Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation ß-blocker and a biased agonist that exhibits agonist-like effects through ß arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac ß arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Evaluation of the characteristics of primary iridociliary cysts using ultrasound biomicroscopy at a tertiary care centre.

OBJECTIVE: To evaluate the ultrasound biomicroscopic characteristics of primary iridociliary cysts presenting to a Canadian tertiary care centre. DESIGN: Retrospective study. PARTICIPANTS: A total of 189 patients (212 eyes) referred to the Sinai Health System (Toronto) for suspected iris abnormalities. METHODS: Clinical records of patients referred between March 2016 and October 2019 were reviewed. All patients were evaluated and received a diagnosis of an iridociliary cyst using ultrasound biomicroscopy (UBM). Data were collected for age, sex, involvement (iris vs ciliary body), laterality, size, and location on initial examination and subsequent follow-up. RESULTS: Of the 189 patients (212 eyes) with iridociliary cysts, more were female (65.1%) versus male (34.9%). The highest incidence occurred in females aged 21-30 years (13.2%). The iris pigment epithelium was involved in 84.4%, and only the ciliary body was involved in 3.8%. Both the iris pigment epithelium and the ciliary body were involved in 10.8%. The size of the cysts ranged between 0.5 and 4.41 mm in diameter. Cysts greater than 1 mm in diameter occurred in 78.7%, and 86.8% of cysts occurred unilaterally. Twelve percent were multicystic, and 8.5% were multiloculated, with 1% exhibiting both features. Twenty-three eyes (12.2%) were reviewed at 1 year of follow-up with UBM. Stable iridociliary cysts with no appreciable change in size were seen in 73.9% (n = 17). Iridociliary cyst growth was noted at 4 months in 1 patient. CONCLUSION: Information regarding iridociliary cysts is not easily available in the literature. UBM is a helpful clinical tool in the evaluation of iris abnormalities. Iridociliary cysts tend to be stable and compatible with a low rate of complications.

Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate.

Alterations in energy metabolism play a major role in the lineage of cardiomyocytes, such as the dramatic changes that occur in the transition from neonate to newborn. As cardiomyocytes mature, they shift from a primarily glycolytic state to a mitochondrial oxidative metabolic state. Metabolic intermediates and metabolites may have epigenetic and transcriptional roles in controlling cell fate by increasing mitochondrial biogenesis. In the maturing cardiomyocyte, such as in the postnatal heart, fatty acid oxidation increases in conjunction with increased mitochondrial biogenesis driven by the transcriptional coregulator PGC1-α. PGC1-α is necessary for mitochondrial biogenesis in the heart at birth, with deficiencies leading to postnatal cardiomyopathy. While stem cell therapy as a treatment for heart failure requires further investigation, studies suggest that adult stem cells may secrete cardioprotective factors which may regulate cardiomyocyte differentiation and survival. This review will discuss how metabolism influences mitochondrial biogenesis and how mitochondrial biogenesis influences cell fate, particularly in the context of the developing cardiomyocyte. The implications of energy metabolism on stem cell differentiation into cardiomyocytes and how this may be utilized as a therapy against heart failure and cardiovascular disease will also be discussed.

Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition.

Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues' ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.