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.

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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.

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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