Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2.

Clinical predictors of right ventricular dysfunction and association with adverse outcomes in peripartum cardiomyopathy.

Aims: We sought to identify factors associated with right ventricular (RV) dysfunction and elevated pulmonary artery systolic pressure (PASP) and association with adverse outcomes in peripartum cardiomyopathy (PPCM).

Methods And Results: We conducted a multi-centre cohort study to identify subjects with PPCM with the following criteria: left ventricular ejection fraction (LVEF) < 40%, development of heart failure within the last month of pregnancy or 5 months of delivery, and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included a composite of (i) major adverse events (need for extracorporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation, or death) or (ii) recurrent heart failure hospitalization.

The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.

The mitochondrial uniporter (MCU) Ca ion channel represents the primary means for Ca uptake by mitochondria. Mitochondrial matrix Ca plays critical roles in mitochondrial bioenergetics by impinging upon respiration, energy production and flux of biochemical intermediates through the TCA cycle. Inhibition of MCU in oncogenic cell lines results in an energetic crisis and reduced cell proliferation unless media is supplemented with nucleosides, pyruvate or α-KG.

Metabolite signaling in the heart.

The heart is the most metabolically active organ in the body, sustaining a continuous and high flux of nutrient catabolism via oxidative phosphorylation. The nature and relative contribution of these fuels have been studied extensively for decades. By contrast, less attention has been placed on how intermediate metabolites generated from this catabolism affect intracellular signaling.

Riding up the escaLEC-TOR for valvular health.

Endothelial-lined valves assure unidirectional flow in the lymphatic system. In this issue, Saygili Demir et al. (2023.

The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation.

The mitochondrial uniporter (MCU) Ca ion channel represents the primary means for Ca uptake into mitochondria. Here we employed and models with MCU genetically eliminated to understand how MCU contributes to tumor formation and progression. Transformation of primary fibroblasts was associated with increased MCU expression, enhanced mitochondrial Ca uptake, suppression of inactivating-phosphorylation of pyruvate dehydrogenase, a modest increase of basal mitochondrial respiration and a significant increase of acute Ca -dependent stimulation of mitochondrial respiration.

Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy.

Heart failure (HF) is a leading cause of mortality. Failing hearts undergo profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-sequencing, and proteomic studies to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage HF compared with 48 nonfailing donors.

Glutamine uptake and catabolism is required for myofibroblast formation and persistence.

Background: Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g.

Animal Models of Cardiovascular Complications of Pregnancy.

Cardiovascular complications of pregnancy have risen substantially over the past decades, and now account for the majority of pregnancy-induced maternal deaths, as well as having substantial long-term consequences on maternal cardiovascular health. The causes and pathophysiology of these complications remain poorly understood, and therapeutic options are limited. Preclinical models represent a crucial tool for understanding human disease.

Comprehensive nutrient consumption estimation and metabolic profiling during ketogenic diet and relationship with myocardial glucose uptake on FDG-PET.

Aims: The ketogenic diet (KD) is standard-of-care to achieve myocardial glucose suppression (MGS) for assessing inflammation using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET). As KD protocols remain highly variable between centres (including estimation of nutrient intake by dietary logs for adequacy of dietary preparation), we aimed to assess the predictive utility of nutrient intake in achieving MGS.

Methods And Results: Nineteen healthy participants underwent short-term KD, with FDG-PET performed after 1 and 3 days of KD (goal carbohydrate intake <20 g/day).

Folliculin promotes substrate-selective mTORC1 activity by activating RagC to recruit TFE3.

Mechanistic target of rapamycin complex I (mTORC1) is central to cellular metabolic regulation. mTORC1 phosphorylates a myriad of substrates, but how different substrate specificity is conferred on mTORC1 by different conditions remains poorly defined. Here, we show how loss of the mTORC1 regulator folliculin (FLCN) renders mTORC1 specifically incompetent to phosphorylate TFE3, a master regulator of lysosome biogenesis, without affecting phosphorylation of other canonical mTORC1 substrates, such as S6 kinase.

Endothelial Lipid Metabolism.

Endothelial cells (ECs) line all vessels of all vertebrates and are fundamental to organismal metabolism. ECs rely on their metabolism both to transport nutrients in and out of underlying parenchyma, and to support their own cellular activities, including angiogenesis. ECs primarily consume glucose, and much is known of how ECs transport and consume glucose and other carbohydrates.

Truncated titin proteins in dilated cardiomyopathy.

Truncating variants in (TTNtvs) are the most common known cause of nonischemic dilated cardiomyopathy (DCM), but how TTNtvs cause disease has remained controversial. Efforts to detect truncated titin proteins in affected human DCM hearts have failed, suggesting that disease is caused by haploinsufficiency, but reduced amounts of titin protein have not yet been demonstrated. Here, we leveraged a collection of 184 explanted posttransplant DCM hearts to show, using specialized electrophoretic gels, Western blotting, allelic phasing, and unbiased proteomics, that truncated titin proteins can quantitatively be detected in human DCM hearts.

Peripartum cardiomyopathy: from genetics to management.

Peripartum cardiomyopathy (PPCM) is a disease that occurs globally in all ethnic groups and should be suspected in any peripartum women presenting with symptoms and signs of heart failure, towards the end of pregnancy or in the months following delivery, with confirmed left ventricular dysfunction. After good history taking, all women should be thoroughly assessed, and alternative causes should be excluded. Urgent cardiac investigations with electrocardiogram and natriuretic peptide measurement (if available) should be performed.

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in (TTNtvs).

Neighborhood education status drives racial disparities in clinical outcomes in PPCM.

Background: Peripartum cardiomyopathy (PPCM) disproportionately affects women of African ancestry. Additionally, clinical outcomes are worse in this subpopulation compared to White women with PPCM.  The extent to which socioeconomic parameters contribute to these racial disparities is not known.

Soluble Flt1 levels are associated with cardiac dysfunction in Black women with and without severe preeclampsia.

: We evaluate soluble fms-like tyrosine kinase-1 (sFlt-1) levels and cardiac function during pregnancy and postpartum among Black women with and without preeclampsia. : Prospective longitudinal cohort study from 2015 to 2017 of Black women with preterm severe preeclampsia and normotensive pregnant controls.We obtained echocardiograms and sFlt-1 levels during pregnancy and postpartum.

Comprehensive quantification of fuel use by the failing and nonfailing human heart.

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown.

Fat, Obesity, and the Endothelium.

Endothelial cells line all blood vessels in vertebrates. These cells contribute to whole-body nutrient distribution in a variety of ways, including regulation of local blood flow, regulation of trans-endothelial nutrient transport, and paracrine effects. Obesity elicits dramatic whole-body nutrient redistribution, in particular of fat.

Peripartum Cardiomyopathy: JACC State-of-the-Art Review.

Peripartum cardiomyopathy is a form of systolic heart failure affecting young women toward the end of pregnancy or in the months following delivery. Incidence is higher in African-American women and in women with older maternal age, hypertensive disorders of pregnancy, and multiple gestation pregnancies. Symptoms of heart failure mimic those of normal pregnancy, often resulting in a delay in diagnosis and preventable complications.