Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.

BACKGROUND: Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODS: In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTS: The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooled-monotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, -67.2% vs. -50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS: Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.).

Leading Change: A Case Study of the First Independent Critical-Access Hospital to Achieve Magnet® Designation.

OBJECTIVE: The aim of this study was to understand how nurses in a 25-bed critical-access hospital (CAH) led change to become the 1st to achieve Magnet®. BACKGROUND: Approximately 21% of the US population lives in rural areas served by CAHs. Rural nurse executives are particularly challenged with limited resources. METHODS: Staff nurses, nurse managers, interprofessional care providers, the chief nursing officer, and board of directors (n = 27) were interviewed. Observations of hospital units and administrative meetings were done, and hospital reports were analyzed. RESULTS: Nine themes emerged to support a conceptual model of leading change. The CAH spent 3 years of its 6-year journey establishing organizational readiness. Nurses overcame complex challenges by balancing operational support and fostering relationships. The Magnet journey led to significantly improved nurse and patient outcomes. A new organizational culture centered on shared governance, evidence-based practice, and higher education emerged. CONCLUSIONS: The journey to Magnet leads to improved nurse, patient, and organization outcomes.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

BACKGROUND: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. OBJECTIVE: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. METHODS: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). RESULTS: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. CONCLUSIONS: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. TRIAL REGISTRATION NUMBER: NCT01178073, post results.

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation.

RATIONALE: Stimulation of ß3-adrenoreceptors (ß3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and ß3-AR protective signaling has yet to be explored. OBJECTIVE: We tested the hypothesis that ß3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. METHODS AND RESULTS: Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased ß3-AR gene expression. Co-administration of the ß3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. CONCLUSION: ß3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to ß3-AR receptor stimulation.

Geriatric gynecology: promoting health and avoiding harm.

Age increases vulnerability, commonly accompanied by greater reliance on others and susceptibility to maltreatment. Physiologic processes become less resilient; the potential for harm from medical care increases. Awareness of frailty, functional, social, and potential maltreatment issues enables early referrals to help the patient maintain her independence. Health issues that may impede both gynecologic care and self-sufficiency include sensory deficits, physical disability, and cognitive impairment. Speaking slowly and providing contextual information enhance patient comprehension. Cancer screening depends on life expectancy. Osteoporosis treatment requires managing fall risk. Gynecologic symptoms more likely have multiple contributing factors than one etiology. Incontinence is a particularly complex issue, but invariably includes bladder diary assessment and pelvic floor muscle training. Function and frailty measures best predict perioperative morbidity. Communication with the patient, her family, other providers, and health care organizations is an important frontier in avoiding errors and adverse outcomes.

Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling.

OBJECTIVE: Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice. METHODS: Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling. RESULTS: LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids. CONCLUSIONS: Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia.

Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

Speaker-specific processing of anomalous utterances.

Existing work shows that readers often interpret grammatical errors (e.g., The key to the cabinets *were shiny) and sentence-level blends ("without-blend": Claudia left without her headphones *off) in a non-literal fashion, inferring that a more frequent or more canonical utterance was intended instead. This work examines how interlocutor identity affects the processing and interpretation of anomalous sentences. We presented anomalies in the context of "emails" attributed to various writers in a self-paced reading paradigm and used comprehension questions to probe how sentence interpretation changed based upon properties of the item and properties of the "speaker." Experiment 1 compared standardised American English speakers to L2 English speakers; Experiment 2 compared the same standardised English speakers to speakers of a non-Standardised American English dialect. Agreement errors and without-blends both led to more non-literal responses than comparable canonical items. For agreement errors, more non-literal interpretations also occurred when sentences were attributed to speakers of Standardised American English than either non-Standardised group. These data suggest that understanding sentences relies on expectations and heuristics about which utterances are likely. These are based upon experience with language, with speaker-specific differences, and upon more general cognitive biases.

Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial.

BACKGROUND: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.

Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity.

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob, db/db, and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.

Fall risk and function in older women after gynecologic surgery.

PURPOSE OF STUDY: To examine change in balance-related fall risk and daily functional abilities in the first 2 post-operative weeks and up to 6 weeks after gynecologic surgery. MATERIALS AND METHODS: Prospective cohort study in gynecologic surgery patients age 65 and older. Balance confidence (Activities-specific Balance Confidence Scale) and functional status (basic and instrumental activities of daily living) were recorded pre- and post-operatively daily for 1 week and twice the second week. Physical performance balance and functional mobility were measured pre- and 1 week post-operatively using the Tinetti Fall Risk Scale, Timed Up and Go, and 6-Minute Walk test. Measures were repeated 6 weeks after surgery. Non-parametric tests for paired data were used comparing scores baseline to post-operative (POD) 7 and to POD 42. RESULTS: Median age was 72 years (range 65-88). Fall risk was elevated during the first 2 post-operative weeks, greatest on the median discharge day, POD 2 (p<0.01). Balance performance and functional mobility at 1 week were significantly lower than baseline (p<0.01). Functional abilities declined, including new dependence in medication management at home in 22% of these independent and cognitively intact women. CONCLUSIONS: After gynecologic surgery, older women's fall risk is highest on POD 2 and remains elevated from baseline for 2 weeks. Functional limitations in the early home recovery period include the anticipated (bathing, cooking, etc.) and some unanticipated (medication management) ones. This information may help with post-operative discharge planning.

Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice.

Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-ß ligands, with increased TGF-ß signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-ß, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-ß ligand expression that culminates in both autocrine and paracrine overdrive of TGF-ß signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study.

BACKGROUND: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. METHODS: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. FINDINGS: The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73). INTERPRETATION: These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. FUNDING: Gilead, GlaxoSmithKline.

Stress urinary incontinence in women: review and update on neurological control.

BACKGROUND: Female stress urinary incontinence (SUI) is a common disease that involves leakage of urine during coughing, sneezing, or other increases in intraabdominal pressure. Treatments for SUI include pelvic floor muscle training, electrical stimulation, surgery, and off-label alpha-adrenergic agonists that stimulate contraction of the urethral smooth muscle. None of these treatments is universally or completely effective, and because drug therapy with the alpha- adrenergic agonists phenylpropanolamine and ephedrine can cause serious pressor adverse effects, the former has been banned in the United States, and the latter is under scrutiny. The central nervous system (CNS) affects reflexes that control urine storage and micturition, and norepinephrine and serotonin play a key role in maintaining storage capability by means of contraction of the external striated muscle of the urethral sphincter. Duloxetine hydrochloride, which inhibits reuptake of both of these neurotransmitters, has been shown to promote striated urethral sphincter contraction in animal models and to reduce the incidence of involuntary urine release in women with SUI without interfering with micturition. CONCLUSION: Neuromodulation of noradrenergic and serotonergic neurotransmitters with such drugs as duloxetine provides an additional treatment option for women with SUI.

An academic-business partnership for advancing clinical informatics.

A jointly funded partnership between the school of nursing at a large midwestern university and a premier health care information technology supplier represents a pioneering event for education and for the health care information technology industry. The impetus for this partnership arose from Institute of Medicine reports published in late 1999 and early 2001 addressing the quality, error, and waste in the health care system in the United States. The Simulated E-hEalth Delivery System (SEEDS) provides opportunities based on best practices in education to learn and practice clinical skills in a state-of-the-art environment using a live-production, clinical information system designed for care delivery. A pilot project that began with a small cohort of baccalaureate nursing students has been implemented and extended. SEEDS will also be extended to other health professional programs.

Developing the academic nursing practice in the midst of new realities in higher education.

The academic nursing practice has a role in replenishing the diminished resources that confront higher education and, if well conceived and managed, is a viable option to support existing academic program stability and growth. An alternative model for defining the academic practice--beyond traditional nurse-managed centers--is presented in this article. The cohesive interconnection of the education, research, and practice missions is addressed with examples of how each contributes to a variety of communities of interest and expands professional nursing roles through innovative care model testing and development. With effective business planning and infrastructure support, faculty practice plans can evolve to a second generation, with heightened societal accountability for service, academic, and collaborative research outcomes.

Beyond tradition: synergizing intellectual and material capital to forge the new academic-service partnership.

Academic-service partnerships are being touted as a solution to workforce problems. "Traditional" approaches to these partnerships have been directed primarily at academic and hospital institutions for mutual benefit. An expanded model of partnership possibilities is presented through three detailed exemplars that include population health (with descriptors from an Institute of Medicine study addressing the public's health in the 21st century), public-private ventures (public institution with faith-based and community agencies), and nursing-corporate opportunities (academia and a proprietary information technology corporate supplier). The benefits of these expanded partnerships and the criteria for selecting a partnership sensitive to the scholarship of practice and the mission/purpose/goals of each partnering organization is highlighted.

Beneficial cardiac effects of caloric restriction are lost with age in a murine model of obesity.

Obesity is associated with increased diastolic stiffness and myocardial steatosis and dysfunction. The impact of aging on the protective effects of caloric restriction (CR) is not clear. We studied 2-month (younger) and 6-7-month (older)-old ob/ob mice and age-matched C57BL/6J controls (WT). Ob/ob mice were assigned to diet ad libitum or CR for 4 weeks. We performed echocardiograms, myocardial triglyceride assays, Oil Red O staining, and measured free fatty acids, superoxide, NOS activity, ceramide levels, and Western blots. In younger mice, CR restored diastolic function, reversed myocardial steatosis, and upregulated Akt phosphorylation. None of these changes was observed in the older mice; however, CR decreased oxidative stress and normalized NOS activity in these animals. Interestingly, myocardial steatosis was not associated with increased ceramide, but CR altered the composition of ceramides. In this model of obesity, aging attenuates the benefits of CR on myocardial structure and function.