A digital approach to create a virtual implant preliminary cast for the fabrication of a splinted framework and custom open tray for multiple implants impression making: A dental technique.

A digital approach is described for fabricating a splinted framework and custom open tray for the impression of multiple implants based on a virtually created implant cast with the digital prediction of the future impression coping positions. In this technique, impression copings to be used in the definitive impression-making process were digitally scanned and aligned to a preliminary cast using installed protective caps of screw-retained abutments as references, which resulted in a virtual cast that offers information both about the impression coping positions and their surrounding tissues and could allow a splinted framework and custom open tray to be digitally designed and fabricated. Creation of a virtual cast through digital technologies eliminates the traditional manual splinted framework and custom tray fabrication procedures. Additionally, only one set of impression copings and analogs is needed in this technique, thereby reducing treatment time and cost. It also offers a splinted framework and custom open tray with consistent quality.

Correlation of hyperpolarized 13 C-MRI data with tissue extract measurements.

Hyperpolarized (HP) 13C MRI provides the means to monitor lactate metabolism noninvasively in tumours. Since 13C -lactate signal levels obtained from HP 13C imaging depend on multiple factors, such as the rate of 13C substrate delivery via the vasculature, the expression level of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH), and the local lactate pool size, the interpretation of HP 13C metabolic images remains challenging. In this study, ex vivo tissue extract measurements (i.e., NMR isotopomer analysis, western blot analysis) derived from an MDA-MB-231 xenograft model in nude rats were used to test for correlations between the in vivo 13C data and the ex vivo measures. The lactate-to-pyruvate ratio from HP 13C MRI was strongly correlated with [1- 13C ]lactate concentration measured from the extracts using NMR (R = 0.69, p < 0.05), as well as negatively correlated with tumour wet weight (R = -  0.60, p < 0.05). In this tumour model, both MCT1 and MCT4 expressions were positively correlated with wet weight ( ρ = 0.78 and 0.93, respectively, p < 0.01). Lactate pool size and the lactate-to-pyruvate ratio were not significantly correlated.

Probing the cardiac malate-aspartate shuttle non-invasively using hyperpolarized [1,2-13 C2 ]pyruvate.

Previous studies have demonstrated that using hyperpolarized [2-13 C]pyruvate as a contrast agent can reveal 13 C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13 C]pyruvate are the result of several metabolic steps. In the instance of the [5-13 C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate-aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate-α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13 C]pyruvate metabolism. Using hyperpolarized [1,2-13 C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13 C-glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13 C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13 C]lactate and [1-13 C]alanine with higher workload. 13 C-Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13 C]pyruvate label, we observed that 13 C-acetylcarnitine production increased 2.5-fold in proportion to the 13 C-bicarbonate signal, whereas the 13 C-glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13 C-glutamate signal relative to the amount of 13 C-labeled acetyl-coenzyme A (acetyl-CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate-aspartate shuttle is limited on adrenergic activation. Changes in [5-13 C]glutamate production from [2-13 C]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required.

Ultrasmall Magnetically Engineered Ag2Se Quantum Dots for Instant Efficient Labeling and Whole-Body High-Resolution Multimodal Real-Time Tracking of Cell-Derived Microvesicles.

Cell-derived microvesicles (MVs) are natural carriers that can transport biological molecules between cells, which are expected to be promising delivery vehicles for therapeutic purposes. Strategies to label MVs are very important for investigation and application of MVs. Herein, ultrasmall Mn-magnetofunctionalized Ag2Se quantum dots (Ag2Se@Mn QDs) integrated with excellent near-infrared (NIR) fluorescence and magnetic resonance (MR) imaging capabilities have been developed for instant efficient labeling of MVs for their in vivo high-resolution dual-mode tracking. The Ag2Se@Mn QDs were fabricated by controlling the reaction of Mn(2+) with the Ag2Se nanocrystals having been pretreated in 80 °C NaOH solution, with an ultrasmall size of ca. 1.8 nm, water dispersibility, high NIR fluorescence quantum yield of 13.2%, and high longitudinal relaxivity of 12.87 mM(-1) s(-1) (almost four times that of the commercial contrast agent Gd-DTPA). The ultrasmall size of the Ag2Se@Mn QDs enables them to be directly and efficiently loaded into MVs by electroporation, instantly and reliably conferring both NIR fluorescence and MR traceability on MVs. Our method for labeling MVs of different origins is universal and free of unfavorable influence on intrinsic behaviors of MVs. The complementary imaging capabilities of the Ag2Se@Mn QDs have made the long-term noninvasive whole-body high-resolution dual-mode tracking of MVs in vivo realized, by which the dynamic biodistribution of MVs has been revealed in a real-time and in situ quantitative manner. This work not only opens a new window for labeling with QDs, but also facilitates greatly the investigation and application of MVs.

Voxel-by-voxel correlations of perfusion, substrate, and metabolite signals in dynamic hyperpolarized (13) C imaging.

In this study, a mixture of pyruvic acid and the perfusion agent HP001 was co-polarized for simultaneous assessment of perfusion and metabolism in vivo. The pre-polarized mixture was administered to rats with subcutaneous MDA-MB-231 breast cancer xenografts and imaged using an interleaved sequence with designed spectral-spatial pulses and flyback echo-planar readouts. Voxel-by-voxel signal correlations from 10 animals (15 data sets) were analyzed for tumour, kidney, and muscle regions of interest. The relationship between perfusion and hyperpolarized signal was explored on a voxel-by-voxel basis in various metabolically active tissues, including tumour, healthy kidneys, and skeletal muscle. Positive pairwise correlations between lactate, pyruvate, and HP001 observed in all 10 tumours suggested that substrate delivery was the dominant factor limiting the conversion of pyruvate to lactate in the tumour model used in this study. On the other hand, in cases where conversion is the limiting factor, such as in healthy kidneys, both pyruvate and lactate can act as excellent perfusion markers. In intermediate cases between the two limits, such as in skeletal muscle, some perfusion information may be inferred from the (pyruvate + lactate) signal distribution. Co-administration of pyruvate with a dynamic nuclear polarization (DNP) perfusion agent is an effective approach for distinguishing between slow metabolism and poor perfusion and a practical strategy for lactate signal normalization to account for substrate delivery, especially in cases of rapid pyruvate-to-lactate conversion and in poorly perfused regions with inadequate pyruvate signal-to-noise ratio for reliable determination of the lactate-to-pyruvate ratio. Copyright © 2016 John Wiley & Sons, Ltd.

Immuno-modification of enhancing stem cells targeting for myocardial repair.

Despite the controversy in mechanism, rodent and clinical studies have demonstrated beneficial effects of stem/progenitor cell therapy after myocardial infarction (MI). In a rat ischaemic reperfusion MI model, we investigated the effects of immunomodification of CD 34(+) cells on heart function and myocardial conduction. Bispecific antibody (BiAb), consisting of an anti-myosin light chain antibody and anti-CD45 antibody, injected intravenously was used to direct human CD34(+) cells to injured myocardium. Results were compared to echocardiography guided intramyocardial (IM) injection of CD34(+) cells and PBS injected intravenously. Treatment was administered 2 days post MI. Echocardiography was performed at 5 weeks and 3 months which demonstrated LV dilatation prevention and fractional shortening improvement in both the BiAb and IM injection approaches, with BiAb achieving better results. Histological analyses demonstrated a decrease in infarct size and increase in arteriogenesis in both BiAb and IM injection. Electrophysiological properties were studied 5 weeks after treatments by optical mapping. Conduction velocity (CV), action potential duration (APD) and rise time were significantly altered in the MI area. The BiAb treated group demonstrated a more normalized activation pattern of conduction and normalization of CV at shorter pacing cycle lengths. The ventricular tachycardia inducibility was lowest in the BiAb treatment group. Intravenous administration of BiAb offers an effective means of stem cell delivery for myocardial repair post-acute MI. Such non-invasive approach was shown to offer a distinct advantage to more invasive direct IM delivery.

A calibration-based approach to real-time in vivo monitoring of pyruvate C1 and C2 polarization using the JCC spectral asymmetry.

A calibration-based technique for real-time measurement of pyruvate polarization by partial integral analysis of the doublet from the neighbouring J-coupled carbon is presented. In vitro calibration data relating the C2 and C1 asymmetries to the instantaneous C1 and C2 polarizations, respectively, were acquired in blood. The feasibility of using the in vitro calibration data to determine the instantaneous in vivo C1 and C2 polarizations was demonstrated in the analysis of rat kidney and pig heart spectral data. An approach for incorporating this technique into in vivo protocols is proposed.

Ultrasmall near-infrared Ag2Se quantum dots with tunable fluorescence for in vivo imaging.

A strategy is presented that involes coupling Na(2)SeO(3) reduction with the binding of silver ions and alanine in a quasi-biosystem to obtain ultrasmall, near-infrared Ag(2)Se quantum dots (QDs) with tunable fluorescence at 90 °C in aqueous solution. This strategy avoids high temperatures, high pressures, and organic solvents so that water-dispersible sub-3 nm Ag(2)Se QDs can be directly obtained. The photoluminescence of the Ag(2)Se QDs was size-dependent over a wavelength range from 700 to 820 nm, corresponding to sizes from 1.5 ± 0.4 to 2.4 ± 0.5 nm, with good monodispersity. The Ag(2)Se QDs are less cytotoxic than other nanomaterials used for similar applications. Furthermore, the NIR fluorescence of the Ag(2)Se QDs could penetrate through the abdominal cavity of a living nude mouse and could be detected on its back side, demonstrating the potential applications of these less toxic NIR Ag(2)Se QDs in bioimaging.

Near-infrared electrogenerated chemiluminescence of ultrasmall Ag2Se quantum dots for the detection of dopamine.

The near-infrared (NIR) electrogenerated chemiluminescence (ECL) of water-dispersed Ag(2)Se quantum dots (QDs) with ultrasmall size was presented for the first time. The Ag(2)Se QDs have shown a strong and efficient cathodic ECL signal with K(2)S(2)O(8) as coreactant on the glassy carbon electrode (GCE) in aqueous solution. The ECL spectrum exhibited a peak at 695 nm, consistent with the peak in photoluminescence (PL) spectrum of the Ag(2)Se QDs solution, indicating that the Ag(2)Se QDs had no deep surface traps. Dopamine was chosen as a model analyte to study the potential of Ag(2)Se QDs in the ECL analytical application. The ECL signal of Ag(2)Se QDs can also be used for the detection of the dopamine concentration in the practical drug (dopamine hydrochloride injection) containing several adjuvants such as edetate disodium, sodium bisulfite, sodium chloride and so on. The Ag(2)Se QDs could be a promising candidate emitter of ECL biosensors in the future due to their fantastic features, such as ultrasmall size, low toxicity, good water solubility, and near infrared (NIR) fluorescent emission.

Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and pH, using hyperpolarized [1,2-(13)C2]pyruvate in vivo.

(13)C MR spectroscopy studies performed on hearts ex vivo and in vivo following perfusion of prepolarized [1-(13)C]pyruvate have shown that changes in pyruvate dehydrogenase (PDH) flux may be monitored non-invasively. However, to allow investigation of Krebs cycle metabolism, the (13)C label must be placed on the C2 position of pyruvate. Thus, the utilization of either C1 or C2 labeled prepolarized pyruvate as a tracer can only afford a partial view of cardiac pyruvate metabolism in health and disease. If the prepolarized pyruvate molecules were labeled at both C1 and C2 positions, then it would be possible to observe the downstream metabolites that were the results of both PDH flux ((13)CO(2) and H(13)CO(3)(-)) and Krebs cycle flux ([5-(13)C]glutamate) with a single dose of the agent. Cardiac pH could also be monitored in the same experiment, but adequate SNR of the (13)CO(2) resonance may be difficult to obtain in vivo. Using an interleaved selective RF pulse acquisition scheme to improve (13)CO(2) detection, the feasibility of using dual-labeled hyperpolarized [1,2-(13)C(2)]pyruvate as a substrate for dynamic cardiac metabolic MRS studies to allow simultaneous investigation of PDH flux, Krebs cycle flux and pH, was demonstrated in vivo.

Birth defects data from hospital-based birth defect surveillance in Guilin, China, 2018-2020.

Objectives: Birth defects (BDs) are a major contributor to perinatal and infant mortality, morbidity and lifelong disability worldwide. A hospital-based study on birth defects was designed in Guilin city in the Guangxi province of Southwestern China aiming to determine the prevalence of BDs in the studied region, and the classify the BDs based on clinical presentation and causation. Methods: The study involved BDs among all pregnancy outcomes (live births, stillbirths, death within 7 days, and pregnancy terminations) born in the 42 registered hospitals of Guilin between 2018 and 2020. The epidemiological characteristics of BDs and the etiologic profile of BDs were evaluated in this study. Results: Of the total 147,817 births recorded during the study period, 2,003 infants with BDs were detected, giving a total prevalence rate of 13.55 per 1,000 births. The top five BD types were congenital heart defects, polydactyly, syndactyly, malformations of the external ear, and talipes equinovarus, whereas, neural tube defects, congential esophageal atresia, gastroschisis, extrophy of urinary bladder, were the least common BD types in these 3 years. Only 8.84% of cases were assigned a known etiology, while most cases (91.16%) could not be conclusively assigned a specific cause. Conclusion: This study provides an epidemiological description of BDs in Guilin, which may be helpful for understanding the overall situation in Southwest China of BDs and aid in more comprehensive studies of BDs in future healthcare systems, including funding investment, policy-making, monitor, prevention. Strong prevention strategies should be the priority to reduce BDs and improve the birth quality.

(13)C MR reporter probe system using dynamic nuclear polarization.

Reporter-based cell detection and localization in vivo may become an important imaging tool with the emergence of cellular therapy. With the strong signal enhancement provided by dynamic nuclear polarization, an NMR-based reporter probe system utilizing specific enzyme expression and activity can potentially provide stable, high-resolution visualization of the cells of interest noninvasively. In this work, a proof-of-concept (13) C MR reporter system, using the aminoacylase-1 reporter gene (Acy-1) and prepolarized [1-(13) C]N-acetyl-L-methionine as the paired substrate, was developed. Using a 3-T MR scanner, the feasibility of detecting and imaging de-acetylation of the prepolarized (13) C-labeled substrate by the aminoacylase-1 enzyme was demonstrated with purified protein in solution by dynamic (13) C MRS and two-dimensional MRSI experiments. The potential to perform targeted MRI of cells using this system was also demonstrated by (13) C MR measurement of aminoacylase-1 activity in HEK 293 cells transfected with the Acy-1 gene. The de-acetylation of the substrate was not observed in control cells.

Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations.

BACKGROUND: Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing (RMRP) gene. Typical features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity. OBJECTIVE: We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients with RMRP mutations who were referred to 2 different institutions for immunologic evaluation. METHODS: We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. T-cell repertoire was investigated by quantitating Vbeta families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output. RESULTS: All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported. CONCLUSION: This report broadens the spectrum of phenotypes associated with RMRP mutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.

Three-Dimensional Visual Patient Based on Electronic Medical Diagnostic Records.

OBJECTIVE: an innovative concept and method is introduced to use a 3-D anatomical graphic pattern called visual patient (VP) visually to index, represent, and render the medical diagnostic records (MDRs) of a patient, so that a doctor can quickly learn the current and historical medical status of the patient by manipulating VP. The MDRs can be imaging diagnostic reports and DICOM images, laboratory reports and clinical summaries which can have clinical information relating to medical status of human organs or body parts. METHODS: the concept and method included three steps. First, a VP data model called visual index object (VIO) and a VP graphic model called visual anatomic object (VAO) were introduced. Second, a series of processing methods of parsing and extracting key information from MDRs were used to fill the attributes of the VIO model of a patient. Third, a VP system (VPS) was designed to map VIO to VAO, to create a VP instance for each patient. RESULTS: a prototype VPS has been implemented in a simulated hospital PACS/RIS integrated environment. Two evaluation results showed that more than 70% participating radiologists would like to use the VPS in their radiological imaging tasks, and the efficiency of using VPS to review the tested patients' MDRs was 2.24 times higher than that of using PACS/RIS, while the average accuracy by using PACS/RIS was better than that by using VPS; however, this difference was only about 4%. CONCLUSION: the developed VPS can show the medical status of patient organs/sub-organs with 3-D anatomical graphic pattern and will be welcomed by radiologists with better efficiency in reviewing the patients' MDRs and with acceptable accuracy. SIGNIFICANCE: the VP introduces a new way for medical professionals to access and interact with a huge amount of patient records with better efficiency in the big data era.

Tissue engineering and stem cell therapy for myocardial repair.

Cardiovascular disease is a major public health problem in the United States. In many survivors, extensive tissue damage from myocardial infarction leads to the development of congestive heart failure. Unfortunately, thus far, heart transplantation has remained the only viable treatment for end-stage congestive heart failure. Lack of available donor hearts has thus led to search for alternative therapies. Among these, cell therapy has raised a great enthusiasm for myocardial repair. However, it suffers limitations associated with cell retention, survival and differentiation. In addition, the results from preclinical and clinical studies based on such treatments have generated mixed results. For this reason, hybrid therapies that incorporate tissue engineering are being developed as potentially new therapeutic approaches for repair of myocardial tissue. Here, we review the current progress in cardiac tissue repair and engineering; and discuss the new emerging technologies.

Effect of IGF-1 on the balance between autophagy of dysfunctional mitochondria and apoptosis.

Mutations in mitochondrial DNA (mtDNA) cause excessive production of mitochondrial reactive oxygen species (ROS) and shorten animal life span. We examined the mechanisms responsible for removal of mitochondria with deleterious mtDNA mutations by autophagy. Incubation of primary cells and cell lines in the absence of serum promotes autophagy of mitochondria with deleterious mtDNA mutations but spares their normal counterparts. The effect of serum withdrawal on the autophagy of dysfunctional mitochondria is prevented by the addition of IGF-1. As a result of the elimination of mitochondria with deleterious mutations, excessive ROS production, characteristic of dysfunctional mitochondria, is greatly reduced. Mitochondrial autophagy shares a common mechanism with mitochondrial-induced cell apoptosis, including mitochondrial transition pore formation and increased ROS production.

Intrinsic contrast for characterization of acute radiofrequency ablation lesions.

BACKGROUND: Both intrinsic contrast (T1 and T2 relaxation and the equilibrium magnetization) and contrast agent (gadolinium)-enhanced MRI are used to visualize and evaluate acute radiofrequency ablation lesions. However, current methods are imprecise in delineating lesion extent shortly after the ablation. METHODS AND RESULTS: Fifteen lesions were created in the endocardium of 13 pigs. A multicontrast inversion recovery steady state free precession imaging method was used to delineate the acute ablation lesions, exploiting T1-weighted contrast. T2 and Mo(*) maps were also created from fast spin echo data in a subset of pigs (n=5) to help characterize the change in intrinsic contrast in the lesions. Gross pathology was used as reference for the lesion size comparison, and the lesion structures were confirmed with histological data. In addition, a colorimetric iron assay was used to measure ferric and ferrous iron content in the lesions and the healthy myocardium in a subset of pigs (n=2). The lesion sizes measured in inversion recovery steady state free precession images were highly correlated with the extent of lesion core identified in gross pathology. Magnetic resonance relaxometry showed that the radiofrequency ablation procedure changes the intrinsic T1 value in the lesion core and the intrinsic T2 in the edematous region. Furthermore, the T1 shortening appeared to be correlated with the presence of ferric iron, which may have been associated with metmyoglobin and methemoglobin in the lesions. CONCLUSIONS: The study suggests that T1 contrast may be able to separate necrotic cores from the surrounding edematous rims in acute radiofrequency ablation lesions.

Probing early tumor response to radiation therapy using hyperpolarized [1-¹³C]pyruvate in MDA-MB-231 xenografts.

Following radiation therapy (RT), tumor morphology may remain unchanged for days and sometimes weeks, rendering anatomical imaging methods inadequate for early detection of therapeutic response. Changes in the hyperpolarized [1-¹³C]lactate signals observed in vivo following injection of pre-polarized [1-¹³C]pyruvate has recently been shown to be a marker for tumor progression or early treatment response. In this study, the feasibility of using ¹³C metabolic imaging with [1-¹³C]pyruvate to detect early radiation treatment response in a breast cancer xenograft model was demonstrated in vivo and in vitro. Significant decreases in hyperpolarized [1-¹³C]lactate relative to [1-¹³C]pyruvate were observed in MDA-MB-231 tumors 96 hrs following a single dose of ionizing radiation. Histopathologic data from the treated tumors showed higher cellular apoptosis and senescence; and changes in the expression of membrane monocarboxylate transporters and lactate dehydrogenase B were also observed. Hyperpolarized ¹³C metabolic imaging may be a promising new tool to develop novel and adaptive therapeutic regimens for patients undergoing RT.

Hyperpolarized (13)C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart.

AIMS: Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease. METHODS AND RESULTS: Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively. CONCLUSION: Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression.

In silico cardiac risk assessment in patients with long QT syndrome: type 1: clinical predictability of cardiac models.

OBJECTIVES: The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1). BACKGROUND: Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm. METHODS: A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients. RESULTS: Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; ≥upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; ≥upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP. CONCLUSIONS: These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information.