Surfactant Enhanced Laser-Induced Vapor Bubbles for Potential use in Thulium Fiber Laser Lithotripsy.

The Thulium fiber laser (TFL) is being explored as a potential alternative to the gold standard Holmium:YAG laser for infrared laser ablation of kidney stones. Laser-induced vapor bubbles contribute to both the ablation mechanism and stone retropulsion. In this preliminary study, a biocompatible surfactant with concentrations of 1-5% was used to enhance the vapor bubble dimensions during the laser pulse. Bubble dimensions using surfactant increased on average by 25% compared with water only (control). With further development, introduction of the surfactant into the saline irrigation flow typically delivered through the working channel of the ureteroscope during laser lithotripsy, may contribute to more efficient stone ablation.Clinical Relevance-This preliminary study demonstrates that the dimensions of laser-induced vapor bubbles created during infrared laser lithotripsy can be enhanced by up to 25%, for potential clinical translation into more efficient lithotripsy and use in the "popcorn" ablation method.

Discrimination Between Explosive Materials and Isomers Using a Human Color Vision-Inspired Sensing Method.

This paper describes the application of a human color vision approach to infrared (IR) chemical sensing for the discrimination between multiple explosive materials deposited on aluminum substrates. This methodology classifies chemicals using the unique response of the chemical vibrational absorption bands to three broadband overlapping IR optical filters. For this effort, Fourier transform infrared (FT-IR) spectroscopy is first used to computationally examine the ability of the human color vision sensing approach to discriminate between three similar explosive materials, 1,3,5,-Trinitro-1,3,5-triazinane (RDX), 2,2-Bis[(nitrooxy)methyl]propane-1,3,-diyldinitrate (PETN), and 1,3,5,7-Tetranitro-1,3,5,7-tetrazocane (HMX). A description of a laboratory breadboard optical sensor designed for this approach is then provided, along with the discrimination results collected for these samples using this sensor. The results of these studies demonstrate that the human color vision approach is capable of high-confidence discrimination of the examined explosive materials.

Coronary Artery-Left Ventricular Fistula and Takotsubo Cardiomyopathy - An Association or an Incidental Finding? A Case Report.

BACKGROUND A coronary artery-left ventricular fistula is an anomalous communication between the coronary arteries and the cardiac chambers and is a rare congenital coronary anomaly that is often small and asymptomatic. Takotsubo cardiomyopathy, on the other hand, is a syndrome characterized by transient regional systolic dysfunction of the left ventricle, mimicking myocardial infarction, but in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. We present the case of an elderly woman who presented with Takotsubo cardiomyopathy and who was incidentally discovered to have an associated coronary artery-left ventricular fistula. CASE REPORT We report the case of a 68-years-old woman with a family history of premature cardiac diseases who presented with ischemic chest pain and elevated troponin levels. Her EKG and troponins were suggestive of non-ST-elevation myocardial infarction (NSTEMI), for which she was initially treated medically and later underwent coronary angiography. Unexpectedly, the angiography revealed patent coronary arteries, and we discovered evidence of coronary artery to left ventricular fistula in the addition to angiographic evidence of Takotsubo cardiomyopathy. A working diagnosis of Takotsubo was made, for which she was treated medically with resulting improvement of her symptoms and later in the imaging findings. CONCLUSIONS This described case illustrates a rare association between coronary artery fistulas and Takotsubo cardiomyopathy. It is unclear if this association has played a role in the pathogenesis or perhaps is just an incidental finding. More similar cases are needed to expand the clinical presentation of both conditions and add to the literature.

Kinematics of the Pelvis, Torso, and Lower Limb During Obstacle Negotiation While Under Temporal Constraints.

Biomechanics of unobstructed locomotion consists of synchronized complex movements of the pelvis, torso, and lower limbs. These movement patterns become more complex as individuals encounter obstacles or negotiate uneven terrain. To date, limited research has explored how specifically the pelvis, torso, and lower limb segments relate to obstacle negotiation of varying sized objects combined with temporal constraints to perform the task. Understanding pelvis and adjoining segment movements during object negotiation will provide necessary information in identifying abnormal mechanics and potential fall risk characteristics in balance compromised patient populations. In this prospective cohort study, we aimed to compare pelvic, torso, and lower limb kinematics during unobstructed locomotion with obstacle negotiation of varying heights. Ten healthy young adults (7 females and 3 males, mean age 28.4 ± 4.1 years, mean body mass index 22.5 ± 3.6 kg/m2 ) enrolled in this study. Analysis of within-subject differences revealed a significant increase in sagittal (posterior tilt) and frontal (ipsilateral hike) plane pelvic angular displacement and higher sagittal plane posterior torso lean angular displacement with increased obstacle height. Furthermore, both sagittal plane hip and knee maximum joint flexion were significantly higher with increasing heights of the obstacles during negotiation. These data provide insight on segment mechanics within a non-mobility-impaired population; therefore, providing a baseline to understand the kinematic demands necessary for safe and effective gait in mobility-compromised populations. Anat Rec, 300:732-738, 2017. © 2017 Wiley Periodicals, Inc.

Analysis of thulium fiber laser induced bubble dynamics for ablation of kidney stones.

The Thulium fiber laser (TFL) is being explored as an alternative to the Holmium : YAG laser for lithotripsy. TFL parameters differ in several fundamental ways from Holmium laser, including smaller fiber delivery, more strongly absorbed wavelength, low pulse energy/high pulse rate operation, and more uniform temporal pulse structure. High speed imaging of laser induced bubbles was performed at 105,000 frames per second and 10 µm spatial resolution to determine influence of these laser parameters on bubble formation and needle hydrophone data was also used to measure pressure transients. The TFL was operated at 1908 nm with pulse energies of 5-65 mJ, and pulse durations of 200-1000 µs, delivered through 105-µm-core and 270-µm-core silica optical fibers. Bubble dynamics using Holmium laser at a wavelength of 2100 nm with pulse energies of 200-1000 mJ and pulse duration of 350 µs was studied, for comparison. A single, 500 µs TFL pulse produced a bubble stream extending 1200 ± 90 µm and 1070 ± 50 µm from fiber tip, with maximum bubble widths averaging 650 ± 20 µm and 870 ± 40 µm (n = 4), for 105 µm and 270 µm fibers, respectively. These observations are consistent with previous studies which reported TFL ablation stallout at working distances beyond 1.0 mm. TFL bubble dimensions were four times smaller than for Holmium laser due to lower peak power and smaller fiber diameter used. The maximum pressure transients measured 0.6 bars at 35 mJ pulse energy for TFL and 7.5 bars at 600 mJ pulse energy for Holmium laser. These fundamental studies of bubble dynamics as a function of specific laser and fiber parameters may assist with optimization of the TFL parameters for safe and efficient lithotripsy in the clinic. Image of bubble formation during fiber optic delivery of Thulium fiber laser energy in saline (35 mJ, 500 µs).

A Miniaturized, 1.9F Integrated Optical Fiber and Stone Basket for Use in Thulium Fiber Laser Lithotripsy.

The thulium fiber laser (TFL) is being explored as an alternative laser lithotripter to the standard holmium:yttrium-aluminum-garnet laser. The more uniform beam profile of the TFL enables higher power transmission through smaller fibers. In this study, a 100-µm core, 140-µm outer-diameter (OD) silica fiber with 5-mm length hollow steel tip was integrated with 1.3F (0.433-mm OD) nitinol wire basket to form a 1.9F (0.633-mm OD) device. TFL energy of 30 mJ, 500 µs pulse duration, and 500 Hz pulse rate was delivered to human uric acid stones, ex vivo. Stone ablation rates measured 1.5 ± 0.2 mg/s, comparable to 1.7 ± 0.3 mg/s using bare fiber tips separately with stone basket. With further development, this device may minimize stone retropulsion, allowing more efficient TFL lithotripsy at higher pulse rates. It may also provide increased flexibility, higher saline irrigation rates through the ureteroscope working channel, reduce fiber degradation compared with separate fiber and basket manipulation, and reduce laser-induced nitinol wire damage.

Collateral damage to the ureter and Nitinol stone baskets during thulium fiber laser lithotripsy.

BACKGROUND: The experimental Thulium fiber laser (TFL) is currently being studied as a potential alternative lithotripter to the clinical gold standard Holmium:YAG laser. Safety studies characterizing undesirable Holmium:YAG laser-induced damage to ureter tissue and stone baskets have been previously reported. Similarly, this study characterizes TFL induced ureter and stone basket damage. METHODS: A TFL beam with energy of 35 mJ per pulse, pulse duration of 500 µs, and variable pulse rates of 50-500 Hz, was delivered through 100-µm-core optical fibers, to either porcine ureter wall, in vitro, or a standard 1.9-Fr Nitinol stone basket wire. Ureter perforation times were measured and gross, histological, and optical coherence tomography images of the ablation area were acquired. Stone basket damage was graded as a function of pulse rate, number of pulses, and working distance. RESULTS: TFL operation at 150, 300, and 500 Hz produced mean ureter perforation times of 7.9, 3.8, and 1.8 seconds, respectively. Collateral damage widths averaged 510, 370, and 310 µm. Nitinol wire damage decreased with working distance and was non-existent at distances greater than 1.0 mm. In contact mode, 500 pulses delivered at pulse rates ≥300 Hz (≤1.5 seconds) were sufficient to cut Nitinol wires. CONCLUSIONS: The TFL, operated in low pulse energy and high pulse rate mode, may provide a greater safety margin than the standard Holmium:YAG laser for lithotripsy, as evidenced by longer TFL ureter perforation times and shorter non-contact working distances for stone basket damage than previously reported with Holmium:YAG laser.

Comparison of Four Lasers (λ = 650, 808, 980, and 1075 nm) for Noninvasive Creation of Deep Subsurface Lesions in Tissue.

Lasers have been used in combination with applied cooling methods to preserve superficial skin layers (100's µm's) during cosmetic surgery. Preservation of a thicker tissue surface layer (millimeters) may also allow development of other noninvasive laser procedures. We are exploring noninvasive therapeutic laser applications in urology (e.g. laser vasectomy and laser treatment of female stress urinary incontinence), which require surface tissue preservation on the millimeter scale. In this preliminary study, four lasers were compared for noninvasive creation of deep subsurface thermal lesions. Laser energy from three diode lasers (650, 808, and 980 nm) and a Ytterbium fiber laser (1075 nm) was delivered through a custom built, side-firing, laser probe with integrated cooling. An alcohol-based solution at -5°C was circulated through a flow cell, cooling a sapphire window, which in turn cooled the tissue surface. The probe was placed in contact with porcine liver tissue, ex vivo, kept hydrated in saline and maintained at ~ 35°C. Incident laser power was 4.2 W, spot diameter was 5.3 mm, and treatment time was 60 s. The optimal laser wavelength tested for creation of deep subsurface thermal lesions during contact cooling of tissues was 1075 nm, which preserved a surface layer of ~ 2 mm. The Ytterbium fiber laser provides a compact, low maintenance, and high power alternative laser source to the Neodymium:YAG laser for noninvasive thermal therapy.

Thulium fiber laser lithotripsy in an in vitro ureter model.

Using a validated in vitro ureter model for laser lithotripsy, the performance of an experimental thulium fiber laser (TFL) was studied and compared to the clinical gold standard holmium:YAG laser. The holmium laser (λ = 2120 nm) was operated with standard parameters of 600 mJ, 350 µs, 6 Hz, and 270-µm-core optical fiber. The TFL (λ=1908 nm) was operated with 35 mJ, 500 µs, 150 to 500 Hz, and a 100-µm-core fiber. Urinary stones (60% calcium oxalate monohydrate/40% calcium phosphate) of uniform mass and diameter (4 to 5 mm) were laser ablated with fibers through a flexible video-ureteroscope under saline irrigation with flow rates of 22.7 and 13.7 ml/ min for the TFL and holmium laser, respectively. The temperature 3 mm from the tube's center and 1 mm above the mesh sieve was measured by a thermocouple and recorded throughout each experiment for both lasers. Total laser and operation times were recorded once all stone fragments passed through a 1.5-mm sieve. The holmium laser time measured 167±41 s (n=12). TFL times measured 111±49, 39±11, and 23±4 s, for pulse rates of 150, 300, and 500 Hz, respectively (n=12 each). Mean peak saline irrigation temperatures reached 24±1°C for holmium, and 33±3°C, 33±7°C, and 39±6°C, for TFL at pulse rates of 150, 300, and 500 Hz, respectively. To avoid thermal buildup and provide a sufficient safety margin, TFL lithotripsy should be performed with pulse rates below 500 Hz and/or increased saline irrigation rates. The TFL rapidly fragmented kidney stones due in part to its high pulse rate, high power density, high average power, and observation of reduced stone retropulsion and may provide a clinical alternative to the conventional holmium laser for lithotripsy.

Obesogenic high fat western diet induces oxidative stress and apoptosis in rat heart.

Feeding Wistar rats a high calorie "Western" diet (45% fat) for up to 48 weeks induces obesity and cardiac dysfunction, while a high fat diet (60% fat) induces obesity only. Here we investigated the molecular "footprints" of the two forms of diet-induced obesity in the heart. In rats fed Western diet for a long term, cardiac mRNA transcript levels of malic enzyme were decreased (-72%, P < 0.05), suggesting impaired anaplerotic flux of the Krebs cycle (KC) and mitochondrial dysfunction. In addition, there was a marked decrease in the expression of the transcription factor MEF2C (myocyte enhancer factor 2C) and its target gene SERCA2a (sarco-endo-plasmic reticulum Ca(2+)-ATPase). Oxidative stress was reflected in reduced transcript levels of manganese superoxide dismutase, glutathione peroxidase 1, and increased protein levels of mitochondrial transcription factor A, suggesting compensatory mitochondrial biogenesis in the face of increased mitochondrial damage. Oxidant injury was accompanied by increased protein glycosylation, increased transcript levels of glutamine fructose 6-phosphate amidotransferase 2, and decreased protein levels of acetyl Co-A carboxylase. Lastly, apoptosis was evident by TUNEL positivity and elevated mRNA transcript levels and activity of caspase 3. Consistent with these results, protein levels of Bcl2 were markedly reduced. We conclude that inadequate supplementation of KC intermediates due to reduced levels of malic enzyme, downregulation of MEF2C and its target gene SERCA2a, oxidative stress, and programmed cell death are all potential contributors to contractile dysfunction of the heart.

Metabolic adaptation follows contractile dysfunction in the heart of obese Zucker rats fed a high-fat "Western" diet.

The normal heart responds to changes in its metabolic milieu by changing relative oxidation rates of energy-providing substrates. We hypothesized that this flexibility is lost when genetically obese rats are fed a high-caloric, high-fat "Western" diet (WD). Male Zucker obese (ZO) and Zucker lean (ZL) rats were fed either control or WD composed of 10 kcal% and 45 kcal% fat, respectively, for 7 or 28 days. Cardiac triglycerides and mRNA transcript levels were measured in situ. Substrate oxidation rates and cardiac power were measured ex vivo. Hearts from ZO rats fed WD for 7 days showed decreased cardiac power and increased cardiac triglyceride content, but no change in oleate oxidation rates or mRNA transcript levels of pyruvate dehydrogenase kinase-4 (PDK-4), uncoupling protein-3 (UCP-3), and mitochondrial (MTE-1) and cytosolic thioesterase-1(CTE-1). When fed WD for 28 days, ZO rats showed no further decrease in cardiac power and no further increase in intramyocardial triglyceride levels compared to ZO rats fed the same diet for 7 days only, but did show significantly increased oleate oxidation rates and transcript levels of CTE-1, MTE-1, PDK-4, and UCP-3. In contrast, hearts from ZL rats fed WD showed increased rates of oleate oxidation and increased transcript levels of the fatty acid responsive genes investigated, and no further deterioration of contractile function. We conclude that exposing a genetic model of obesity to the nutrient stress of WD results in an early reversible loss of metabolic flexibility of the heart that is accompanied by contractile dysfunction.

Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis.

The "lipotoxic footprint" of cardiac maladaptation in diet-induced obesity is poorly defined. We investigated how manipulation of dietary lipid and carbohydrate influenced potential lipotoxic species in the failing heart. In Wistar rats, contractile dysfunction develops at 48 weeks on a high-fat/high-carbohydrate "Western" diet, but not on low-fat/high-carbohydrate or high-fat diets. Cardiac content of the lipotoxic candidates--diacylglycerol, ceramide, lipid peroxide, and long-chain acyl-CoA species--was measured at different time points by high-performance liquid chromatography and biochemical assays, as was lipogenic capacity in the heart and liver by qRT-PCR and radiometric assays. Changes in membranes fluidity were also monitored using fluorescence polarization. We report that Western feeding induced a 40% decrease in myocardial palmitoleoyl-CoA content and a similar decrease in the unsaturated-to-saturated fatty acid ratio. These changes were associated with impaired cardiac mitochondrial membrane fluidity. At the same time, hepatic lipogenic capacity was increased in animals fed Western diet (+270% fatty acid elongase activity compared with high-fat diet), while fatty acid desaturase activity decreased over time. Our findings suggest that dysregulation of lipogenesis is a significant component of heart failure in diet-induced obesity.

Patterns and predictors of early recurrence in postmenopausal women with estrogen receptor-positive early breast cancer.

Previous studies suggest that disease recurrence peaks at around 2 years in patients with early stage breast cancer (EBC), but provide no data regarding recurrence type. This retrospective analysis aimed to identify early recurrence types and risk factors in estrogen receptor-positive (ER+) EBC patients treated with adjuvant tamoxifen following breast cancer surgery. Postmenopausal women diagnosed with ER+ EBC from 1995 to 2004 were evaluated. Annual hazard ratios (HR) for recurrence at different sites were calculated. Time-dependent Cox regression analysis was used to identify predictors of recurrence within 2.5 years of diagnosis, including factors that were more strongly predictive of early than later recurrence. Of 3,614 patients evaluated, 476 developed recurrence during the 5-year median follow-up. Cumulative recurrence rates at 2.5 years (95% confidence interval) were: overall 6.3% (5.5-7.1), locoregional 1.1% (0.7-1.5), contralateral 0.5% (0.3-0.7), and distant 4.8% (4.0-5.6). The annual HR of overall recurrence peaked at 2 years (4.3% per annum). The majority of this peak represented distant recurrence (3.4% per annum). In Cox regression analysis, tumor size and grade, lymph node involvement, lymphovascular invasion, and symptomatic presentation were significant independent predictors of early recurrence. Age at diagnosis was independently predictive of recurrence within 2.5 years of diagnosis but not later recurrence. This study identified an early recurrence peak at 2 years, most of which were distant recurrences. Implementing an aromatase inhibitor after an initial 2-3 years of tamoxifen fails to address this early peak of distant recurrence and the potential breast cancer-associated mortality.

Indirect fluorescent determination of selected nitro-aromatic and pharmaceutical compounds via UV-photolysis of 2-phenylbenzimidazole-5-sulfonate.

An indirect fluorescence (FL) detection method via the reactivity of UV-photolyzed 2-phenylbenzimidazole-5-sulfonate (PBSA) has been developed for non-fluorescent aromatic compounds. At high pH with UV photolysis, PBSA in the excited state is known to be quenched by reaction with oxygen species and analyte compounds that are reactive toward these oxygen species produced during photolysis can lessen the loss of PBSA FL. After off-line photolysis of PBSA in the presence of various nitro-aromatic test compounds, the increase in PBSA FL is clearly evident. A flow injection (FI) instrument using a PBSA mobile phase propelled through a Teflon coil wrapped around a Hg lamp is optimized and modified for use for liquid chromatography (LC). For the on-line FI determination of the non-fluorescent nitro-aromatic compounds such as 4-nitroaniline, 2-nitrophenol, 3-nitrophenol, 4-nitrophenol, and alpha-nitronaphthalene, a positive linear response for PBSA FL from about 0.5 to 15 microM and detection limits generally between 0.2 and 1 microM (4-20 pmol) are found. Linear responses and detection limits of selected pharmaceutical compounds such as the antibacterial nitrofurantoin, antihistamines chlorpheniramine and brompheniramine, and other compounds were similar. In general, detection limits using UV detection at about 214 nm were not as good in the 1-2 microM range but linearity extended up to 100 microM. The amino acid phenylalanine and small peptides containing this aromatic amino acid were also determined using this method. Application of this detection method for the liquid chromatography determination of 4-nitroaniline, 2-nitrophenol, nitrofurantoin, and salicylate is shown.

Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats.

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that 'Western' and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, 'Western' or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4-8 weeks), intermediate (16-24 weeks) or long (32-48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.

Ménage-à-trois 1 is critical for the transcriptional function of PPARgamma coactivator 1.

The Cdk7/cyclin H/ménage-à-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by Gq-, calcineurin-, and biomechanical stress-dependent pathways for hypertrophic growth. Using cardiac-specific Cre, we have ablated MAT1 in myocardium. Despite reduced Cdk7 activity, MAT1-deficient hearts grew normally, but fatal heart failure ensued at 6-8 weeks. By microarray profiling, quantitative RT-PCR, and western blotting at 4 weeks, genes for energy metabolism were found to be suppressed selectively, including targets of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1). Cardiac metabolic defects were substantiated in isolated perfused hearts and isolated mitochondria. In culture, deleting MAT1 with Cre disrupted PGC-1 function: PGC-1alpha failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1alpha was functionally defective, and PGC-1beta was likewise deficient. PGC-1 bound to both MAT1 and Cdk7 in coprecipitation assays. Thus, we demonstrate a requirement for MAT1 in the operation of PGC-1 coactivators that control cell metabolism.

Proteome analysis of isolated perfused organ effluent as a novel model for protein biomarker discovery.

The discovery of novel serological biomarkers is critical for improving disease diagnosis and monitoring treatment response. Proteomic analysis of model systems, such as isolated cells in culture and patient plasma and serum, represents the current state-of-the-art. Here, we coupled proteomics with isolated organ perfusion, which allows a disease state to be studied in a physiologic, yet controlled, environment. Potential markers specific to the disease or to changes in the surrounding tissue may be discovered. The effectiveness of this model was evaluated using proteomic analysis of effluent fractions collected from isolated beating rat hearts during reperfusion after brief episodes of ischemia. The detection of clinical markers for myocardial ischemia in this effluent was robust and analytically straightforward, validating the potential of isolated organ perfusion in diagnostic protein discovery.

Metabolic energetics and genetics in the heart.

From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The "multitasking" of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post-translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.