-phosphate. Inhibition of glycolytic flux at the level of PGI caused G6P accumulation, which correlated with increased mTOR activation. Using click chemistry, we labeled newly synthesized proteins and confirmed that inhibition of PGI increases protein synthesis. Conclusions: The reduction of PGI activity directly affects myocyte growth by regulating mTOR activation.
This study found that only assignment to group 3, initial lactic acid level of ≥ 4 mmol/L, was independently associated with increased mortality after correcting for underlying severity of illness and organ dysfunction. However, rising lactate levels in the other two groups were associated with increased severity of illness and were inversely proportional to prognosis.
Ewing sarcoma is the second most prevalent malignant primary bone tumor but constitutes only a small proportion of cardiac metastases. We present a case of asymptomatic Ewing sarcoma metastatic to the right ventricle.A 1 Approximately 25% of primary cardiac tumors are malignant.1 Metastases to the heart are 20 to 40 times more prevalent than are primary cardiac malignancies.1 The estimated incidence of metastasis to the heart is 10% to 15.4%; lung tumors, lymphomas, and carcinomas of the breast are the typical metastatic sources. 2,3Ewing sarcoma is the second most frequent primary malignant bone tumor (after osteosarcoma) but accounts for only a small proportion of cardiac metastases. 4-6 Its metastatic incidence in the right ventricle (RV) is not precisely known. We present the case of a patient who had asymptomatic Ewing sarcoma metastatic to the RV. Case ReportIn December 2013, a 36-year-old asymptomatic man presented for evaluation of a mass in his RV. Three years earlier, because of translocation-negative Ewing sarcoma, he had undergone below-the-knee amputation of the left leg and consequent chemotherapy. Two years later, he was found to have a lung metastasis. Genetic analysis of the resected lung tissue identified mechanistic target of rapamycin (mTOR) E1799K, Ewing sarcoma breakpoint region 1 (EWSR1) gene fusion with nuclear factor of activated Tcell cytoplasmic 2 gene (NFATc2), and topoisomerase 1 (TOP1) amplification lesions. These were consistent with Ewing sarcoma and prompted further chemotherapy.Three months after the lung resection, magnetic resonance images (MRI) of the lungs revealed a 3.5 × 2.6-cm enhancing mass in the RV (Fig. 1), and the patient presented at our institution for possible resection of the mass. He was exceptionally physically fit and had no history of cardiac diseases. Results of positron emission tomography (PET) confirmed the presence of a metabolically active tumor (Fig. 2). The patient underwent cardiac evaluation and was cleared for surgery.An intraoperative transesophageal echocardiogram showed a preserved left ventricular (LV) ejection fraction. Other than a pedunculated mass attached to the RV, there were no structural abnormalities of the heart.Under direct vision, with a normothermic beating heart, the tumor was resected with negative margins and no residual mass. Right atrial biopsies were also performed (with 2-mm negative margins on a frozen section). The total cardiopulmonary bypass time was 22 min. Postoperative transthoracic echocardiograms (TTEs) showed normal LV and RV size and function.The morphology and immunohistochemical stains of the resected mass were consistent with a metastatic Ewing sarcoma tumor deposit. It was composed of highly malignant cells with moderate nuclear pleomorphism, a high nuclear-to-cytoplasmic ratio, frequent mitoses (16 per 10 high-power fields), and clear-to-finely vacuolated
SUMOylation, a reversible post-transcriptional modification process, of proteins are involved in cellular differentiation, growth, and even motility by regulating various protein functions. SUMOylation is not limited to cytosolic proteins as recent evidence shows that nuclear proteins, those associated with membranes, and mitochondrial proteins are also SUMOylated. Moreover, it is now known that SUMOylation plays an important role in the process of major human ailments such as malignant, cardiovascular and neurological diseases. In this chapter, we will highlight and discuss how the localization of SUMO protease and SUMO E3 ligase in different compartments within a cell regulates biological processes that depend on SUMOylation. First, we will discuss the key role of SUMOylation in the nucleus, which leads to the development of endothelial dysfunction and atherosclerosis. We will then discuss how SUMOylation of plasma membrane potassium channel proteins are involved in epilepsy and arrhythmia. Mitochondrial proteins are known to be also SUMOylated, and the importance of dynamic-related protein 1 (DRP1) SUMOylation on mitochondrial function will be discussed. As we will emphasize throughout this review, SUMOylation plays crucial roles in different cellular compartments, which is coordinately regulated by the translocation of various SUMO proteases and SUMO E3 ligase. Comprehensive approach will be necessary to understand the molecular mechanism for efficiently moving around various enzymes that regulate SUMOylation within cells.
Background Prolonged length of stay (LOS) and post‐acute care after percutaneous coronary intervention (PCI) is common and costly. Risk models for predicting prolonged LOS and post‐acute care have limited accuracy. Our goal was to develop and validate models using artificial neural networks (ANN) to predict prolonged LOS > 7days and need for post‐acute care after PCI. Methods We defined prolonged LOS as ≥7 days and post‐acute care as patients discharged to: extended care, transitional care unit, rehabilitation, other acute care hospital, nursing home or hospice care. Data from 22 675 patients who presented with ACS and underwent PCI was shuffled and split into a derivation set (75% of dataset) and a validation dataset (25% of dataset). Calibration plots were used to examine the overall predictive performance of the MLP by plotting observed and expected risk deciles and fitting a lowess smoother to the data. Classification accuracy was assessed by a receiver‐operating characteristic (ROC) and area under the ROC curve (AUC). Results Our MLP‐based model predicted prolonged LOS with an accuracy of 90.87% and 88.36% in training and test sets, respectively. The post‐acute care model had an accuracy of 90.22% and 86.31% in training and test sets, respectively. This accuracy was achieved with quick convergence. Predicted probabilities from the MLP models showed good (prolonged LOS) to excellent calibration (post‐acute care). Conclusions Our ANN‐based models accurately predicted LOS and need for post‐acute care. Larger studies for replicability and longitudinal studies for evidence of impact are needed to establish these models in current PCI practice.
Objectives Therapeutic hypothermia has been shown to improve neurologic outcome and survival in out‐of‐hospital cardiac arrest (OHCA) following return of spontaneous circulation (ROSC), and current guidelines recommend therapeutic hypothermia for all comatose survivors of OHCA. However, recommendations for nonshockable rhythms are not as strongly supported. Our study aims to provide further evidence on the use of therapeutic hypothermia in nonshockable rhythms. Methods A multivariate analysis with propensity score matching was performed using a cardiac arrest registry maintained by the Houston Fire Department. The analysis was limited to adult patients achieving ROSC following OHCA secondary to nonshockable rhythm in Houston from 2007 to 2012 with definitive information regarding the implementation of therapeutic hypothermia. The primary outcome was survival to hospital discharge. Results Of 9,479 records identified for analysis, 7,839 had an initial nonshockable rhythm. Of these, 2,609 (33.3%) had sustained ROSC and 1,768 (22.6%) were admitted to the hospital. Data on therapeutic hypothermia use were available for 696 patients, with 335 (48.1%) receiving therapeutic hypothermia. Propensity score matching yielded 260 case/control pairs. The odds of survival to hospital discharge was an odds ratio of 1.07 (95% confidence interval = 0.71 to 1.60) for those in the therapeutic hypothermia group versus the nontherapeutic hypothermia group (p = 0.79). Conclusions Based on this retrospective study, therapeutic hypothermia is not associated with improved survival in patients with OHCA secondary to nonshockable rhythms. Given the limitations of our study, further prospective trials to assess the effect of therapeutic hypothermia for OHCA with nonshockable rhythms are warranted.
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